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COVID-19 is an immune-mediated inflammatory disease caused by SARS-CoV-2 infection, the combination of anti-inflammatory and antiviral therapy is predicted to provide clinical benefits. We recently demonstrated that mast cells (MCs) are an essential mediator of SARS-CoV-2-initiated hyperinflammation. We also showed that spike protein-induced MC degranulation initiates alveolar epithelial inflammation for barrier disruption and suggested an off-label use of antihistamines as MC stabilizers to block degranulation and consequently suppress inflammation and prevent lung injury. In this study, we emphasized the essential role of MCs in SARS-CoV-2-induced lung lesions新冠肺炎（COVID-19）是由新型冠状病毒（SARS-CoV-2）感染导致的炎症相关疾病。抗病毒药物和抗炎药物联用有望在临床治疗取得有益的效果。我们最近证明，肥大细胞（Mast cell，MC）是SARS-CoV-2引发炎症的重要效应细胞。发现SARS-CoV-2刺突蛋白（Spike）通过诱导MC脱颗粒诱发肺泡上皮细胞炎症从而造成组织通透性破坏，并发现临床上治疗过敏性疾病的抗组胺药物可作为MC稳定剂，阻止Spike诱导的MC脱颗粒,进而抑制炎症发生和保护肺损伤。在该研究中，我们进一步阐述MC在SARS-CoV-2引发肺损伤中的作用，并评价抗组胺药物和抗病毒药物联用对病毒复制和炎症损伤的双重抑制效果。证明Spike诱导的MC脱颗粒可导致肺泡毛细血管损伤，而抗组胺药物预处理肺微血管内皮细胞，可防止细胞间紧密连接的破坏；特别重要一点，发现抗组胺药物HR1(histamine receptor)拮抗剂氯雷他定（Loratadine）和抗病毒药物瑞德西韦（Remdesivir）联用，可同时抑制SARS-CoV-2复制和缓解炎症造成的小鼠肺部损伤。该研究再次证明了MC在SARS-CoV-2诱导肺部炎症和导致肺损伤中的重要作用，并提出一种COVID-19抗病毒药物和抗炎药物联用治疗策略。.

Accumulating evidence has confirmed that chronic obstructive pulmonary disease (COPD) is a risk factor for development of severe pathological changes in the peripheral lungs of patients with COVID-19. However, the underlying molecular mechanisms remain unclear. Because bronchiolar club cells are crucial for maintaining small airway homeostasis, we sought to explore whether the altered susceptibility to SARS-CoV-2 infection of the club cells might have contributed to the severe COVID-19 pneumonia in COPD patients. Our investigation on the quantity and distribution patterns of angiotensin-converting enzyme 2 (ACE2) in airway epithelium via immunofluorescence staining revealed that the mean fluorescence intensity of the ACE2-positive epithelial cells was significantly higher in club cells than those in other epithelial cells (including ciliated cells, basal cells, goblet cells, neuroendocrine cells, and alveolar type 2 cells). Compared with nonsmokers, the median percentage of club cells in bronchiolar epithelium and ACE2-positive club cells was significantly higher in COPD patients. In vitro, SARS-CoV-2 infection (at a multiplicity of infection of 1.0) of primary small airway epithelial cells, cultured on air-liquid interface, confirmed a higher percentage of infected ACE2-positive club cells in COPD patients than in nonsmokers. Our findings have indicated the role of club cells in modulating the pathogenesis of SARS-CoV-2-related severe pneumonia and the poor clinical outcomes, which may help physicians to formulate a novel therapeutic strategy for COVID-19 patients with coexisting COPD.

Background Cerebral small vessel disease (CSVD) is a common syndrome in the older population, with a prevalence ranging from 5% in subjects aged 50 years to almost 100% in those aged 90 years and older. It is regarded to be a major cause of vascular cognitive impairment. Existing prevention and treatment approaches have not yet shown ideal clinical outcomes. Dengyinnaotong Capsule has shown great potential for improving cognitive function. This trial (De-CSVD trial) is designed to investigate the efficacy and safety of Dengyinnaotong Capsule on cognitive function in patients with CSVD . Methods This multicenter, randomized, open-label, controlled trial is planned to recruit at least 270 patients with mild cognitive impairment related to CSVD in 25 centers in China. Recruitment started on 10 May 2021 and is foreseen to end on 31 December 2022. The final follow-up of participants will be completed by the end of March 2023. Participants will be randomized in a ratio of 1:1 to the experimental group (routine basic treatment plus Dengyinnaotong Capsule) or the control group (routine basic treatment). The primary outcome is the change in the Montreal Cognitive Assessment score from baseline to week 12. Secondary outcomes are changes in Shape Trail Test, Activities of Daily Living, Geriatric Depression Scale, and Dizziness Handicap Inventory score from baseline to week 12, new vascular events, and the changes in serum level of homocysteine, high-sensitivity C-reactive protein, and D-dimer from baseline to week 4 and 12, respectively. The exploratory outcome is the changes in the Tinetti performance-oriented mobility assessment score from baseline to week 12. Safety assessment is performed by monitoring vital signs, general biochemical examinations, 12-lead electrocardiogram examinations, and incidence of cardiovascular and cerebrovascular ischemia or bleeding events. Visits will be performed at week 0 (baseline, pre-randomization), week 4, and week 12 in the treatment period (post-randomization). Discussion This trial is the first to investigate the efficacy and safety of Dengyinnaotong Capsule on cognitive impairment in patients with CSVD. The findings of this study might provide convincing evidence regarding the efficacy of Dengyinnaotong Capsule in patients with mild cognitive impairment related to CSVD. Trial registration Chinese Clinical Trial Registry ChiCTR2100045831. Registered on 25 April 2021.

Cathepsin L (CTSL), a cysteine protease that can cleave and activate the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, could be a promising therapeutic target for coronavirus disease 2019 (COVID-19). However, there is still no clinically available CTSL inhibitor that can be used. Here, we applied Chemprop, a newly trained directed-message passing deep neural network approach, to identify small molecules and FDA-approved drugs that can block CTSL activity to expand the discovery of CTSL inhibitors for drug development and repurposing for COVID-19. We found 5 molecules (Mg-132, Z-FA-FMK, leupeptin hemisulfate, Mg-101 and calpeptin) that were able to significantly inhibit the activity of CTSL in the nanomolar range and inhibit the infection of both pseudotype and live SARS-CoV-2. Notably, we discovered that daptomycin, an FDA-approved antibiotic, has a prominent CTSL inhibitory effect and can inhibit SARS-CoV-2 pseudovirus infection. Further, molecular docking calculation showed stable and robust binding of these compounds with CTSL. In conclusion, this study suggested for the first time that Chemprop is ideally suited to predict additional inhibitors of enzymes and revealed the noteworthy strategy for screening novel molecules and drugs for the treatment of COVID-19 and other diseases with unmet needs.

Emerging SARS-CoV-2 variants of concern (VOCs) harboring multiple mutations in the spike protein raise concerns on effectiveness of current vaccines that rely on the ancestral spike protein. Here, we design a quadrivalent mosaic nanoparticle vaccine displaying spike proteins from the SARS-CoV-2 prototype and 3 different VOCs. The mosaic nanoparticle elicits equivalent or superior neutralizing antibodies against variant strains in mice and non-human primates with only small reduction in neutralization titers against the ancestral strain. Notably, it provides protection against infection with prototype and B.1.351 strains in mice. These results provide a proof of principle for the development of multivalent vaccines against pandemic and potential pre-emergent SARS-CoV-2 variants.

Previous studies have revealed a diagnostic role of pathogen-specific IgA in respiratory infections. However, co-detection of serum specific IgA for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and common respiratory pathogens remains largely unexplored. This study utilizes a protein microarray technology for simultaneous and quantitative measurements of specific IgAs for eight different respiratory pathogens including adenovirus, respiratory syncytial virus, influenza virus type A, influenza virus type B, parainfluenza virus, mycoplasma pneumoniae, chlamydia pneumoniae, and SARS-CoV-2 in serum sample of patients with coronavirus disease 2019 (COVID-19). A total of 42 patients with COVID-19 were included and categorized into severe cases (20 cases) and nonsevere cases (22 cases). The results showed that co-detection rate of specific-IgA for SARS-CoV-2 with at least one pathogen were significantly higher in severe cases than that of nonsevere cases (72.2% vs. 46.2%, p = .014). Our study indicates that co-detection of IgA antibodies for respiratory pathogens might provide diagnostic value for the clinics and also be informative for risk stratification and disease management in patients with COVID-19.

Importance Lymphopenia is common and correlates with poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19). Objective To determine whether a therapy that increases peripheral blood leukocyte and lymphocyte cell counts leads to clinical improvement in patients with COVID-19. Design, Setting and Participants Between February 18 and April 10, 2020, we conducted an open-label, multicenter, randomized clinical trial at 3 participating centers in China. The main eligibility criteria were pneumonia, a blood lymphocyte cell count of 800 per μL (to convert to ×109/L, multiply by 0.001) or lower, and no comorbidities. Severe acute respiratory syndrome coronavirus 2 infection was confirmed with reverse-transcription polymerase chain reaction testing. Exposures Usual care alone, or usual care plus 3 doses of recombinant human granulocyte colony-stimulating factor (rhG-CSF, 5 μg/kg, subcutaneously at days 0-2). Main Outcomes and Measures The primary end point was the time from randomization to improvement of at least 1 point on a 7-category disease severity score. Results Of 200 participants, 112 (56%) were men and the median (interquartile range [IQR]) age was 45 (40-55) years. There was random assignment of 100 patients (50%) to the rhG-CSF group and 100 (50%) to the usual care group. Time to clinical improvement was similar between groups (rhG-CSF group median of 12 days (IQR, 10-16 days) vs usual care group median of 13 days (IQR, 11-17 days); hazard ratio, 1.28; 95% CI, 0.95-1.71;P = .06). For secondary end points, the proportion of patients progressing to acute respiratory distress syndrome, sepsis, or septic shock was lower in the rhG-CSF group (rhG-CSF group, 2% vs usual care group, 15%; difference, −13%; 95%CI, −21.4% to −5.4%). At 21 days, 2 patients (2%) had died in the rhG-CSF group compared with 10 patients (10%) in the usual care group (hazard ratio, 0.19; 95%CI, 0.04-0.88). At day 5, the lymphocyte cell count was higher in the rhG-CSF group (rhG-CSF group median of 1050/μL vs usual care group median of 620/μL; Hodges-Lehmann estimate of the difference in medians, 440; 95% CI, 380-490). Serious adverse events, such as sepsis or septic shock, respiratory failure, and acute respiratory distress syndrome, occurred in 29 patients (14.5%) in the rhG-CSF group and 42 patients (21%) in the usual care group. Conclusion and Relevance In preliminary findings from a randomized clinical trial, rhG-CSF treatment for patients with COVID-19 with lymphopenia but no comorbidities did not accelerate clinical improvement, but the number of patients developing critical illness or dying may have been reduced. Larger studies that include a broader range of patients with COVID-19 should be conducted. Trial Registration Chinese Clinical Trial Registry:ChiCTR2000030007

In comparison to severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2 appears to be more contagious [1], and Coronavirus Disease 2019 (COVID-19) patients demonstrate varied clinical manifestations distinct from those seen in patients with SARS-CoV and middle east respiratory syndrome coronavirus (MERS-CoV) infections [2]. Collective results from the clinical and epidemiological observations suggest a distinct viral-host interaction in COVID-19 patients. Profiling of the antibody response during SARS-CoV-2 infection may help improve our understanding of the viral-host interaction and the immunopathological mechanisms of the disease., Humoral immune response to SARS-CoV-2 showed an early response of IgA, instead of IgM, in COVID-19 patients. As highlighted by our study, enhanced IgA responses observed in severe COVID-19 might confer damaging effects in severe COVID-19.

The current study investigated the electrophysiological characteristics and radiofrequency ablation in patients with localized reentry within the left atrial appendage during repeated ablation for recurrent atrial fibrillation (AF). A total of 76 patients (21 paroxysmal, 55 persistent) undergoing repeated catheter ablation for recurrent AF were enrolled in this study. Local reentry tachycardia within the left atrial appendage (LAA) was identified through combining activation and entrainment mapping. Left atriography was performed prior to radiofrequency ablation to identify the focus in the LAA. Three patients (1 paroxysmal, 2 persistent) with sustained atrial tachycardias (ATs) were identified during repeated ablation in this cohort. Combined activation and entrainment mapping were applied to localize the reentry. Postpacing interval-tachycardia cycle length differences were

Objective: The aim of this study is to investigate the clinical effect of goal-directed fluid therapy in elderly patients with radical resection of bladder cancer. Materials and Methods: Seventy-six elderly patients with radical resection of bladder cancer were selected from October 2012 to October 2014 and randomly divided into two groups, in which 38 patients received routine treatment as the control group and 38 patients received goal-directed fluid therapy based on routine treatment as the observation group. The treatment effect was compared between two groups. Results: The cardiac index, stroke volume variability, mean arterial pressure, central venous pressure, central venous oxygen saturation, oxygen supply index, oxygen consumption index, and oxygen uptake rate in observation group were distinctly higher than those in control group at T1, T2, T3, and T4 while the artery serum lactate and S100-β were apparently lower than those in control group at T1, T2, T3, and T4. The urine volume and colloidal infusion were obviously elevated when compared with those in control group at T1, T2, T3, and T4 while the crystalloid infusion volume, total liquid infusion volume, hospitalization time, and expenses were significantly less than those in control group; further, similar tendency was also found regarding the complication incidences of nausea, vomiting, or hypotension in observation group. The postoperative flatus and postoperative food-taking times were visibly earlier than those in control group (both P < 0.05). Conclusion: The goal-directed fluid therapy is beneficial for stabilization of hemodynamic status and maintenance of oxygen balance of supply and demand, and it is worthy of clinical expansion for good microcirculation perfusion, reduction in therapeutic time and expenses of patients, and less complications and superior security.

A new α-pyrone derivative 1 and six known α-pyrone derivatives 2–7, along with known compounds 8–10 were isolated from the fermentation products of the endophytic fungus Diaporthe sp. RJ-41. Among them, nine compounds (1–9) were reported for the first time from the genus Diaporthe. This work expanded the knowledge of the chemical diversity of the genus Diaporthe, and the chemotaxonomic significance of the isolates was also discussed.

We aim to investigate the effects of sevoflurane on the ATPase activity of the hippocampal neurons in rats with cerebral ischemia-reperfusion injury (IRI) via the cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) signaling pathway. Sixty rats were assigned into the normal, model and sevoflurane groups (n = 20, the latter two groups were established as focal cerebral IRI models). The ATPase activity was detected using an ultramicro Na (+)-K (+)-ATP enzyme kit. Immunohistochemical staining was used to detect the positive protein expression of cAMP and PKA. The hippocampal neurons were assigned to the normal, IRI, IRI + sevoflurane, IRI + forskolin, IRI + H89 and IRI + sevoflurane + H89 groups. qRT-PCR and Western blotting were performed for the expressions of cAMP, PKA, cAMP-responsive element-binding protein (CREB) and brain derived neurotrophic factor (BDNF). The normal and sevoflurane groups exhibited a greater positive protein expression of cAMP and PKA than the model group. Compared with the normal group, the expressions of cAMP, PKA, CREB and BDNF all reduced in the IRI, model and IRI + H89 groups. The sevoflurane group showed higher cAMP, PKA, CREB and BDNF expressions than the model group. Compared with the IRI group, ATPase activity and expressions of cAMP, PKA, CREB and BDNF all increased in the normal, IRI + sevoflurane and IRI + forskolin groups but decreased in the IRI + H89 group. It suggests that sevoflurane could enhance ATPase activity in hippocampal neurons of cerebral IRI rats through activating cAMP-PKA signaling pathway.

A new task-flow based task system has been developed for live-line maintenance tasks done by a live working robot. Its aim is to improve the procession efficiency and intelligent of human-computer interaction. This system design is based on a new approach of task-flow. This paper introduces characteristics and function of each parts of live working task system, impresses connection and relationship between the task flows. The results of a system experiment confirmed that the system enables the live-line maintenance tasks to be performed orderly and efficiently in accordance with the task procedure.

In order to analysis wave characteristic of drainage wire, considering the shortcoming of existed measuring systems, including lack of accuracy and heavy load of data transmission, and combining with the PDR system which has been widely used in absolute position of a pedestrian, the on-line monitoring method for drainage wire galloping is proposed, which is based on accelerometer and gyroscope. Min-vector of angular velocity is applied to capture the onset/end of each gallop. ZUPT algorithm is implemented to correct the galloping velocity at onset when errors existed. Cluster sampling and quadratic integral are used to measure Galloping parameters accurately. The galloping orbit is also displayed dynamically. Finally, practical experiments are carried out. The feasibility and availability of the on-line monitoring method based on PDR system are demonstrated. The method can measure wave amplitude, wave speed and wave trajectory precisely, and offer technical support for in-depth research of drainage wire galloping.

IEEE Std. 1687, or IJTAG, defines flexible serial scan-based architectures for accessing embedded instruments efficiently. In this paper, we present a novel test architecture that employs IEEE Std. 1687 together with an efficient test controller to carry out 3D-IC testing autonomously. The test controller can deliver parallel test data for the IEEE Std. 1687 structures and the cores under test, and provide required control signals to control the whole test procedure. This design can achieve at-speed, autonomous and programmable testing in 3D-ICs. Experimental results show that the additional area and test cycle overhead of this architecture is small considering its autonomous test capability.