Serositis and lymphopenia are common features of systemic lupus erythematosus following SARS-CoV-2 infection: A case report and literature review.

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can affect a number of human systems, including the respiratory, cardiovascular, neurological, gastrointestinal, and musculoskeletal systems. These symptoms persist long after the acute infection has healed and is called "long COVID". Interestingly, there have been a series of reports that SARS-CoV-2 infections trigger the development of various autoimmune diseases such as systemic lupus erythematosus (SLE), inflammatory arthritis, myositis, vasculitis. Here, we report a novel case of SLE characterized by persistent pleural effusion and lymphopenia following SARS-CoV-2 infection. This is the first case in the Western Pacific region to our knowledge. Furthermore, we reviewed 10 similar cases including our case. By looking at the characteristics of each case, we found that serositis and lymphopenia are common features of SLE following SARS-CoV-2 infection. Our finding suggests that patients with prolonged pleural effusion and/or lymphopenia after COVID-19 should be checked for autoantibodies.

Superior mesenteric vein thrombosis and osteoporotic vertebral fractures.

Superior mesenteric vein (SMV) thrombosis is relatively rare disease with unspecific symptoms. Thrombus formation within the SMV eventually leads to congestive intestinal necrosis. In most cases, the lack of specific symptoms makes early diagnosis difficult. Therefore, it is important to suspect the disease and actively investigate it, given a causative factor. Here, we report a case of SMV thrombosis with a novel predisposing factor, compression of SMV by deformed spine, found on contrast medium-enhanced computed tomography. Treatment with intravenous heparin followed by oral anticoagulants resulted in favorable outcome. This is the first picture showing the novel mechanism of SMV thrombus formation relating to spinal deformity. Treating osteoporosis before spinal deformity could prevent SMV thrombosis with such a mechanism.

IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome.

Cytokine release syndrome (CRS) is a life-threatening complication induced by systemic inflammatory responses to infections, including bacteria and chimeric antigen receptor T cell therapy. There are currently no immunotherapies with proven clinical efficacy and understanding of the molecular mechanisms of CRS pathogenesis is limited. Here, we found that patients diagnosed with CRS from sepsis, acute respiratory distress syndrome (ARDS), or burns showed common manifestations: strikingly elevated levels of the four proinflammatory cytokines interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), and IL-10 and the coagulation cascade activator plasminogen activator inhibitor-1 (PAI-1). Our in vitro data indicate that endothelial IL-6 trans-signaling formed an inflammation circuit for robust IL-6, IL-8, and MCP-1 production and promoted PAI-1 production; additionally, an IL-6 signaling blockade by the human monoclonal antibody tocilizumab blunted endothelial cell activation. Plasma from severe COVID-19 patients similarly exhibited increased IL-6, IL-10, and MCP-1 levels, but these levels were not as high as those in patients with CRS from other causes. In contrast, the PAI-1 levels in COVID-19 patients were as highly elevated as those in patients with bacterial sepsis or ARDS. Tocilizumab treatment decreased the PAI-1 levels and alleviated critical illness in severe COVID-19 patients. Our findings suggest that distinct levels of cytokine production are associated with CRS induced by bacterial infection and COVID-19, but both CRS types are accompanied by endotheliopathy through IL-6 trans-signaling. Thus, the present study highlights the crucial role of IL-6 signaling in endothelial dysfunction during bacterial infection and COVID-19.

Semaphorin 6D reverse signaling controls macrophage lipid metabolism and anti-inflammatory polarization.

Polarization of macrophages into pro-inflammatory or anti-inflammatory states has distinct metabolic requirements, with mechanistic target of rapamycin (mTOR) kinase signaling playing a critical role. However, it remains unclear how mTOR regulates metabolic status to promote polarization of these cells. Here we show that an mTOR-Semaphorin 6D (Sema6D)-Peroxisome proliferator receptor γ (PPARγ) axis plays critical roles in macrophage polarization. Inhibition of mTOR or loss of Sema6D blocked anti-inflammatory macrophage polarization, concomitant with severe impairments in PPARγ expression, uptake of fatty acids, and lipid metabolic reprogramming. Macrophage expression of the receptor Plexin-A4 is responsible for Sema6D-mediated anti-inflammatory polarization. We found that a tyrosine kinase, c-Abl, which associates with the cytoplasmic region of Sema6D, is required for PPARγ expression. Furthermore, Sema6D is important for generation of intestinal resident CX3CR1hi macrophages and prevents development of colitis. Collectively, these findings highlight crucial roles for Sema6D reverse signaling in macrophage polarization, coupling immunity, and metabolism via PPARγ.

Electronic, heat-not-burn, and combustible cigarette use among chronic disease patients in Japan: A cross-sectional study.

INTRODUCTION: Although tobacco smoking adversely affects health, many people continue to smoke while suffering from chronic disease. Few studies have examined electronic and heat-not-burn cigarette use among chronic disease patients. Our objective was to investigate electronic, heat-not-burn and combustible cigarette use among chronic disease patients with hypertension, diabetes, cerebrovascular disease, COPD (chronic obstructive pulmonary disease), asthma, atopic dermatitis, cancer, or mental disorders. METHODS: We analyzed 4432 eligible respondents aged 40-69 years from a 2015 internet survey (randomly sampled research agency panelists) with a propensity score weighting adjustment for 'being a respondent in an internet survey' in Japan. The outcome measure was the prevalence of electronic, heat-not-burn, and combustible cigarette use. Intention to quit was also calculated. RESULTS: In all, 32.1% (n=80) of male patients with more than two diseases and 10.3% (n=16) of female patients were current smokers. Of the patients who had no intention to quit smoking, 15.5% were male patients with atopic dermatitis and 63.7% with mental disorders. Of the men, 7.7% without any diseases had ever used e-cigarettes, while 7.7% and 6.4% of men with one disease or more than two diseases, respectively, had ever used e-cigarettes. Of the women, 3.5% without any diseases had ever used e-cigarettes, while 2.1% and 2.9% of women with one disease or more than two diseases, respectively, had ever used e-cigarettes. Percentage of heat-not-burn tobacco current or ever use was low (<0.1%) among both men and women. CONCLUSIONS: Differences in the use of electronic and combustible cigarettes according to the number of diseases were not obvious. However, sex differences for smoking among chronic disease patients, especially in atopic dermatitis and mental disorders, were found.

Live cell off-target identification of lapatinib using ligand-directed tosyl chemistry.

We demonstrate that ligand-directed tosyl (LDT) chemistry is applicable to off-target identification in live cells. Lapatinib (Lap)-based LDT reagents not only labeled a receptor tyrosine kinase, HER2, target protein, but also the protein disulfide isomerase (PDI) that should be an off-target protein for Lap.

Fluorophore labeling of native FKBP12 by ligand-directed tosyl chemistry allows detection of its molecular interactions in vitro and in living cells.

Introducing synthetic fluorophores into specific endogenous proteins and analyzing their function in living cells are a great challenge in chemical biology. Toward this end, we demonstrate the target-selective and site-specific fluorescent labeling of native FKBP12 (FK506-binding protein 12) in vitro and in living cells using ligand-directed tosyl (LDT) chemistry. The LDT-mediated labeling yielded a semisynthetic FKBP12 containing the Oregon green (OG) dye near the catalytic pocket. The OG-labeled FKBP12 (OG-FKBP12) acted as a fluorescent reporter that allows monitoring of its interaction with rapamycin and FRB (FKBP-rapamycin-binding domain) in vitro. We also successfully demonstrated the visualization of the rapamycin-mediated complexation of the OG-FKBP12 and FRB inside of living cells by the combined use with fluorescent protein-tag technology and Förster resonance energy-transfer imaging.

Quantitative comparison of protein dynamics in live cells and in vitro by in-cell (19)F-NMR.

Here we describe how a (19)F-probe incorporated into an endogenous protein by a chemical biology method revealed protein dynamics. By explicit determination of ligand-bound and unbound structures with X-ray crystallography, the quantitative comparison of the protein's dynamics in live cells and in vitro is presented. These results clearly demonstrated the greater conformational fluctuations of the intracellular protein, partially due to macromolecular crowding effects.