Kynurenine-3-monooxygenase (KMO) broadly inhibits viral infections via triggering NMDAR/Ca2+ influx and CaMKII/ IRF3-mediated IFN-ß production.

Tryptophan (Trp) metabolism through the kynurenine pathway (KP) is well known to play a critical function in cancer, autoimmune and neurodegenerative diseases. However, its role in host-pathogen interactions has not been characterized yet. Herein, we identified that kynurenine-3-monooxygenase (KMO), a key rate-limiting enzyme in the KP, and quinolinic acid (QUIN), a key enzymatic product of KMO enzyme, exerted a novel antiviral function against a broad range of viruses. Mechanistically, QUIN induced the production of type I interferon (IFN-I) via activating the N-methyl-d-aspartate receptor (NMDAR) and Ca2+ influx to activate Calcium/calmodulin-dependent protein kinase II (CaMKII)/interferon regulatory factor 3 (IRF3). Importantly, QUIN treatment effectively inhibited viral infections and alleviated disease progression in mice. Furthermore, kmo-/- mice were vulnerable to pathogenic viral challenge with severe clinical symptoms. Collectively, our results demonstrated that KMO and its enzymatic product QUIN were potential therapeutics against emerging pathogenic viruses.

Recognition of Oligonucleotide C by Polydopamine-Coated Solid-State Nanopores.

Selective recognition of short oligonucleotides at the single-molecule level is particularly important for early disease detection and treatment. In this work, polydopamine (PDA)-coated nanopores were prepared via self-polymerization as a solid-state nanopore sensing platform for the recognition of oligonucleotide C (PolyC). The PDA coating possesses abundant active sites, such as indole, amino, carboxyl, catechol, and quinone structures, which had interactions with short oligonucleotides to slow down the translocation rate. PDA-coated nanopores selectively interact with PolyC20 by virtue of differences in hydrogen bonding forces, generating a larger blocking current, while polyA and polyT demonstrated very small blockings. At the same time, PDA-coated nanopores can sensitively distinguish PolyC with different lengths, such as 20, 14, and 10 nt. The functionalization of PDA on the solid-state nanopore provides an opportunity for the rational design of the recognition surface for biomolecules.

Exacerbated AIDS Progression by PD-1 Blockade during Therapeutic Vaccination in Chronically Simian Immunodeficiency Virus-Infected Rhesus Macaques after Interruption of Antiretroviral Therapy.

The persistence of cells latently infected with HIV-1, named the latent reservoir, is the major barrier to HIV-1 eradication, and the formation and maintenance of the latent reservoir might be exacerbated by activation of the immunoinhibitory pathway and dysfunction of CD8+ T cells during HIV-1 infection. Our previous findings demonstrated that prophylactic vaccination combined with PD-1 blockade generated distinct immune response profiles and conferred effective control of highly pathogenic SIVmac239 infection in rhesus macaques. However, to our surprise, herein we found that a therapeutic vaccination in combination with PD-1 blockade resulted in activation of the viral reservoir, faster viral rebound after treatment interruption, accelerated AIDS progression, and, ultimately, death in chronically SIV-infected macaques after antiretroviral therapy (ART) interruption. Our study further demonstrated that the SIV provirus was preferentially enriched in PD-1+CD4+ T cells due to their susceptibility to viral entry, potent proliferative ability, and inability to perform viral transcription. In addition, the viral latency was effectively reactivated upon PD-1 blockade. Together, these results suggest that PD-1 blockade may be a double-edged sword for HIV-1 immunotherapy and provide important insight toward the rational design of immunotherapy strategies for an HIV-1 cure. IMPORTANCE As it is one of the most challenging public health problems, there are no clinically effective cure strategies against HIV-1 infection. We demonstrated that prophylactic vaccination combined with PD-1 blockade generated distinct immune response profiles and conferred better control of highly pathogenic SIVmac239 infection in rhesus macaques. In the present study, to our surprise, PD-1 blockade during therapeutic vaccination accelerated the reactivation of latent reservoir and AIDS progression in chronically SIV-infected macaques after ART interruption. Our study further demonstrated that the latent SIV provirus was preferentially enriched in PD-1+CD4+ T cells because of its susceptibility to viral entry, inhibition of SIV transcription, and potent ability of proliferation, and the viral latency was effectively reactivated by PD-1 blockade. Therefore, PD-1 blockade might be a double-edged sword for AIDS therapy. These findings provoke interest in further exploring novel treatments against HIV-1 infection and other emerging infectious diseases.

Characteristics of genotype, drug resistance, and molecular transmission network among newly diagnosed HIV-1 infections in Shenzhen, China.

The HIV-1 pandemic has persisted for four decades, and poses a major challenge to global public health. Shenzhen, a city with large number of migrant populations in China, is suffering HIV-1 epidemic. It is necessary to continuously conduct the molecular surveillance among newly diagnosed HIV-1 patients in these migrant population. In this study, plasma samples of newly diagnosed and ART-naive HIV-1 infections were collected from Shenzhen city in China. The partial genes of HIV-1 gag and pol were amplified and sequenced for the analysis of genotype, drug resistance, and molecular transmission network. Ninety-one sequences of pol gene were obtained from newly diagnosed HIV-1 infections in Shenzhen, and seven HIV-1 subtypes were revealed in this investigation. Among them, the circulating recombinant form (CRF) 07_BC was the mostly frequent subtype (53.8%, 49/91), followed by CRF01_AE (20.9%, 19/91), CRF55_01B (9.9%, 9/91), unique recombinant forms (URFs) (8.8%, 8/91), B (3.3%, 3/91), CRF59_01B (2.2%, 2/91), and CRF08_BC (1.1%, 1/91). The overall prevalence of pretreatment drug resistance (PDR) was 23.1% (21/91), and 52.38% (11/21) of the PDR was specific for the nonnucleotide reverse transcriptase inhibitors (NNRTIs). Furthermore, a total of 3091 pol gene sequences were used to generate 19 molecular transmission clusters, and then one growing cluster, a new cluster, and a cluster with growth reactivation were identified. The result revealed that more sexual partner, CRF_07BC subtype, and seven amino acid deletions in gag p6 region might be the influencing factors associated with the high risk of transmission behavior. Compared with CRF01_AE subtype, CRF07_BC subtype strains were more likely to form clusters in molecular transmission network. This suggests that long-term surveillance of the HIV-1 molecular transmission should be a critical measure to achieve a precise intervention for controlling the spread of HIV-1 in China.

Uniform Colloidal Polymer Rods by Stabilizer-Assisted Liquid-Crystallization-Driven Self-Assembly.

The synthesis of anisotropic colloidal building blocks is essential for their self-assembly into hierarchical materials. Here, a highly efficient stabilizer-assisted liquid-crystallization-driven self-assembly (SA-LCDSA) strategy was developed to achieve monodisperse colloidal polymer rods. This strategy does not require the use of block copolymers, but only homopolymers or random copolymers. The resulting rods have tunable size and aspect ratios, as well as well-defined columnar liquid crystal structures. The integrated triphenylene units enable the rods to exhibit unusual photo-induced fluorescence enhancement and accompanying irradiation memory effect, which, as demonstrated, are attractive for information encryption/decryption of paper documents. In particular, unwanted document decryption during delivery can be examined by fluorescence kinetics. This SA-LCDSA-based approach can be extended to synthesize other functional particles with desired π-molecular units.

[Mediating effect of adulthood BMI/waist circumference on correlation between juvenile BMI/waist circumference and adulthood blood pressure].

OBJECTIVE: To analyze the relationship between juvenile body mass index(BMI)/waist circumference(WC) and adult blood pressure(BP), and to further explore the mediating role of adult BMI/WC in this association. METHODS: Based on the data of China Health and Nutrition Survey(CHNS) from 1993 to 2015, 1313 subjects were selected, who participated in the survey both in juvenile(6-17 years old) and adult(18-35 years old). The mediating effect model was used to analyze the effect of adult BMI/WC in the association between juvenile BMI/WC and adult BP. RESULTS: There was a positive correlation between juvenile BMI/WC and adult systolic blood pressure [ß(SE)_(adjusted)=0.10(0.03)/0.08(0.03)] and diastolic blood pressure [ß(SE)_(adjusted)=0.13(0.03)/0.08(0.03)] with P <0.01. Adult BMI/WC played partial mediating effect in the association between juvenile BMI/WC and adult systolic blood pressure and diastolic blood pressure: the percentage of mediating effect of BMI were 70.00%(95%CI 42.68%-73.33%)for SBP and 23.08%(95%CI 14.29%-26.32%) for DBP, the percentage of mediating effect of WC were 37.50%(95%CI 20.00%-41.67%)for SBP and 25.00%(95%CI 20.00%-35.71%) for DBP, respectively. CONCLUSION: There is a positive correlation between juvenile BMI/WC and adult BP, and adult BMI/WC might mediate the effect of juvenile BMI and WC on adult BP.

Changing patterns of prenatal depression and anxiety status in different trimesters and modified form of Zung scales for pregnant women.

BACKGROUND: We described the changing patterns of depression and anxiety status in different trimesters among Chinese pregnant women, and identified the modified form of SDS/SAS for pregnant women and assessed its reliability and validity. METHODS: Changing patterns of depression/ anxiety status in different trimesters were described. The modified form of SDS/SAS was identified for pregnant women. Cohen's Kappa to measure agreement with SDS/SAS, and the ROC analysis was performed to assess its validity. RESULTS: The SDS score in 1st trimester was higher than 2nd and 3rd trimester; there was no significant difference between SDS score in 2nd and 3rd trimester. Modified form of SDS evaluated the depression; the areas under the curve (AUC) in testing group were up to 0.988, 0.989 and 0.992 for 1st, 2nd and 3rd trimester, respectively. Modified form of SAS evaluated the anxiety, the AUC in testing group were up to 0.987, 0.985, 0.987 for 1st, 2nd and 3rd trimester, respectively. CONCLUSION: Pregnant women had higher severity of depression and anxiety status in 1st trimester than that in 2nd and 3rd trimester. The modified form of SDS/SAS may be more brief and suitable to assess the depression and anxiety status in pregnant women.KEY POINTSPregnant women had a higher severity of depression and anxiety status in the 1st trimester than that in the 2nd and 3rd trimester.The present study suggests that prenatal depression and anxiety status are prevalent in Chinese pregnant women.Prevention or treatments focus on high-score items of SDS and SAS would be beneficial for rectifying prenatal depression and anxiety.

Role of TRPC1 channels in pressure-mediated activation of airway remodeling.

BACKGROUND: Bronchoconstriction and cough, a characteristic of the asthmatic response, leads to development of compressive stresses in the airway wall. We hypothesized that progressively pathological high mechanical stress could act on mechanosensitive cation channels, such as transient receptor potential channel 1 (TRPC1) and then contributes to airway remodeling. METHODS: We imitate the pathological airway pressure in vitro using cyclic stretch at 10 and 15% elongation. Ca2+ imaging was applied to measure the activity of TRPC1 after bronchial epithelial cells exposed to cyclic stretch for 0, 0.5, 1, 1.5, 2, 2.5 h. To further clarify the function of channnel TRPC1 in the process of mechano-transduction in airway remodeling, the experiment in vivo was implemented. The TRPC1 siRNA and budesonide were applied separately to asthmatic models. The morphological changes were measured by HE and Massion method. The expression levels of TRPC1 were evaluated by real-time PCR, western blot and immunohistochemistry. The protein expression level of IL-13, TGF-ß1 and MMP-9 in BALF were measured by ELISA. RESULTS: The result showed that cyclic stretch for 15% elongation at 1.5 h could maximize the activity of TRPC1 channel. This influx in Ca2+ was blocked by TRPC1 siRNA. Higher TRPC1 expression was observed in the bronchial epithelial layer of ovalbumin induced asthmatic models. The knockdown of TRPC1 with TRPC1 siRNA was associated with a hampered airway remodeling process, such as decreased bronchial wall thickness and smooth muscle hypertrophy/hyperplasia, a decreased ECM deposition area and inflammation infiltration around airway wall. Meantime, expression of IL-13, TGF-ß1 and MMP-9 in OVA+TRPC1 siRNA also showed reduced level. TRPC1 intervention treatment showed similar anti-remodeling therapeutic effect with budesonide. CONCLUSIONS: These results demonstrate that most TRPC1 channels expressed in bronchial epithelial cells mediate the mechanotransduction mechanism. TRPC1 inducing abnormal Ca2+ signal mediates receptor-stimulated and mechanical stimulus-induced airway remodeling. The inhibition of TRPC1 channel could produce similar therapeutic effect as glucocortisteroid to curb the development of asthmatic airway remodeling.

Association of trimester-specific gestational weight gain with birth weight and fetal growth in a large community-based population.

BACKGROUND: Previous studies showed that the association of gestational weight gain (GWG) with fetal birthweight and offspring developmental growth was unclear. The aim of this study is to investigate the respective effect of 1 kg of GWG during three trimesters on birthweight and offspring growth from birth to 3 years of age. METHODS: We extracted the decoded information from the Maternal and Child Health Information Management System of Zhoushan Maternal and Child Health Hospital in Zhejiang, China from October 2001 to March 2015, and used multiple linear and logistic regression models. RESULTS: This study included 20,232 women with a full-term singleton birth and 15,557 newborns who took regular health check-ups. Compared to that in the 2nd and 3rd trimester, 1 kg GWG increasing in the 1st trimester had the strongest positive association with higher birthweight, body weight, and height from 1 to 36 months. Their associations with BMI after birth were similar among the three trimesters. In addition, some positive dose-response effects found between quartiles of GWG in the 1st trimester and offspring body weight, as well as BMI. The 1 kg GWG in 1st trimester played the strongest role in contributing to birth weight and benefiting to body growth among children aged up to 3 years. CONCLUSION: The 1 kg GWG in 1st trimester contributed more to birth weight and body development from birth to 3 years compared to the 2nd and 3rd trimesters. The possible beneficial effects of GWG in the 1st trimester on birthweight and offspring development in under/normal weight mothers are found.

Serum uric acid to creatinine ratio correlates with ß-cell function in type 2 diabetes.

BACKGROUND: The correlation between serum uric acid (SUA) and ß-cell function remains controversial. The present study aims to use a new index, renal function-normalized SUA, to observe its correlation with ß-cell function in patients with type 2 diabetes (T2DM). METHODS: A total of 713 patients with T2DM received standard 75-g oral glucose tolerance and insulin release test. Renal function-normalized SUA was calculated using SUA/creatinine and ß-cell function was assessed by HOMA-B. Binary logistic regression analysis was used to estimate the association between SUA/creatinine and ß-cell function. RESULTS: There are positive correlations between SUA/creatinine and HOMA-B (r = 0.143, P < 0.001), as well as other indexes of ß-cell function including modified ß-cell function index (r = 0.104, P = 0.007), InsAUC30 (r = 0.100, P = 0.008), and InsAUC120 (r = 0.124, P = 0.001). SUA/creatinine also positively correlates with insulin resistance (HOMA-IR: r = 0.161, P < 0.001). Moreover, multivariate analysis revealed that SUA/creatinine was significantly associated with preserved ß-cell function, independently of potential confounders including sex, BMI, and renal function. CONCLUSIONS: SUA to creatinine ratio correlates with ß-cell function in T2DM patients.

The relationship of dietary diversity score with depression and anxiety among prenatal and post-partum women.

AIM: The objective of the study is to explore the relationship between the dietary diversity score (DDS) and anxiety and depression of perinatal women. METHODS: The Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS) and the dietary recall questionnaire were used to measure the status of depression, anxiety and dietary diversity at T1 (first trimester), T2 (second trimester), T3 (third trimester) and T4 (post-partum). The association of dietary diversity and food groups with depression and anxiety status were estimated by linear and logistic regression models. RESULTS: The prevalence of depression and anxiety status were the highest at T1, which were 35.58% and 22.57%, respectively. Cross-sectional and longitudinal association of DDS with SDS and SAS was estimated by ordinary or multilevel linear or logistic model. In the cross-sectional analysis, high dietary status (>6) was negatively associated with depression status [T1: OR (95% CI) = 0.56 (0.46, 0.69); T2: 0.55 (0.36, 0.84); T3: 0.45 (0.31, 0.65); T4: 0.58 (0.34, 0.99)] and anxiety status [T1: OR (95% CI) = 0.70 (0.56, 0.88); T2: 0.42 (0.27, 0.65)]. In the longitudinal analysis, it was demonstrated that the DDS level was negatively associated with SDS [ß(se) = -0.99 (0.09), P = <0.0001] and SAS scores [ß(se) = -0.37 (0.08), P = <0.0001] throughout pregnancy. There was a negative relationship between some food groups and SDS or SAS scores at different periods. CONCLUSION: A negative relationship between DDS and depression as well as anxiety was found among prenatal and post-partum women.

Prevalence and relevant factors of anxiety and depression among pregnant women in a cohort study from south-east China.

OBJECTIVE: To describe the prevalence rate of prenatal anxiety and depression among pregnant women in a prospective cohort study and to explore the relevant factors of anxiety and depression during each trimester. METHODS: Pregnant women were recruited into the Zhoushan Pregnant Women Cohort at Zhoushan Maternal and Child Care Hospital from September 2011 to March 2015. A self-made questionnaire was used to collect information about social demography, reproductive history, physical activity, and life behaviour at the first, second and third trimester, respectively. The Self-Rating Anxiety Scale (SAS) and the Self-Rating Depression Scale (SDS) were used to assess anxiety and depression status at each trimester, respectively. Prevalence rates of prenatal anxiety and depression at each trimester were described. RESULTS: The prevalence of anxiety status was 22.7%, 17.4% and 20.8% in the first, second and third trimester, respectively. The corresponding prevalence rate of depression status was 35.7%, 24.0% and 26.1%, respectively. Furthermore, women with a lower education level (junior high school or below) and a more physical occupation had higher prevalence of anxiety and depression status. CONCLUSIONS: The prevalence of prenatal anxiety and depression status was very common during pregnancy among pregnant women. Lower educational level and more physical occupations were associated with higher prevalence of anxiety and depression status.

Sleep was associated with depression and anxiety status during pregnancy: a prospective longitudinal study.

The purpose of this study was to reveal the cross-sectional and longitudinal association of sleep with depression and anxiety among Chinese pregnant women. Pregnant women were recruited in Zhoushan Pregnant Women Cohort at Zhoushan Maternal and Child Care Hospital from 2011 to 2015. Self-rating depression scales (SDS) and self-rating anxiety scales (SAS) were used for evaluating depression and anxiety status at each trimester; corresponding sleep quality and duration were reported by pregnant women. Ordinary or multilevel linear and logistic regression model were used to estimate the cross-sectional or longitudinal association of sleep with depression and anxiety. The prevalence rates were 35.64, 24.23, and 26.24% for depression and 22.57, 17.41, and 21.04% for anxiety at 1st (T1), 2nd (T2), and 3rd trimester (T3), respectively. Controlling for potential confounders, it revealed significant cross-sectional and longitudinal associations of sleep with depression and anxiety status. In cross-sectional analysis, women who slept less than 8 h/day had higher risk of depression (T1: OR (95%CI) = 1.75 (1.39, 2.20); T2: 1.52 (1.26, 2.05); T3: 1.60 (1.18, 2.05)) and anxiety (T1: 2.00 (1.57, 2.55); T2: 1.86 (1.37, 2.54); T3: 1.33 (0.99, 1.79)). In the longitudinal analysis, multilevel model revealed that women with subjective "fair" or "bad" sleep quality had elevated risk of depression (OR ranging from 1.54 to 3.71) and anxiety (2.38 to 7.53) during pregnancy. Prenatal depression and anxiety status were prevalent in pregnant women. Sleep quality was associated with depression and anxiety status in both cross-sectional and longitudinal analyses, implying that improving sleep quality should benefit for mental health of pregnant women.

Serum thyroid hormone levels among Chinese pregnant women.

AIM: The aim of this study is to examine gestational serum thyroid hormone levels and influencing factors among Chinese pregnant women with high dietary iodine intake. METHODS: The study was conducted from 2011 and 2013 in Zhoushan Women & Children's Hospital, Zhejiang, China. A total of 1991 pregnant women were enrolled and their serum levels of free thyroid hormones (FT4, FT3, and TSH) were detected by chemiluminescence method. RESULTS: Gestational serum FT4 and FT3 decreased with gestational week while TSH increased. Furthermore, the prevalence rate of subclinical hypothyroid increased with gestational stages, especially in the third trimester. Women aged more than 30 years had lower FT4 and FT3 in the first trimester and lower FT4 in the second trimester. No significant difference was found in the association of gestational serum thyroid hormones with maternal height and the gender of fetuses. CONCLUSION: Gestational serum thyroid hormones significantly changed with gestational week and were associated with the age of women. Specific normal range of thyroid hormones might be modified so as to better evaluate the thyroid hormone levels of pregnant women during pregnancy.

Outdoor temperature and temperature maintenance associated with blood pressure in 438,811 Chinese adults.

OBJECTIVES: The association of temperature maintenance with blood pressure (BP) has not been studied and the association of temperature with season-related BP was not being well understood. The present study aims to be further aware of season-related BP variation in Chinese adults. METHODS: We used decoded data from adults who visited the hospital for health examination from January 2008 to November 2013. Multivariate regression models were used to analyses the association between outdoor temperature and BP. RESULTS: The analysis included 438,811 adults. Larger change of BP accompanied with unit change of average outdoor temperature among outpatient than inpatient patients. The association of temperature with BP was stronger in normotensives than that in hypertensives. Compared with temperature variation, the impact of temperature maintenance on BP was smaller. These associations were stronger in men, older individuals. CONCLUSIONS: Temperature was strongly inversely associated with BP in Chinese adults. Temperature maintenance was mildly associated with BP compared to temperature variance. Seasonal temperature variation should be considered when screening for hypertension.

[Effects of Mechanical Stretch on Expression of Airway Remodeling Associated Factors in Human Bronchial Epithelioid Cells].

This study is aimed to investigate the effects of mechanical stretch on the expression of transforming growth factor-ß1（TGF-ß1）and fibroblast growth factor-2（FGF-2）,and the signaling pathway in human bronchial epithelioid（16HBE）cells under mechanical stretch.Using loading device with flexible substrate（FX-4000T）to stretch 16 HBE cells,we found that the stretching elongation was 15%,at frequency of 1Hz,stretching for 0.5h,1h,1.5hand 2h.Choosing the higher expression of TGF-ß1,FGF-2and Ca2+group to carry out intervention experiments,we used the cells pretreated with canonical transient receptor potential 1（TRPC1）channel antagonist SKF96365,protein kinase C（PKC）inhibitor HA-100,and thereafter mechanical stretch to interpose.Compared with those in the blank control group,TGF-ß1and FGF-2'protein and mRNA,intracellular Ca2+fluorescence intensity were higher,and the differences were statistically significant（P<0.05）at the 4time points,0.5h,1h,1.5h and 2h.At 0.5h,the increasing rate was the highest.TGF-ß1protein and mRNA,FGF-2protein and mRNA,intracellular Ca2+luorescence intensity in the stretch+SKF96365and stretch+ HA-100 intervented group were decreased,the differences were statistically significant than those in 0.5hstretch group（P<0.05）without intervention.The expression of TGF-ß1,FGF-2 was up-regulated in 16 HBE cells under mechanical stretch,PKC,TRPC1,and Ca2+may participate in the signal path.

Image-Guided Marking versus Manual Marking in Phacoemulsification with Toric Intraocular Lens (IOL) Implantation: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

PURPOSES: The purpose of this meta-analysis is to systematically compare the alignment accuracy and post uncorrected distance visual acuity (UDVA) between image-guided marking and manual marking for toric intraocular lens (IOL) in cataract surgery. METHODS: This work was done through the data searched from the PubMed, EMBASE and the Cochrane Library. The Cochrane Handbook was also used to evaluate the quality of the included studies. In addition, this meta-analysis was performed using Revman 5.4 software. RESULTS: A total of 6 randomized controlled trials (RCTs) were included. Compared with manual marking group, image-guided marking group had less toric IOL axis misalignment (MD, -1.98; 95%CI, -3.27 to -0.68; p = .003), less postoperative astigmatism (MD, -0.13; 95%CI, -0.21 to -0.05; p = .001), better postoperative UDVA (MD, -0.02; 95%CI, -0.04 to -0.01; p = .0003) and smaller difference vector (MD, -0.10; 95%CI, -0.14 to -0.06; p(0.00001). For the proportion of patients with residual refractive cylinder within 0.5 D, there was no difference between two groups (p = .07). CONCLUSION: Image-guided marking is prior to manual marking. As it can bring less toric IOL axis misalignment, less postoperative astigmatism, better postoperative UDVA and smaller difference vector for the patients with toric IOL implantation.

In silico design of a broad-spectrum multiepitope vaccine against influenza virus.

Influenza remains a global health concern due to its potential to cause pandemics as a result of rapidly mutating influenza virus strains. Existing vaccines often struggle to keep up with these rapidly mutating flu viruses. Therefore, the development of a broad-spectrum peptide vaccine that can stimulate an optimal antibody response has emerged as an innovative approach to addressing the influenza threat. In this study, an immunoinformatic approach was employed to rapidly predict immunodominant epitopes from different antigens, aiming to develop an effective multiepitope influenza vaccine (MEV). The immunodominant B-cell linear epitopes of seasonal influenza strains hemagglutinin (HA) and neuraminidase (NA) were predicted using an antibody-peptide microarray, involving a human cohort including vaccinees and infected patients. On the other hand, bioinformatics tools were used to predict immunodominant cytotoxic T-cell (CTL) and helper T-cell (HTL) epitopes. Subsequently, these epitopes were evaluated by various immunoinformatic tools. Epitopes with high antigenicity, high immunogenicity, non-allergenicity, non-toxicity, as well as exemplary conservation were then connected in series with appropriate linkers and adjuvants to construct a broad-spectrum MEV. Moreover, the structural analysis revealed that the MEV candidates exhibited good stability, and the docking results demonstrated their strong affinity to Toll-like receptors 4 (TLR4). In addition, molecular dynamics simulation confirmed the stable interaction between TLR4 and MEVs. Three injections with MEVs showed a high level of B-cell and T-cell immune responses according to the immunological simulations in silico. Furthermore, in-silico cloning was performed, and the results indicated that the MEVs could be produced in considerable quantities in Escherichia coli (E. coli). Based on these findings, it is reasonable to create a broad-spectrum MEV against different subtypes of influenza A and B viruses in silico.

Glucocorticoid Alleviates Mechanical Stress-Induced Airway Inflammation and Remodeling in COPD via Transient Receptor Potential Canonical 1 Channel.

Background: Increased airway resistance and hyperinflation in chronic obstructive pulmonary disease (COPD) are associated with increased mechanical stress that modulate many essential pathophysiological functions including airway remodeling and inflammation. Our present study aimed to investigate the role of transient receptor potential canonical 1 (TRPC1), a mechanosensitive cation channel in airway remodeling and inflammation in COPD and the effect of glucocorticoid on this process. Methods: In patients, we investigated the effect of pathological high mechanical stress on the expression of airway remodeling-related cytokines transforming growth factor ß1 (TGF-ß1), matrix metalloproteinase-9 (MMP9) and the count of inflammatory cells in endotracheal aspirates (ETAs) by means of different levels of peak inspiratory pressure (PIP) under mechanical ventilation, and analyzed their correlation with TRPC1. Based on whether patients regularly used inhaled corticosteroid (ICS), COPD patients were further divided into ICS group (n = 12) and non-ICS group (n=15). The ICS effect on the expression of TRPC1 was detected by Western blot. In vitro, we imitated the mechanical stress using cyclic stretch and examined the levels of TGF-ß1 and MMP-9. The role of TRPC1 was further explored by siRNA transfection and dexamethasone administration. Results: Our results revealed that the TRPC1 level and the inflammatory cells counts were significantly higher in COPD group. After mechanical ventilation, the expression of TGF-ß1 and MMP-9 in all COPD subgroups was significantly increased, while in the control group, only high PIP subgroup increased. Meanwhile, TRPC1 expression was positively correlated with the counts of inflammatory cells and the levels of TGF-ß1 and MMP-9. In vitro, mechanical stretch significantly increased TGF-ß1 and MMP-9 levels and such increase was greatly attenuated by TRPC1 siRNA transfection and dexamethasone administration. Conclusion: Our results suggest that the increased TRPC1 may play a role in the airway inflammation and airway remodeling in COPD under high airway pressure. Glucocorticoid could in some degree alleviate airway remodeling via inhibition of TRPC1.

Enhancement of SARS-CoV-2 N Antigen-Specific T Cell Functionality by Modulating the Autophagy-Mediated Signal Pathway in Mice.

The frequent SARS-CoV-2 variants have caused a continual challenge, weakening the effectiveness of current vaccines, and thus it is of great importance to induce robust and conserved T cellular immunity for developing the next-generation vaccine against SARS-CoV-2 variants. In this study, we proposed a conception of enhancing the SARS-CoV-2 specific T cell functionality by fusing autophagosome-associated LC3b protein to the nucleocapsid (N) (N-LC3b). When compared to N protein alone, the N-LC3b protein was more effectively targeted to the autophagosome/lysosome/MHC II compartment signal pathway and thus elicited stronger CD4+ and CD8+ T cell immune responses in mice. Importantly, the frequency of N-specific polyfunctional CD4+ and CD8+ T cells, which can simultaneously secrete multiple cytokines (IFN-γ+/IL-2+/TNF-α+), in the N-LC3b group was significantly higher than that in the N alone group. Moreover, there was a significantly improved T cell proliferation, especially for CD8+ T cells in the N-LC3b group. In addition, the N-LC3b also induced a robust humoral immune response, characterized by the Th1-biased IgG2a subclass antibodies against the SARS-CoV-2 N protein. Overall, these findings demonstrated that our strategy could effectively induce a potential SARS-CoV-2 specific T cellular immunity with enhanced magnitude, polyfunctionality, and proliferation, and thus provided insights to develop a promising strategy for the design of a novel universal vaccine against SARS-CoV-2 variants and other emerging infectious diseases.