Disease 2019 (COVID-19) as a pandemic. As of 22 April, more than 2.4 million cases have been confirmed worldwide 1 . In light of the widely documented lung injuries related with COVID-19 2-3 , concerns are raised regarding the assessment of the lung injury for discharged patients. A recent report portrayed that discharged patients with COVID-19 pneumonia are still having residual abnormalities in chest CT scans, with ground-glass opacity as the most common pattern 4 . Persistent impairment of pulmonary function and exercise capacity have been known to last for months or even years [5][6][7][8] in the recovered survivors with other coronavirus pneumonia (severe acute respiratory syndrome/SARS and middle east respiratory syndrome/MERS). However, until now, there is no report in regard to pulmonary function in discharged COVID-19 survivors. Our manuscript aims to describe the characteristics of pulmonary function in these subjects.We recruited laboratory confirmed non-critical COVID-19 cases, from February 5th to March 17th from admitted patients. According to the WHO interim guidance 9 and the guidance from china 10 , disease severity were categorized as mild illness(mild symptoms without radiographic appearance of pneumonia), pneumonia(having symptoms and the radiographic evidence of pneumonia, with no requirement for supplemental oxygen), severe pneumonia(having pneumonia, including one of the following: respiratory rate > 30 breaths/minute; severe respiratory distress; or SpO2 ≤ 93% on room air at rest), and critical cases (e.g. respiratory failure requiring mechanical ventilation, Septic shock, other organ failure occurrence or admission into the ICU). Critical cases were excluded from our study.Spirometry and pulmonary diffusion capacity test (Cosmed PFT Quark, Rome, Italy) were performed following the ATS-ERS guidelines on the day of or one day before discharge. To minimize cross infections, carbon monoxide diffusion capacity (DLCO) was measured by the single-breath method. Written informed consent was obtained from all patients, and the study was approved by the ethics committee of The Guangzhou Eighth People's Hospital.One-hundred and ten discharged cases were recruited, which included 24 cases of mild illness, 67 cases of pneumonia and 19 cases of severe pneumonia (Table 1). The mean age of these cases was 49.1 years and fifty-five of them were females. Forty-four (40%) patients had at least one underlying comorbidity, of which 23.6% had hypertension and 8.2% had diabetes. Only 3 patients (2.7%) were reported having chronic respiratory diseases (one patient with asthma, one with chronic bronchitis and one with bronchiectasis). No significant differences were found among the three groups of cases, in the relation to gender, smoking status, underlying disease and the BMI value. The duration from onset of disease to pulmonary function test was 20±6 days in cases with mild illness, 29±8 days in cases with pneumonia and 34±7 days in cases that presented severe pneumonia. On the day of discharge, the SpO2% on ro...

The phytohormone abscisic acid (ABA) is crucial for plant responses to environmental challenges. The SNF1-regulated protein kinase 2s (SnRK2s) are key components in ABA-receptor coupled core signaling, and are rapidly phosphorylated and activated by ABA. Recent studies have suggested that Raf-like protein kinases (RAFs) participate in ABA-triggered SnRK2 activation. In vitro kinase assays also suggest the existence of autophosphorylation of SnRK2s. Thus, how SnRK2 kinases are quickly activated during ABA signaling still needs to be clarified. Here, we show that both B2 and B3 RAFs directly phosphorylate SnRK2.6 in the kinase activation loop. This transphosphorylation by RAFs is essential for SnRK2 activation. The activated SnRK2s then intermolecularly trans-phosphorylate other SnRK2s that are not yet activated to amplify the response. High-order Arabidopsis mutants lacking multiple B2 and B3 RAFs show ABA hyposensitivity. Our findings reveal a unique initiation and amplification mechanism of SnRK2 activation in ABA signaling in higher plants.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and joint stiffness, finally leading to tissue destruction. Connective tissue growth factor (CTGF) is a critical factor in RA progression, which promotes fibroblast-like synoviocyte (FLS) proliferation, pannus formation, and the damage of cartilage as well as bone. Resolvin D1 (RvD1) can promote inflammation resolution in acute inflammatory diseases, and recently, effects of RvD1 on chronic inflammatory diseases also attracted attention. This study aimed to examine the effect of RvD1 on pannus formation in RA and the underlying mechanism. Methods: Serum levels of RvD1 and CTGF were determined in RA patients and healthy persons by UPLC-MS/MS and ELISA respectively. The levels of CTGF and inflammatory factors were assessed by qRT-PCR and ELISA. MicroRNA expression profile was determined by miRNA microarray. The effects of CTGF, RvD1, and miR-146a-5p on angiogenesis were evaluated with tube formation and chick chorioallantoic membrane (CAM) assays. Collagen-induced arthritis (CIA) mice were constructed to detect the effects of RvD1 and miR146a-5p on RA. STAT3 activation was determined by Western blotting. Results: RvD1 levels decreased while CTGF levels increased in RA patients' serum, and an inverse correlation of the concentrations of RvD1 and CTGF in the serum of RA patients was synchronously observed. In CIA mice, RvD1 suppressed angiopoiesis and decreased the expression of CTGF. Simultaneously, RvD1 significantly decreased CTGF and proinflammation cytokines levels in RA FLS. Furthermore, CTGF suppressed angiopoiesis and RvD1 inhibited the proliferation and migration of RA FLS and angiopoiesis. MiRNA microarray and qRT-PCR results showed that RvD1 upregulated miRNA-146a-5p. The transfection experiments demonstrated that miRNA-146a-5p could decrease inflammatory factors and CTGF levels. Moreover, miRNA-146a-5p decreased the proliferation of FLS and angiogenesis in vivo. MiRNA-146a-5p also suppressed angiogenesis and downregulated the expression of CTGF in CIA mice. Finally, Western blot results revealed that miRNA-146a-5p inhibited the activation of STAT3.

TEA domain transcription factor 4 (TEAD4) is an important member of the TEAD family. As a downstream effector of the Hippo pathway, TEAD4 has essential roles in cell proliferation, cell survival, tissue regeneration, and stem cell maintenance. TEAD4 contains a TEA DNA binding domain that binds the promoters of target genes and a Yesassociated protein/transcriptional co-activator with PDZ-binding motif (YAP/TAZ) binding domain that associates with transcriptional cofactors. TEAD4 coordinates with YAP, TAZ, VGLL, and other transcription factors to regulate different cellular processes in cancer via its transcriptional output. Moreover, TEAD4 undergoes post-translational modifications and subcellular translocations, and both processes have been shown to shed new insights on how TEAD transcriptional activity can be modified. In summary, TEAD4 has important roles in cancer, including epithelial-mesenchymal transition (EMT), metastasis, cancer stem cell dynamics, and chemotherapeutic drug resistance, suggesting that TEAD4 may be a promising prognostic biomarker in cancer.

Background The dynamic trends of pulmonary function in coronavirus disease 2019 (COVID-19) survivors since discharge have been rarely described. We aimed to describe the changes of lung function and identify risk factors for impaired diffusion capacity.Methods Non-critical COVID-19 patients admitted to the Guangzhou Eighth People's Hospital, China, were enrolled from March to June 2020. Subjects were prospectively followed up with pulmonary function tests at discharge, three and six months after discharge.Findings Eighty-six patients completed diffusion capacity tests at three timepoints. The mean diffusion capacity for carbon monoxide (D LCO )% pred was 79.8% at discharge and significantly improved to 84.9% at Month-3. The transfer coefficient of the lung for carbon monoxide (K CO )% pred significantly increased from 91.7% at discharge to 95.7% at Month-3. Both of them showed no further improvement at Month-6. The change rates of D LCO % pred and K CO % pred were significantly higher in 0−3 months than in 3−6 months. The alveolar ventilation (V A ) improved continuously during the follow-ups. At Month-6, impaired D LCO % pred was associated with being female ; p = 0.004) and peak total lesion score (TLS) of chest CT > 8.5 ]; p = 0.007). D LCO % pred and K CO % pred were worse in females at discharge. And in patients with impaired diffusion capacity, females' D LCO % pred recovered slower than males.Interpretation The first three months is the critical recovery period for diffusion capacity. The impaired diffusion capacity was more severe and recovered slower in females than in males. Early pulmonary rehabilitation and individualized interventions for recovery are worthy of further investigations.

Aim. The feasibility and safety of performing the combined procedure of catheter ablation (CA) and left atrial appendage closure (LAAC) for atrial fibrillation (AF) have been reported by observational studies without controls. The aim of this study was to compare the procedural and long-term outcomes of combined procedures with isolated CA or LAAC. Methods and Results. This study included patients who underwent combined CA and LAAC (combined group), CA alone (CA-only group), or LAAC alone (LAAC-only group). Propensity score matching was used to select controls from the CA-only and LAAC-only groups. Each group contained 76 subjects. The procedures were successfully performed in all the patients. Procedure-related complications of the combined group included one pericardial effusion and two groin haematomas, which did not differ significantly with those of the CA-only group (3.9% vs. 2.6%, P=0.650) or the LAAC-only group (3.9% vs. 2.6%, P=0.650), respectively. The AF-free rate of the combined group was comparable with that of the CA-only group after a mean of 2 years follow-up (67.1% vs. 69.7%, P=0.727). Compared with the LAAC-only group, the combined group achieved similar complete occlusion rate at implant (94.7% vs. 93.4%) and at 45 days (82.9% vs. 85.5%). At the end of follow-up, ischemic stroke and bleeding events of the combined group were low (3.9%) and were comparable with those of the CA-only group (5.3%) and the LAAC-only group (2.6%). Conclusions. The combination of AF-CA and LAAC is safe and efficacious compared with single procedures alone.

Objectives To explore the value of detecting the peri‐device leak (PDL) and device endothelialization after left atrial appendage closure (LAAC) by cardiac computed tomography (CT) in patients with atrial fibrillation (AF), who underwent Watchman LAAC combined with radiofrequency ablation of atrial fibrillation (AFCA). Methods Patients with symptomatic drug‐refractory atrial fibrillation at high risk of stroke (CHA2DS2‐VASc Score ≥ 2), who underwent Watchman LAAC combined with AFCA in our center from March 2017 to December 2018 were enrolled. Maximum diameter of LAA orifice was determined by preoperative CCTA. A standardized view of Watchman device was obtained by postoperative CCTA multiplannar reconstruction to evaluate the PDL and device endothelialization. Results Approximately 84 patients post successful LAAC and AFCA were enrolled in this study. The satisfactory LAA occlusion rate was 100%. There was no death, bleeding, stroke, and device‐related thrombus (DRT) events. At 6‐month postprocedure, CCTA images evidenced complete endothelialization in 44 patients (no contrast enhancement in LAA); contrast enhancement in LAA and visible PDL in 33 patients; contrast enhancement in LAA but without PDL in seven patients (incomplete device endothelialization). Maximum diameter of LAA orifice could independently predict the occurrence of PDL (odds ratio, 1.31; 95% confidence interval, 1.11–1.55; p = .002), sensitivity was 69.7% and specificity was 80.4% with the cutoff value of maximum diameter of LAA orifice more than 28.2 mm on predicting PDL. Conclusions CCTA is feasible to evaluate PDL and device endothelialization after LAAC. The maximum diameter of LAA orifice derived from CT can independently predict the occurrence of post‐LAAC PDL.

Temozolomide (TMZ) is the first choice chemotherapy agent against glioblastoma, but the TMZ chemotherapy resistance has restricted the clinical application. Although autophagy is considered an adaptive response for cell survival under the pressure of chemotherapy and associated with chemotherapy resistance, its initiator and the precise molecular mechanism remains unknown. In the present study, it was determined that TMZ increases the transient receptor potential cation channel subfamily C member 5 (TRPC5) protein expression and the basal autophagy level, and the upregulation of autophagy is mediated by TRPC5 in glioma cells. Additionally, knockdown of TRPC5 upregulated the chemotherapy sensitivity in vitro and in vivo. Furthermore, TRPC5-small interfering RNA and pharmacological inhibition indicated that the Ca 2+ /calmodulin dependent protein kinase β (CaMKKβ)/AMP-activated protein kinase α (AMPKα)/mechanistic target of rapamycin kinase (mTOR) pathway mediates cell survival autophagy during TMZ treatment. In addition, TMZ-resistant U87/TMZ cells retained a high basal autophagy level, while silence of TRPC5 expression or inhibition of autophagy reversed TMZ resistance. Thus, the present study revealed that TRPC5, an initiator of autophagy, upregulated TMZ resistance via the CaMKKβ/AMPKα/mTOR pathway and this indicated a novel therapeutic site for drug resistance in glioma chemotherapy.