Discovery in clinical and translational medicine.

With the rapid development of biotechnologies and deep improvement of knowledge, "Discovery" is the initial period and source of innovation of clinical and translational medicine. The international journal of Clinical and Translational Discovery serves to highlight unknown or unclear aspects of clinical and translational medicine-associated knowledge, technologies, mechanisms, and therapies (https://onlinelibrary.wiley.com/journal/27680622). The Discovery aims to define the interaction between genes, proteins, and cells, and explore molecular mechanisms of intercommunication and inter-regulation. More discoveries of technologies and equipment are expected to improve method sensitivity, specificity, stability, analysis, and clinical significance. The first priority of Clinical and Translational Discovery is to turn gene-, protein-, drug-, cell-, and interaction-based discoveries into health advancements. Clinical and Translational Discovery highly focuses on the discoveries of biological therapies and precision medicine-based therapy elicited from computational chemistry, DNA libraries, target-dependent small molecular drugs, high-throughput screening, vaccination, immune therapy, cell implantations, gene editing, and RNA- or protein-based inhibitors. Thus, Clinical and Translational Discovery sincerely welcome you to join and share the rapid development and future successes to come.

Chinese Guideline on Allergen Immunotherapy for Allergic Rhinitis: The 2022 Update.

In the last few decades, there has been a progressive increase in the prevalence of allergic rhinitis (AR) in China, where it now affects approximately 250 million people. AR prevention and treatment include allergen avoidance, pharmacotherapy, allergen immunotherapy (AIT), and patient education, among which AIT is the only curative intervention. AIT targets the disease etiology and may potentially modify the immune system as well as induce allergen-specific immune tolerance in patients with AR. In 2017, a team of experts from the Chinese Society of Allergy (CSA) and the Chinese Allergic Rhinitis Collaborative Research Group (C2AR2G) produced the first English version of Chinese AIT guidelines for AR. Since then, there has been considerable progress in basic research of and clinical practice for AIT, especially regarding the role of follicular regulatory T (TFR) cells in the pathogenesis of AR and the use of allergen-specific immunoglobulin E (sIgE) in nasal secretions for the diagnosis of AR. Additionally, potential biomarkers, including TFR cells, sIgG4, and sIgE, have been used to monitor the incidence and progression of AR. Moreover, there has been a novel understanding of AIT during the coronavirus disease 2019 pandemic. Hence, there was an urgent need to update the AIT guideline for AR by a team of experts from CSA and C2AR2G. This document aims to serve as professional reference material on AIT for AR treatment in China, thus improving the development of AIT across the world.

SARS-CoV-2 ORF10 impairs cilia by enhancing CUL2ZYG11B activity.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal pathogen of the ongoing global pandemic of coronavirus disease 2019 (COVID-19). Loss of smell and taste are symptoms of COVID-19, and may be related to cilia dysfunction. Here, we found that the SARS-CoV-2 ORF10 increases the overall E3 ligase activity of the CUL2ZYG11B complex by interacting with ZYG11B. Enhanced CUL2ZYG11B activity by ORF10 causes increased ubiquitination and subsequent proteasome-mediated degradation of an intraflagellar transport (IFT) complex B protein, IFT46, thereby impairing both cilia biogenesis and maintenance. Further, we show that exposure of the respiratory tract of hACE2 mice to SARS-CoV-2 or SARS-CoV-2 ORF10 alone results in cilia-dysfunction-related phenotypes, and the ORF10 expression in primary human nasal epithelial cells (HNECs) also caused a rapid loss of the ciliary layer. Our study demonstrates how SARS-CoV-2 ORF10 hijacks CUL2ZYG11B to eliminate IFT46 and leads to cilia dysfunction, thereby offering a powerful etiopathological explanation for how SARS-CoV-2 causes multiple cilia-dysfunction-related symptoms specific to COVID-19.

Roles of pulmonary telocytes in airway epithelia to benefit experimental acute lung injury through production of telocyte-driven mediators and exosomes.

BACKGROUND: Telocytes (TCs) are experimentally evidenced as an alternative of cell therapies for organ tissue injury and repair. The aims of the present studies are to explore direct roles of TCs and the roles of TC-derived exosomes in support of experimental acute lung injury (ALI) in vivo or in vitro. MATERIALS AND METHODS: The roles of TCs in experimental ALI were firstly estimated. Phosphoinositide 3-kinase (PI3K) p110δ and α/δ/ß isoform inhibitors were used in study dynamic alterations of bio-behaviors, and in expression of functional factors of TCs per se and TC-co-cultured airway epithelial cells during the activation with lipopolysaccharide (LPS). TC-driven exosomes were furthermore characterized for intercellular communication by which activated or non-activated TCs interacted with epithelia. RESULTS: Our results showed that TCs mainly prevented from lung tissue edema and hemorrhage and decreased the levels of VEGF-A and MMP9 induced by LPS. Treatment with CAL101 (PI3K p110δ inhibitor) and LY294002 (PI3Kα/δ/ß inhibitor) could inhibit TC movement and differentiation and increase the number of dead TCs. The expression of Mtor, Hif1α, Vegf-a, or Mmp9 mRNA increased in TCs challenged with LPS, while Mtor, Hif1α, and Vegf-a even more increased after adding CAL101 or Mtor after adding LY. The rate of epithelial cell proliferation was higher in co-culture of human bronchial epithelial (HBE) and TCs than that in HBE alone under conditions with or without LPS challenge or when cells were treated with LPS and CAL101 or LY294002. The levels of mTOR, HIF1α, or VEGF-A significantly increased in mono-cultured or co-cultured cells, challenged with LPS as compared with those with vehicle. LPS-pretreated TC-derived exosomes upregulated the expression of AKT, p-AKT, HIF1α, and VEGF-A protein of HBE. CONCLUSION: The present study demonstrated that intraperitoneal administration of TCs ameliorated the severity of lung tissue edema accompanied by elevated expression of VEGF-A. TCs could nourish airway epithelial cells through nutrients produced from TCs, increasing epithelial cell proliferation, and differentiation as well as cell sensitivity to LPS challenge and PI3K p110δ and α/δ/ß inhibitors, partially through exosomes released from TCs.

How to translate the knowledge of COVID-19 into the prevention of Omicron variants.

Omicron variants are part of the "Coronavirus disease 2019 [COVID-19] Variants of Concerns" and has the potential to spread around the world rapidly and can harm human life. We can anticipate that the endemic state of COVID-19 will be characterized by the development of new strains with surges that will predominate in unvaccinated and immunodeficient populations. Thus, there will be an important role in promoting vaccinations, boosters and accessible testing to prevent disease transmission and to rapidly detect surges. There is an urgent need to explore the virology and biology of Omicron variants, define clinical phenomes and therapies, monitor dynamics of genetic changes, and translate the knowledge of COVID-19 into new variants. Clinical and translational medicine will be impactful in addressing these challenges by providing new insights for understanding and predicting new variants-associated transmissibility, disease severity, immune escape, diagnostic or therapeutic failure.

How to translate the knowledge of COVID-19 into prevention of Omicron variants

Omicron variants are part of the ?COVID-19 variants of concerns? and have the potential to spread around the world rapidly and can harm human life. We can anticipate that the endemic state of COVID-19 will be characterized by development of new strains with surges that will predominate in unvaccinated and immunodeficient populations. Thus, there will be an important role for promoting vaccinations, boosters and accessible testing to prevent disease transmission and to rapidly detect surges. There is an urgent need to explore the virology and biology of Omicron variants, define clinical phenomes and therapies, monitor dynamics of genetic changes and translate the knowledge of COVID-19 into new variants. Clinical and translational medicine will be impactful in addressing these challenges by providing new insights for understanding and predicting new variants-associated transmissibility, disease severity, immune escape, diagnostic, or therapeutic failure.

Using the Internet Big Data to Investigate the Epidemiological Characteristics of Allergic Rhinitis and Allergic Conjunctivitis.

BACKGROUND: To explore the epidemiological characteristics of allergic rhinitis (AR) and allergic conjunctivitis (AC) based on the Internet big data. METHODS: The Baidu index (BDI) of keywords "allergic rhinitis" and "allergic conjunctivitis" in Mandarin, the daily pollen concentration (PC) released by the Beijing Meteorological Bureau and the volumes of outpatient visits (OV) of the Beijing Tongren Hospital (Beijing) and the Third Affiliated Hospital of Sun Yat-sen University (Guangzhou) from 2017 to 2020 were obtained. The temporal and spatial changes of AR and AC were discussed. The correlations between BDI and PC/OV were analyzed by Spearman correlation analysis. RESULTS: The trends of BDI of "AR"/"AC" in Beijing showed obvious seasonal variations, but not in Guangzhou. The BDI of "AR" and "AC" was consistent with the OV in both cities (r1AR-BJ=0.580, P<0.001; r1AR-GZ=0.360, P=0.031; r1AC-BJ=0.885, P<0.001; r1AC-GZ=0.694, P<0.001). The BDI of "AR" and "AC" was highly consistent with the change of the PC in Beijing (r AR-Pollen=0.826, P<0.001; r AC-Pollen=0.564, P<0.001). The OV of AR in Beijing and Guangzhou decreased significantly in the first half of 2020, but there was no significant change in AC. In the first half of 2020, the OV of AC in Beijing was significantly higher than that of AR, while that of AC in Guangzhou was slightly higher than that of AR. CONCLUSION: The BDI could reflect the real-world situation to some extent and has the potential to predict the epidemiological characteristics of AR and AC. The BDI and OV of AR decreased significantly, but those of AC were still at a high level, during the COVID-19 pandemic, in the environment where most people in Beijing and Guangzhou wore masks without eye protection.

Sinonasal manifestations and dynamic profile of RT-PCR results for SARS-CoV-2 in COVID-19 patients.

BACKGROUND: Sinonasal symptoms were usually reported to appear initially, yielding the symptoms important for the early detection of coronavirus disease 2019 (COVID-19). This study was conducted retrospectively to investigate the detailed sinonasal manifestations and dynamic profile of real-time reverse transcription polymerase chain reaction (RT-PCR) results for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in COVID-19 patients longitudinally. METHODS: This retrospective study included 11 consecutive patients. The prevalence, timing and severity of sinonasal manifestations were analyzed. Oropharyngeal, nasal, sputum and stool specimens were collected to detect RT-PCR for SARS-CoV-2 over COVID-19 period. RESULTS: Among the 11 patients, 6 (54.5%) were female, and the median age was 51 (IQR, 36-62) years. Seven patients (63.6%) experienced sinonasal symptoms, with 6 (54.5%) exhibiting sinonasal symptoms on the onset day. Seven patients (63.6%) demonstrated nasal obstruction, 5 (45.5%) had rhinorrhea, and 4 (36.4%) exhibited olfactory dysfunction. All six patients with sinonasal symptoms on the onset day had non-severe infections. Most patients (85.7%) with sinonasal symptoms had non-severe infections. Sinonasal symptoms commonly appeared early. The positive RT-PCR rate for SARS-CoV-2 in various specimens was highest in the first week (73.3%), then gradually decreased over the disease course, but 3 patients (27.3%) had experienced a long-lasting fluctuated positive RT-PCR results since 29 days of illness in both groups, especially for two patients with airway comorbidities. CONCLUSIONS: Sinonasal symptoms were more prevalent in patients with mild or moderate COVID-19 and usually appeared early. In addition, regular nucleic acid testing for SARS-CoV-2 should be considered for COVID-19 patients with certain airway comorbidities.

A new and rapid approach for detecting COVID-19 based on S1 protein fragments.

The pandemic of novel coronavirus disease 2019 (COVID-19) seriously threatened the public health all over the world. A colloidal gold immunochromatography assay for IgM/IgG antibodies against the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S1 protein was established to assess its rapid diagnostic value. We first designed and manufactured all contents of the test cassette of SARS-CoV-2 rapid test kit: the colloidal gold-labeled mouse-antihuman lgM/lgG antibody, the recombinant SARS-CoV-2 antigen, the nitrocellulose membrane control line, and specimen diluents. Furthermore, reverse transcription-polymerase chain reaction (RT-PCR) assay, colloidal gold immunochromatography assay, serological validation of cross reaction with other common viruses, and clinical validation were performed. The kit was finally evaluated by 75 serum/plasma samples of SARS-CoV-2 infection cases and 139 healthy samples as control, with the result of that the sensitivity, specificity, and accuracy for IgM were 90.67%, 97.84%, and 95.33%, whereas for IgG were 69.33%, 99.28%, and 88.79%, respectively; the combination of IgM and IgG could improve the value: 92.00%, 97.12%, and 95.33%, respectively. Therefore, the rapid detection kit has high sensitivity and specificity, especially for IgM&IgG, showing a critical value in clinical application and epidemic control of COVID-19.

Significance of clinical phenomes of patients with COVID-19 infection: A learning from 3795 patients in 80 reports.

A new coronavirus SARS-CoV-2 has caused outbreaks in multiple countries and the number of cases is rapidly increasing through human-to-human transmission. Clinical phenomes of patients with SARS-CoV-2 infection are critical in distinguishing it from other respiratory infections. The extent and characteristics of those phenomes varied depending on the severities of the infection, for example, beginning with fever or a mild cough, progressed with signs of pneumonia, and worsened with severe or even fatal respiratory difficulty in acute respiratory distress syndrome. We summarized clinical phenomes of 3795 patients with COVID-19 based on 80 published reports from the onset of outbreak to March 2020 to emphasize the importance and specificity of those phenomes in diagnosis and treatment of infection, and evaluate the impact on medical services. The data show that the incidence of male patients was higher than that of females and the level of C-reaction protein was increased as well as most patients' imaging included ground-glass opacity. Clinical phenomes of SARS-CoV-2 infection were compared with those of SARS-CoV and MERS-CoV infections. There is an urgent need to develop an artificial intelligence-based machine learning capacity to analyze and integrate radiomics- or imaging-based, patient-based, clinician-based, and molecular measurements-based data to fight the outbreak of COVID-19 and enable more efficient responses to unknown infections in future.

Acute lung injury in patients with COVID-19 infection.

During the 2020 Spring Festival in China, the outbreak of a novel coronavirus, named COVID-19 by WHO, brought on a worldwide panic. According to the clinical data of infected patients, radiologic evidence of lung edema is common and deserves clinical attention. Lung edema is a manifestation of acute lung injury (ALI) and may progress to hypoxemia and potentially acute respiratory distress syndrome (ARDS). Patients diagnosed with ARDS have poorer prognosis and potentially higher mortality. Although no effective treatment is formally approved for COVID-19 infection, support of ventilation with oxygen therapy and sometimes mechanical ventilation is often required. Treatment with systemic and/or local glucocorticoids might be helpful to alleviate the pulmonary inflammation and edema, which may decrease the development and/or consequences of ARDS. In this article, we focus on the lung edema and ALI of patients with this widely transmitted COVID-19 infection in order to provide clinical indications and potential therapeutic targets for clinicians and researchers.