Human angiotensin converting enzyme 2 specific antisense oligonucleotides reduce infection with SARS-CoV-2 variants.

BACKGROUND: The Spike protein mutation of SARS-CoV-2 led to decreased protective effect of various vaccines and monoclonal antibodies, suggesting that blocking SARS-CoV-2 infection by targeting host factors would make the therapy more resilient against virus mutations. Angiotensin converting enzyme 2 (ACE2) is the host receptor of SARS-CoV-2 and its variants, as well as many other coronaviruses. Down-regulation of ACE2 expression in the respiratory tract may prevent viral infection. Antisense oligonucleotides (ASOs) can be rationally designed based on sequence data, require no delivery system, and can be administered locally. OBJECTIVE: We sought to design ASOs that can block SARS-CoV-2 by down-regulating ACE2 in human airway. METHODS: ACE2-targeting ASOs were designed using a bioinformatic method and screened in cell lines. Human primary nasal epithelial cells cultured at the air-liquid interface and humanized ACE2 mice were used to detect the ACE2 reduction levels and the safety of ASOs. ASOs pretreated nasal epithelial cells and mice were infected and then used to detect the viral infection levels. RESULTS: ASOs reduced ACE2 expression on mRNA and protein level in cell lines and in human nasal epithelial cells. Furthermore they efficiently suppressed virus replication of three different SARS-CoV-2 variants in human nasal epithelial cells. In vivo, ASOs also down-regulated human ACE2 in humanized ACE2 mice and thereby reduced viral load, histopathological changes in lungs, and they increased survival of mice. CONCLUSION: ACE2-targeting ASOs can effectively block SARS-COV-2 infection. Our study provides a new approach for blocking SARS-CoV-2 and other ACE2-targeting virus in high-risk populations.

Factors for predicting the outcome of surgery for non-eosinophilic chronic rhinosinusitis with nasal polyps.

BACKGROUND: Despite the large patient base in Asia, the prognostic factors of patients with non-eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP) remain largely undetermined. OBJECTIVE: We aimed to systematically investigate the predictive value of clinical and biological variables for non-eosinophilic CRSwNP. METHODS: Fifty-one patients with non-eosinophilic CRSwNP who underwent functional endoscopic surgery were recruited. Clinical information and assessment were comprehensively collected before and after surgery. A broad spectrum of biomarkers was measured in tissue homogenates using multiple assays. A random forest algorithm and stepwise logistic regression were used to construct clinical, biological, and combined models. RESULTS: A total of 41.2% of non-eosinophilic CRSwNP patients were uncontrolled more than 6 months after surgery. We identified one clinical variable (22-item Sino-Nasal Outcome Test score) and four biomarkers (programmed cell death ligand 1, platelet-derived growth factor subunit B [PDGF-ß], macrophage inflammatory protein-3b, and PDGF-α) that were significantly predictive of the surgical outcome. The clinical, biological, and combined models showed predictive ability with areas under the curve of 0.78, 0.83, and 0.89, respectively. PDGF-ß and programmed cell death ligand 1 were identified as independent biomarkers for the prognosis of patients with CRSwNP without considerable eosinophilic infiltration. CONCLUSION: This study shows that clinical and biological factors, such as the 22-item Sino-Nasal Outcome Test score and PDGF-ß, are predictive of the post-functional endoscopic surgical prognosis of non-eosinophilic CRSwNP patients.

The SMYD3-dependent H3K4me3 status of IGF2 intensifies local Th2 differentiation in CRSwNP via positive feedback.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous and common upper airway disease divided into various inflammatory endotypes. Recent epidemiological findings showed a T helper 2 (Th2)-skewed dominance in CRSwNP patients. Histone modification alterations can regulate transcriptional and translational expression, resulting in abnormal pathogenic changes and the occurrence of diseases. Trimethylation of histone H3 lysine 4 (H3K4me3) is considered an activator of gene expression through modulation of accessibility for transcription, which is closely related to CRSwNP. H3K4me3 levels in the human nasal epithelium may change under Th2-biased inflammatory conditions, resulting in exaggerated local nasal Th2 responses via the regulation of naïve CD4+ T-cell differentiation. Here, we revealed that the level of SET and MYND domain-containing protein 3 (SMYD3)-mediated H3K4me3 was increased in NPs from Th2 CRSwNP patients compared with those from healthy controls. We demonstrated that SMYD3-mediated H3K4me3 is increased in human nasal epithelial cells under Th2-biased inflammatory conditions via S-adenosyl-L-methionine (SAM) production and further found that the H3K4me3high status of insulin-like growth factor 2 (IGF2) produced in primary human nasal epithelial cells could promote naïve CD4+ T-cell differentiation into Th2 cells. Moreover, we found that SAM production was dependent on the c-Myc/methionine adenosyltransferase 2A (MAT2A) axis in the nasal epithelium. Understanding histone modifications in the nasal epithelium has immense potential utility in the development of novel classes of therapeutics targeting Th2 polarization in Th2 CRSwNP. Video Abstract.

Subjective well-being among AIDS orphans in southwest China: the role of school connectedness, peer support, and resilience.

BACKGROUND: Few studies have explored the health and development of AIDS orphans using the positive youth development (PYD) framework. Grounded in this framework, the main objective of this study is to examine how internal assets (i.e., resilience) and external assets (i.e., school connectedness, peer support) affect subjective well-being among Yi AIDS orphans in the Liangshan Yi Autonomous Prefecture, Sichuan province, China. METHODS: A cross-sectional survey was conducted by interviewing 571 AIDS orphans and 979 non-orphans of Yi ethnic minority from 5th-10th grades. Structural equation models (SEM) were utilized to identify and estimate the direct and indirect effects of internal and external assets on subjective well-being. RESULTS: The average score of subjective well-being was significantly lower for AIDS orphans than for in non-orphans (P < 0.05). Resilience, school connectedness, peer support (number of friends, caring friends), and self-rated physical health had significant and positive direct effects on subjective well-being. In addition, the effects of school connectedness, and peer support on subjective well-being were mediated by resilience. CONCLUSIONS: Positive individual and school-related contextual assets can bolster subjective well-being among AIDS orphans. The design of health intervention programs for AIDS orphans should incorporate these positive development assets.

Depression and sleep disorders among AIDS orphans in an HIV/AIDS high-epidemic area in China.

BACKGROUND: The Liangshan Yi Autonomous Prefecture is home to the largest population of Yi ethnic minority within mainland China. Due to the high HIV/AIDS epidemic, many Yi children become AIDS orphans who lost one or both parents to AIDS-related causes. This study explored the prevalence and correlates of AIDS orphans' depressive symptom, sleep disorders and their comorbidity. METHODS: A cross-sectional survey was conducted to collect pertinent information from 467 AIDS orphans and 856 non-orphans of Yi ethnic minority. Depressive symptoms were screened by a two-item Patient Health Questionnaire (PHQ-2). The symptoms of insomnia were assessed by the Insomnia Severity Index (ISI), which was complemented by one item from the Pittsburgh Quality Sleep Index (PSQI) to measure the frequency of nightmare. RESULTS: The prevalence of depression (26.8% vs. 20.4%, P = 0.009) and comorbidity of depression, insomnia and nightmare (7.5% vs. 4.3%, P = 0.046) was significantly higher for AIDS orphans than for non-orphans. Risk factors such as ostracization and self-reported poor physical health had stronger effects on depressive symptoms and sleep disorders for AIDS orphans than for non-orphans. On the other hand, peer support, as an important protective factor, was significantly and negatively associated with depressive symptoms and sleep disorders for AIDS orphans. CONCLUSIONS: AIDS orphans of Yi ethnic minority reported higher levels of depressive symptoms and comorbidity of depression and sleep disorders than their non-orphan counterparts. These symptoms were exacerbated by ostracization and self-rated poor physical health but lowered by peer support.

[Influencing factors of depressive symptoms of rural middle school students in Zizhong County based on two-level Logistic regression model].

OBJECTIVE: To understand the prevalence of depressive symptoms of middle school students in rural areas of Zizhong County, and to analyze its main influencing factors. METHODS: In October 2015, two rural middle schools in Zizhong County, Sichuan Province, were selected to conduct a self-administered questionnaire survey(general demographic characteristics, the center for epidemiological studies depression scale(CES-D), self-esteem scale(SES) and connor-davidson resilience scale(CD-RICS)) on all the students(there were 2744 effective persons, including 1308 boys and 1436 girls, 554 middle school students and 2190 high school students), and then carried out a follow-up survey every semester. RESULTS: The prevalence of depressive symptoms was 30. 5%(in the baseline survey, it was 26. 7%, the third 35. 7% and the fifth 29. 8%), and the rate of female students was 30. 3%, higher than that of male students 22. 9%(χ~2=19. 72, P<0. 05). The main influencing factors of depressive symptoms of rural middle school students in Sichuan were gender(ß=0. 201, P=0. 001), be aware of whether teacher liked or not(ß=0. 228, P=0. 005), be aware of whether classmates liked or not(ß=0. 488, P<0. 001), be aware of the relationship with parents(ß=0. 201, P=0. 001), the power of the psychological resilience(ß=0. 046, P<0. 001) and the optimism of the psychological resilience(ß=-0. 030, P=0. 038), self-esteem(ß=-0. 140, P<0. 001). CONCLUSION: The depression symptoms of adolescents are related to many factors. The self-conscious teachers and classmates do not like himself(herself), and the bad relationship with parents are positively related to the depression symptoms of adolescents, while the psychological resilience and self-esteem are negatively related. The multi-level Model of repeated measurement is suitable for the analysis of the influencing factors and their changing rules in the longitudinal study of depression symptoms.

Depression and Deliberate Self-Harm Among Rural Adolescents of Sichuan Province in Western China: A 2-Year Longitudinal Study.

Objective: To explore the change in the prevalence and association of depression and deliberate self-harm and their common and independent influencing factors among western Chinese rural adolescents. Methods: A total of 2,744 junior and senior high school students from two rural schools in Sichuan Province, China, participated in the baseline survey and were invited to participate in two follow-up surveys. The Center for Epidemiologic Studies-Depression Scale, a deliberate self-harm item, the Social Support Rating Scale, the Rosenberg Self-esteem Scale and the Connor-Davidson Resilience Scale were administered. A bivariate four-level logistic regression model was used for analysis. Results: The prevalence of depression and deliberate self-harm were 39.6 and 21.2%, respectively. Regular physical exercise, a good relationship with parents, high resilience, and high self-esteem were common protective factors for both depression and deliberate self-harm. Feeling disliked by teachers was a common risk factor for both. Being female, having a mother who emigrated as a migrant worker before the student was 3 years old, feeling disliked by classmates and having a poor family economic status were associated only with an increased risk of depression. Participants with medium social support were less likely to report deliberate self-harm than those with low or high support. Depression and deliberate self-harm were clustered at the class level. Conclusions: The comorbidity of depression and deliberate self-harm in rural adolescents should be given ample attention. Interventions should consider the class clustering of depression and deliberate self-harm and their common and unique influencing factors.