Tandem Vinylogous Aldol and Intramolecular [2 + 2] Cycloaddition toward Benzocyclobutenes by UV Light Photocatalysis.

A facile and efficient radical tandem vinylogous aldol and intramolecular [2 + 2] cycloaddition reaction for direct synthesis of cyclobutane-containing benzocyclobutenes (BCBs) under extremely mild conditions without using any photocatalysts is reported. This approach exhibited definite compatibility with functional groups and afforded new BCBs with excellent regioselectivity and high yields. Moreover, detailed mechanism studies were carried out both experimentally and theoretically. The readily accessible, low-cost, and ecofriendly nature of the developed strategy will endow it with attractive applications in organic and medicinal chemistry.

A novel framework for urban flood risk assessment: Multiple perspectives and causal analysis.

Risk assessment and adaptation have become key focuses in the examination of urban flooding risk. In recent decades, global climate change has resulted in a high incidence of extreme weather events, notably flooding. This study introduces a spatial multi-indicator model developed for assessing flood risk at the urban agglomeration scale. A crucial addition to the model is the incorporation of an adaptive capacity within the IPCC risk framework. The model systematically considers various flood risk indicators related to the economic, social, and geographic environments of the central and southern Liaoning urban agglomeration (CSLN). It generates a spatial distribution map of integrated flood risk for multiple scenario combinations. Furthermore, the intricate relationship between different risk indicators and flood risk was analyzed using correlation analysis and the Light Gradient Boosting Machine model (Light GBM). The findings reveal notable variations in flood risk under different scenarios. The inclusion of vulnerability indicators increased flood risk by 33 %, while the subsequent inclusion of adaptive indicators decreased flood risk by 45 %. Dense populations and assets contribute to high flood risk, while adaptive capacity significantly mitigates urban flood risk. The framework adopted in this paper can be applied to other areas where urban agglomeration-scale flood risk assessment is needed, and can contribute to advancing scientific research on flood forecasting and mitigation.

Comparison of the PADUA and IMPROVE scores in assessing venous thromboembolism risk in 42,257 medical inpatients in China.

Venous thromboembolism (VTE) is a major contributor to hospital mortality and disability-adjusted life-year (DALY) loss. Multiple guidelines recommend using the Padua or IMPROVE scores to stratify VTE risk in hospitalized medical patients. However, the IMPROVE score is not recommended in Chinese guidelines, and there is very little evaluation of its clinical application and effectiveness in the Chinese population. The objective of this study is to compare the efficacy of the Padua and IMPROVE scoring models for assessing VTE risk in Chinese medical inpatients. We conducted a retrospective analysis of the clinical characteristics and thrombotic risk of 42,257 medical inpatients at a tertiary hospital in Guangdong, China, between 2021 and 2022. Logistic regression was used to assess thrombotic risk factors. The Receiver Operating Characteristic (ROC) curves, Area Under the Curve (AUC), sensitivity, and specificity were employed to evaluate the performance of the two models. Of the 42,257 patients included, 948 (2.24%) experienced VTE during hospitalization. According to the Padua score, 3,7513 (88.78%) of patients were considered low risk, while 4,744 (18.22%) were classified as high risk. The IMPROVE score identified 20,744 (49.09%) of patients as low risk, 20799(49.22%) as intermediate risk, and 714(1.69%) as high risk. The AUC for the Padua score was 0.735 (95% CI: 0.717-0.753), with a sensitivity of 49.4% and specificity of 89.6%. For the IMPROVE score, the AUC was 0.711 (95% CI: 0.693-0.729), with a sensitivity of 32.5% and specificity of 99.0%. The DeLong test, used to compare the AUCs, yielded a z-value of 1.886 with a P-value of 0.059, indicating no statistical difference. When assessing VTE risk in patients with stroke, cancer, nephrotic syndrome, and critical illness (ICU/CCU stay), both scoring models showed comparable predictive performance with AUCs ranging between 0.7 and 0.8. Both the Padua score and IMPROVE score have good predictive ability for VTE events during hospitalization in medical patients. Among them, the IMPROVE score has objective assessment items, simpler operation, and more detailed risk stratification, which is beneficial for clinicians to take physical and pharmacological preventive measures at different levels.ChiCTR2200056903, February 22, retrospectively registered.

Three new species of Agaricus from Baiyun Mountain, Guangzhou, China.

Agaricus is a species-rich genus with more than 600 species around the world. In this work, three new species, Agaricus cacainus, A. baiyunensis, and A. praeclarefibrillosus are described from the specimens collected at Baiyun Mountain, Guangzhou, China, a subtropical area with a monsoon maritime climate, based on phylogenetic analyses and morphological examinations of internal transcribed spacer (ITS1-5.8S-ITS2 = ITS), D1/D2 domains of the large subunit of ribosomal DNA (28S), and a part of translation elongation factor 1-alpha (TEF1). Agaricus cacainus in A. sect. Amoeni is characterized by a parabolic to applanate, slightly depressed pileus covered with chocolate brown, appressed, triangular squamules against white background, a white, furfuraceous stipe, an unchanging context when cut, a fragile and evanescent annulus, usually 4- or 2-spored basidia, and mostly pyriform cheilocystidia. Agaricus baiyunensis in A. sect. Minores has a pileus with a slightly truncate top covered with light brown, downy-wooly fibrillose scales and a light yellowish stipe with membranous annulus. Agaricus praeclarefibrillosus in A. sect. Brunneopicti is characterized by a pileus surface with brownish, triangular, recurved scales and longitudinally splitting lines toward margin, a cottony stipe with white, tiny, recurved fibrils, a single annulus, and variously shaped cheilocystidia, with sparsely ornamented basidiospores. The detailed comparison of their morphological characteristics with closely related species is provided.

Visible-Light-Mediated Catalyst-Free [2+2] Cycloaddition Reaction for Dihydrocyclobuta[b]naphthalene-3,8-diones Synthesis under Mild Conditions.

A facile and efficient visible-light-mediated method for directly converting 1,4-naphthoquinones into dihydrocyclo-buta[b]naphthalene-3,8-diones (DHCBNDOs) under mild and clean conditions without using any photocatalysts is reported. This approach exhibited favorable compatibility with functional groups and afforded a series of DHCBNDOs with excellent regioselectivity and high yields. Moreover, detailed mechanism studies were carried out both experimentally and theoretically. The readily accessible, low-cost and ecofriendly nature of the developed strategy will endow it with attractive applications in organic and medicinal chemistry.

Higher Sensitivity to Thyroid Hormones May Be Linked to Maintaining the Healthy Metabolic Condition in People with Obesity: New Insight from NHANES.

INTRODUCTION: Obesity contributes to the pathogenesis of diverse metabolic diseases, yet the mechanism underlying metabolically healthy obesity (MHO) remains elusive. Thyroid hormones and sensitivity to them have a major impact on metabolism. Our study aimed to investigate the association between MHO and thyroid hormone sensitivity. METHODS: Thyroid hormone indices, including the thyroid-stimulating hormone (TSH) index (TSHI), the Thyrotroph Thyroxine Sensitivity Index (TTSI), the Thyroid Feedback Quantile-Based Index (TFQI), and the Parametric Thyroid Feedback Quantile-Based Index (PTFQI), were calculated based on a non-institutionalized US sample in the National Health and Nutrition Examination Survey (NHANES, 2007-2012). Participants were divided into four groups (metabolically healthy non-obesity [MHNO], metabolically unhealthy non-obesity [MUNO], MHO, and metabolically unhealthy obesity [MUO]) according to their body mass index and metabolic profiles. Linear regression, logistic regression, and restricted cubic splines were employed to analyze the association between thyroid hormone indices and metabolic phenotypes. RESULTS: A total of 4,857 participants (49.6% men; mean age, 42.6 years) were included, with 1,539 having obesity and 235 identified as MHO. Participants in the MHO group exhibited lower levels of TSH, TSHI, TTSI, TFQI, and PTFQI compared with the MHNO group (all p < 0.05), while the differences among MHNO, MUNO, and MUO groups were not statistically significant (all p > 0.05). Among participants with obesity, TSH, TSHI, TTSI, TFQI, and PTFQI were positively associated with metabolic abnormality (all p < 0.05). CONCLUSION: Participants with MHO exhibited higher thyroid hormone sensitivity among various obesity phenotypes, even when compared with those with MHNO. A positive association was observed between metabolic abnormality and thyroid hormone sensitivity, while the trend of TSH was observed to be consistent with sensitivity to thyroid hormone indices in discriminating metabolic abnormality. Hence, TSH has the potential to serve as a convenient index for detecting sensitivity to thyroid hormones and further metabolic conditions.

[Reducing the Incidence of Postoperative Hypothermia in Patients Undergoing Robotic-Assisted Mitral Valve Surgery].

BACKGROUND & PROBLEMS: Post-operation hypothermia tends to induce complications. Sixty percent of robotic-assisted mitral valve surgery patients experienced hypothermia while admitted to our intensive care unit (ICU), resulting in prolonged ICU stays and 57% (eight) of those patients with hypothermia also experiencing cardiac arrhythmia. The causes of hypothermia in our ICU included low temperature in the operating room, delayed initiation of blanket coverage after surgery, and lack of postoperative thermal blankets, insufficient cardiopulmonary bypass rewarming time, cold ICU beds, lack of in-service training for hypothermia, and lack of procedure auditing. PURPOSE: This intervention was designed to reduce the incidence of hypothermia in ICU patients undergoing robotic-assisted mitral valve surgery upon ICU admission from 60% to 36% and the one-hour hypothermia rate from 43.3% to 26%. RESOLUTIONS: We implemented several measures including increasing the room temperature, pre-heating the ICU bed, achieving team consensus regarding prolonging the rewarming time after cardiopulmonary bypass, establishing a blanket warming area for postoperative patient use, and holding in-service training to enhance the awareness of the nurses were implemented. RESULTS: The incidence of hypothermia in ICU patients receiving robotic-assisted mitral valve surgery upon ICU admission decreased from 60% to 19.4%, while the one-hour hypothermia rate decreased from 43.3% to 19.4%. CONCLUSIONS: Using systemic interprofessional collaboration, combined thermal care can be achieved to significantly reduce the incidence of postoperative hypothermia in patients undergoing robotic-assisted mitral valve surgeries resulting in higher patient care quality and shorter ICU stays. We recommend applying this combined method to improve the quality of perioperative care for long-duration and major surgical procedures that involve large postoperative wounds and for patients who may require wider exposure during their operation.

Construction of refined staging classification systems integrating FIGO/T-categories and corpus uterine invasion for non-metastatic cervical cancer.

BACKGROUND: To investigate the prognostic value of corpus uterine invasion (CUI) in cervical cancer (CC), and determine the necessity to incorporate it for staging. METHODS: A total of 809 cases of biopsy-proven, non-metastatic CC were identified from an academic cancer center. Recursive partitioning analysis (RPA) method was used to develop the refined staging systems with respect to overall survival (OS). Internal validation was performed by using calibration curve with 1000 bootstrap resampling. Performances of the RPA-refined stages were compared against the conventional FIGO 2018 and 9th edition TNM-stage classifications by the receiver operating characteristic curve (ROC) and decision curve analysis (DCA). RESULTS: We identified that CUI was independently prognostic for death and relapse in our cohort. RPA modeling using a two-tiered stratification by CUI (positive and negative) and FIGO/T-categories divided CC into three risk groupings (FIGO I'-III'/T1'-3'), with 5-year OS of 90.8%, 82.1%, and 68.5% for proposed FIGO stage I'-III', respectively (p ≤ 0.003 for all pairwise comparisons), and 89.7%, 78.8%, and 68.0% for proposed T1'-3', respectively (p < 0.001 for all pairwise comparisons). The RPA-refined staging systems were well validated with RPA-predicted OS rates showed optimal agreement with actual observed survivals. Additionally, the RPA-refined stages outperformed the conventional FIGO/TNM-stage with significantly higher accuracy of survival prediction (AUC: RPA-FIGO vs. FIGO, 0.663 [95% CI 0.629-0.695] vs. 0.638 [0.604-0.671], p = 0.047; RPA-T vs. T, 0.661 [0.627-0.694] vs. 0.627 [0.592-0.660], p = 0.036). CONCLUSION: CUI affects the survival outcomes in patients with CC. Disease extended to corpus uterine should be classified as stage III/T3.

Kinetically and thermodynamically controlled one-pot growth of gold nanoshells with NIR-II absorption for multimodal imaging-guided photothermal therapy.

Since the successful clinical trial of AuroShell for photothermal therapy, there is currently intense interest in developing gold-based core-shell structures with near-infrared (NIR) absorption ranging from NIR-I (650-900 nm) to NIR-II (900-1700 nm). Here, we propose a seed-mediated successive growth approach to produce gold nanoshells on the surface of the nanoscale metal-organic framework (NMOF) of UiO-66-NH2 (UiO = the University of Oslo) in one pot. The key to this strategy is to modulate the proportion of the formaldehyde (reductant) and its regulator / oxidative product of formic acid to harness the particle nucleation and growth rate within the same system. The gold nanoshells propagate through a well-oriented and controllable diffusion growth pattern (points → facets → octahedron), which has not been identified. Most strikingly, the gold nanoshells prepared hereby exhibit an exceedingly broad and strong absorption in NIR-II with a peak beyond 1300 nm and outstanding photothermal conversion efficiency of 74.0%. Owing to such superior performance, these gold nanoshells show promising outcomes in photoacoustic (PA), computed tomography (CT), and photothermal imaging-guided photothermal therapy (PTT) for breast cancer, as demonstrated both in vitro and in vivo.

Clinical utility of pretreatment serum squamous cell carcinoma antigen for prognostication and decision-making in patients with early-stage cervical cancer.

Background: To investigate the prognostic role of pretreatment squamous cell carcinoma antigen (SCCA) in early-stage cervical cancer (CC). Methods: We enrolled 487 cases of pathology-proven early-stage [International Federation of Gynecology and Obstetrics (FIGO) I/II] squamous or adenosquamous CC that were treated from 2012 to 2015. Restricted cubic splines (RCS) with a full Cox regression model were used to evaluate the association between SCCA levels and survival outcomes. Recursive partitioning analysis (RPA) was used to construct a risk stratification model for overall survival (OS). The performance of the RPA-based model was assessed using a receiver operating characteristic (ROC) curve. Results: RCS analysis revealed an association between SCCA and OS and disease-free survival (DFS); SCCA ⩾2.5 ng/mL was robust for risk discrimination in our cohort. SCCA had an interaction effect with FIGO classification: Patients with FIGO I and SCCA ⩾2.5 ng/mL overlapped with those with FIGO II and SCCA < 2.5 ng/mL for OS [hazard ratio, 1.04 (95% confidence interval (CI): 0.49-2.24), p = 0.903] and DFS [1.05 (0.56-1.98), p = 0.876]. RPA modeling incorporating SCCA (<2.5 ng/mL and ⩾2.5 ng/mL) and FIGO classification divided CC into three prognostic groups: RPA I, FIGO stage I, and SCCA < 2.5 ng/mL; RPA II, FIGO stage I, and SCCA ⩾ 2.5 ng/mL, or FIGO stage II and SCCA < 2.5 ng/mL; and RPA III, FIGO stage II, and SCCA ⩾ 2.5 ng/mL; with 5-year OS of 94.0%, 85.1%, and 73.5%, respectively (p < 0.001). ROC analysis confirmed that the RPA model outperformed the FIGO 2018 stage with significantly improved accuracy for survival prediction [area under the curve: RPA versus FIGO, 0.663 (95% CI: 0.619-0.705] versus 0.621 (0.576-0.664), p = 0.045]. Importantly, the RPA groupings were associated with the efficacy of treatment regimens. Surgery followed by adjuvant treatment had a higher OS (p < 0.01) and DFS (p = 0.024) than other treatments for RPA III, whereas outcomes were comparable among treatment regimens for RPA I-II. Conclusion: Herein, the role of SCCA for prognostication was confirmed, and a robust clinicomolecular risk stratification system that outperforms conventional FIGO classification in early-stage squamous and adenosquamous CC was presented. The model correlated with the efficacy of different treatment regimes.

COVID discrimination experience: Chinese Canadians' social identities moderate the effect of personal and group discrimination on well-being.

OBJECTIVE: The coronavirus disease (COVID-19) pandemic has amplified preexisting racism and xenophobia. In this study, we investigated (a) whether perceived personal and group discrimination make distinct contributions to Chinese Canadians' negative affect and concern that the heightened discrimination they experienced during the pandemic will continue after the pandemic; (b) whether Canadian and Chinese identities and social support moderate the effect of discrimination on this concern; and (c) whether race-based rejection sensitivity (RS) explains why each type of discrimination predicts negative affect and expectation of future discrimination. METHOD: A sample of Chinese Canadian adults across Canadian provinces (N = 516; Mage = 42.74, 53.3% females) completed a questionnaire assessing personal and group discrimination, Chinese and Canadian identity, a short form of race-based RS, negative affect, and expectation of future discrimination. RESULTS: Personal and group discrimination were intercorrelated and positively associated with negative emotion and expectation of future discrimination. Chinese Canadians who identified more strongly as Chinese experienced a less adverse impact related to group discrimination. However, those who identified more (vs. less) strongly as Canadians were more likely to be impacted by personal discrimination. Finally, path analysis revealed that both personal and group discrimination were positively associated with RS, which in turn predicted an expectation that long-lasting racism would continue after the pandemic. CONCLUSION: Group and personal discrimination play different roles in Chinese Canadians' experiences during and expectations after the pandemic. Maintaining Chinese identity can be beneficial to Chinese Canadians, particularly in mitigating the negative effect of group discrimination during the pandemic. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A long-term survival rat model of spinal cord ischemia injury: Thoracic aortic occlusion combined with aortic bypass circulation.

OBJECTIVE: This study aims to investigate the methods for rat spinal cord ischemia injury models with a high long-term survival rate. METHODS: The rats were divided into three groups: the treatment group, the control group, and the sham operation group. The treatment group had a blocked thoracic aorta (landing zone 3 by Ishimaru - T11) + aortic bypass circulation for 20 min. In the control group, the thoracic aorta at the landing zone 3 was blocked for 20 min. In the sham operation group, only thoracotomy without thoracic aortic occlusion was performed. The mean arterial blood pressure (MABP) of the thoracic aorta and caudal artery before and after thoracic aortic occlusion was monitored intraoperatively. Spinal cord function was monitored by a transcranial motor evoked potential (Tc-MEP) during the operation. Spinal cord function was evaluated by the BBB scale (Basso, Beattie, & Bresnahan locomotor rating scale) scores at multiple postoperative time points. The spinal cord sections of the rats were observed for 7 days after surgery, and the survival curves were analyzed for 28 days after surgery. RESULTS: After aortic occlusion, the MABP of thoracic aorta decreased to 6% of that before occlusion, and the MABP of caudal artery decreased to 63% of that before occlusion in the treatment group. In the control group, the MABP of both thoracic aorta and caudal artery decreased to 19% of that before occlusion. The Tc-MEP waveform of the treatment group disappeared after 6 min, and that of the control group disappeared after 8 min until the end of surgery. There was no change in the Tc-MEP waveform in the sham operation group. The BBB score of the treatment group decreased more obviously than the control group, and there was a significant difference. There was no decrease in the sham group. Spinal cord sections showed a large number of degeneration and necrosis of neurons, infiltration of inflammatory cells, and proliferation of surrounding glial cells in the treatment group. In the control group, multiple neurons were necrotic. The histology of the sham operation group was normal. The 28-day survival rate of the treatment group was 73.3%, which was higher than the control group (40.0%), and there was a significant difference (p < 0.05). CONCLUSION: Thoracic aortic occlusion combined with aortic bypass is an effective modeling method for rats with accurate modeling effects and high long-term survival rates.

MS/MS molecular networking-guided in-depth profiling of triterpenoid saponins from the fruit of Eleutherococcus senticosus and their neuroprotectivity evaluation.

INTRODUCTION: Eleutherococcus senticosus fruit (ESF) is a natural health supplement resource that has been extensively applied as a tonic for the nervous system. The structures and neural bioactivities of triterpenoid saponins (TS), which are the major constituents of ESF, have not been comprehensively analyzed thus far. OBJECTIVE: We conducted a complete in-depth MS/MS molecular networking (MN)-based targeted analysis of TS from the crude extract of ESF and investigated its neuroprotective value. METHODS: An MS/MS MN-guided strategy was used to rapidly present a series of precursor ions (PIs) of TS in a compound cluster as TS-targeted information used in the discovery and characterization of TS. In addition, a prepared TS-rich fraction of ESF was assayed for its restraining effects on ß-amyloid-induced inhibition of neurite outgrowth. RESULTS: A total of 87 TS were discovered using a PI tracking strategy, 28 of which were characterized as potentially undescribed structures according to their high-resolution MS values. Furthermore, the TS-rich fraction can significantly reduce ß-amyloid-induced damage to neural networks by promoting the outgrowth of neurites and axons. CONCLUSION: Our findings reveal the richness of TS in ESF and will accelerate their application in the treatment of neurodegenerative diseases.

Identification and localization of morphological feature-specific metabolites in Reynoutria multiflora roots.

Reynoutria multiflora roots are a classical herbal medicine with unique nourishing therapeutic effects. Anomalous vascular bundle (AVB) forming "cloudy brocade patterns" is a typical morphological feature of R. multiflora roots and has been empirically linked to its quality classification. However, scientific evidence, especially for AVB-specific specialised metabolites, has not been comprehensively revealed thus far. Herein, desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) analysis was applied to carry out an in situ analysis of specialised metabolites distributed specifically at the AVB and cork of R. multiflora roots. To enlarge the scope of compounds by DESI detection, various solvent systems including acetone, acetonitrile, methanol, and water were used to assist in the discoveries of 40 specialised metabolites with determined localization. A series of bioactive constituents including stilbenes, flavonoids, anthraquinones, alkaloids, and naphthalenes were found specifically around the brocade patterns. Notably, phospholipids were detected from R. multiflora roots by in situ analysis for the first time and were found mainly in the phloem of AVB (PAB). This is the first study to use gradient solvent systems in DESI-MSI analysis to locate the specialised metabolites distribution. The discovery of feature-specific compounds will bridge the empirical identification to precision quality control of R. multiflora roots.

The use of progressive addition lenses to improve the daily visual function of children receiving topical atropine treatment.

PURPOSE: To evaluate the changes in visual function when progressive addition lenses (PAL) are added in children using topical atropine as a myopia control therapy. Daily visual complaints and the determination of their near correction were studied. METHODS: Forty children aged 7-12 years were recruited. Distance and near visual acuity, accommodative lag, heterophoria, near point of convergence and stereopsis were examined, and a questionnaire of daily visual complaints was administered. RESULTS: Significant differences in visual functions were found after the near correction was prescribed. Significant improvements in distance and near visual acuity, lag of accommodation and binocular visual function were observed, and fewer visual complaints were reported at the Harmon distance. CONCLUSION: The use of PAL is helpful for children undergoing topical atropine treatment for myopia control, particularly those receiving medium to high doses. This combination therapy could also be applied to younger children who have a low tolerance to contact lenses, with less risk of ocular adverse effects.

The content of PAEs in field soils caused by the residual film has a periodical peak.

The wide use of plastic film mulch has led to the release of phthalate esters (PAEs), which seriously threatens the soil environment and the safety of crop production. However, it is unknown whether there is a maximum threshold of soil PAEs accumulation induced by plastic film residue, and the dynamic changes of soil PAEs under field conditions are still unclear. To address these issues, a field experiment was conducted to investigate the temporal fluctuations of soil PAEs content and the response of microbial community structure in the field with plastic film residue. Results showed that the content of soil PAEs fluctuated during an observation period of one year, had a periodical peak in winter and summer, and was exacerbated by the increase in the aging degree and residual amount of plastic films. The PAEs content in soil with black films was higher than the US soil allowable criteria. High-throughput sequencing analysis showed that the addition of residual film significantly increased the alpha diversity of bacterial communities, changed the structure of bacterial community, and generated significant disturbances in bacterial function. Besides, the residual film recruited more microbiota related to plastic film and PAEs degradation. Results of the present study provide insight into the dynamic variation of soil PAEs caused by plastic film residue in one year, which is important to help evaluate the pollution risk of PAEs on soils and crops caused by residual plastic film.

Epitope spreading in autoimmune bullous diseases / 中华皮肤科杂志

Epitope spreading often occurs in patients with autoimmune bullous diseases (ABDs), resulting in exposure of more antigenic epitopes, aggravation or transformation of pre-existing diseases, or concurrence of other diseases. With the increase in the immunological evidence for epitope spreading, more and more scholars have realized that epitope spreading plays an important role in the development of ABDs. This review introduces the phenomenon of epitope spreading in ABDs from 4 aspects, including the concurrence of or transformation between different types of pemphigoid, different types of pemphigus, pemphigus and pemphigoid, as well as between ABDs and other skin diseases.

Nsp1 proteins of human coronaviruses HCoV-OC43 and SARS-CoV2 inhibit stress granule formation.

Stress granules (SGs) are cytoplasmic condensates that often form as part of the cellular antiviral response. Despite the growing interest in understanding the interplay between SGs and other biological condensates and viral replication, the role of SG formation during coronavirus infection remains poorly understood. Several proteins from different coronaviruses have been shown to suppress SG formation upon overexpression, but there are only a handful of studies analyzing SG formation in coronavirus-infected cells. To better understand SG inhibition by coronaviruses, we analyzed SG formation during infection with the human common cold coronavirus OC43 (HCoV-OC43) and the pandemic SARS-CoV2. We did not observe SG induction in infected cells and both viruses inhibited eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and SG formation induced by exogenous stress. Furthermore, in SARS-CoV2 infected cells we observed a sharp decrease in the levels of SG-nucleating protein G3BP1. Ectopic overexpression of nucleocapsid (N) and non-structural protein 1 (Nsp1) from both HCoV-OC43 and SARS-CoV2 inhibited SG formation. The Nsp1 proteins of both viruses inhibited arsenite-induced eIF2α phosphorylation, and the Nsp1 of SARS-CoV2 alone was sufficient to cause a decrease in G3BP1 levels. This phenotype was dependent on the depletion of cytoplasmic mRNA mediated by Nsp1 and associated with nuclear accumulation of the SG-nucleating protein TIAR. To test the role of G3BP1 in coronavirus replication, we infected cells overexpressing EGFP-tagged G3BP1 with HCoV-OC43 and observed a significant decrease in virus replication compared to control cells expressing EGFP. The antiviral role of G3BP1 and the existence of multiple SG suppression mechanisms that are conserved between HCoV-OC43 and SARS-CoV2 suggest that SG formation may represent an important antiviral host defense that coronaviruses target to ensure efficient replication.

Cyclosporin A Inhibits the Activation of Membrane-Bound Guanylate Cyclase GC-A of Atrial Natriuretic Factor via NAD(P)H Oxidase.

Cyclosporin A (CsA) is a common immunosuppressant wildly used in patients with organ transplant and autoimmune diseases; however, it can cause several adverse effects, such as nephrotoxicity and hypertension. The detailed mechanisms have not been completely understood. Atrial natriuretic factor (ANF) and its receptor (mGC-A) have been shown to play a crucial role in the regulation of blood pressure. Here, we investigated the effects of CsA on the activation of mGC-A in ANF-treated LLC-PK1 cells. In our study, ANF-induced mGC-A activities and superoxide generation in LLC-PK1 cells were measured by guanosine 3',5'-cyclic monophosphate (cGMP) radioimmunoassay and lucigenin-dependent chemiluminescence, respectively. We found that CsA can reduce about 60% of mGC-A activities in ANF-treated LLC-PK1 cells. CsA is known to induce superoxide. Addition of superoxide generators menadione and diamide mimicked the effects of CsA, whereas DPI (a reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase inhibitor) and Tiron (a superoxide quencher) blocked the suppressive effects of CsA on ANF-induced mGC-A activities. We previously showed that the catalytic domain of GC-A (GC-c) expresses guanylate cyclase activities. Addition of menadione, diamide, or peroxynitrite or transfection of Nox-4 NAD(P)H oxidase abolished GC-c activities. In conclusion, CsA inhibits ANF-stimulated mGC-A activities through superoxide and/or peroxynitrite generated by an NAD(P)H oxidase by interacting with the catalytic domain of mGC-A.