Background and aims We aim to assess the safety and immunogenicity of inactivated whole-virion SARS-CoV-2 vaccines in patients with chronic liver diseases (CLD) in this study. Methods This was a prospective, multi-center, open-label study. Participants aged over 18 years with confirmed CLD and healthy volunteers were enrolled. All participants received 2 doses of inactivated whole-virion SARS-CoV-2 vaccines. Adverse reactions were recorded within 14 days after any dose of SARS-CoV-2 vaccine, laboratory testing results were collected after the second dose, and serum samples of enrolled subjects were collected and tested for SARS-CoV-2 neutralizing antibodies at least 14 days after the second dose. Results A total of 581 participants (437 patients with CLD and 144 healthy volunteers) were enrolled from 15 sites in China. Most adverse reactions were mild and transient, and injection site pain (36 [8.2%]) was the most frequently reported adverse event. Three participants had Grade 3 aminopherase elevation (defined as alanine aminopherase>5 upper limits of normal) after the second dose of inactivated whole-virion SARS-CoV-2 vaccination, and only one of them was judged as severe adverse event potentially related to SARS-CoV-2 vaccination. The positive rates of SARS-CoV-2 neutralizing antibodies were 76.8% in non-cirrhotic CLD group, 78.9% in compensated cirrhotic group, 76.7% in decompensated cirrhotic group (P=0.894 among CLD subgroups) and 90.3% in healthy controls (P=0.008 versus CLD group). Conclusion Inactivated whole-virion SARS-CoV-2 vaccines are safe in patients with CLD. Patients with CLD had lower immunological response to SARS-CoV-2 vaccines than healthy population. The immunogenicity is similarly low in non-cirrhotic CLD, compensated cirrhosis and decompensated cirrhosis.

Dynamic and reciprocal epithelial-mesenchymal interactions are critical for the normal morphogenesis and maintenance of epithelia. Epimorphin has been identified as a unique molecule expressed by mesenchymal cells and myofibroblasts and has putative morphogenetic effects in multiple epithelial tissues, including intestine, skin, mammary gland, lung, gallbladder, and liver. To define the in vivo role of epimorphin, we created epimorphin-null mice by targeted inactivation of the epimorphin gene. Male epimorphin-/- mice are sterile due to abnormal testicular development and impaired spermatogenesis. Intestinal growth is increased in epimorphin-/- mice due to augmented crypt cell proliferation and crypt fission during the neonatal (suckling) period, mediated at least in part by changes in bone morphogenetic protein (Bmp) and Wnt/beta-catenin signaling pathways. Colonic mucosal injury and colitis induced by dextran sodium sulfate (DSS) are ameliorated in epimorphin-/- mice, probably due to the increased proliferative capacity of the epimorphin-/- colon. These in vivo findings support the notion that epimorphin is a key stromal regulator of epithelial cell proliferation and growth in the intestine. In addition, our studies demonstrate a novel and critical role for epimorphin in regulating testicular development and growth as well as spermatogenesis.

Epithelial-mesenchymal interactions regulate normal gut epithelial homeostasis and have a putative role in inflammatory bowel disease and colon cancer pathogenesis. Epimorphin is a mesenchymal and myofibroblast protein with antiproliferative, promorphogenic effects in intestinal epithelium. We previously showed that deletion of epimorphin partially protects mice from acute colitis, associated with an increase in crypt cell proliferation. Here we explored the potential therapeutic utility of modulating epimorphin expression by examining the effects of epimorphin deletion on chronic inflammation-associated colon carcinogenesis using the azoxymethane/dextran sodium sulfate (AOM/DSS) model. We found that mice in which epimorphin expression was absent had a marked reduction in incidence and extent of colonic dysplasia. Furthermore, epimorphin deletion in myofibroblasts altered the morphology and growth of cocultured epithelial cells. Loss of epimorphin affected secretion of soluble mesenchymal regulators of the stem cell niche such as Chordin. Importantly, IL-6 secretion from LPS-treated epimorphin-deficient myofibroblasts was completely inhibited, and stromal IL-6 expression was reduced in vivo. Taken together, these data show that epimorphin deletion inhibits chronic inflammation-associated colon carcinogenesis in mice, likely as a result of increased epithelial repair, decreased myofibroblast IL-6 secretion, and diminished IL-6-induced inflammation. Furthermore, we believe that modulation of epimorphin expression may have therapeutic benefits in appropriate clinical settings.

Previous studies have shown that AgRP neurons in the arcuate nucleus (ARC) respond to energy deficits and play a key role in the control of feeding behavior and metabolism. Here, we demonstrate that chronic unpredictable stress, an animal model of depression, decreases spontaneous firing rates, increases firing irregularity and alters the firing properties of AgRP neurons in both male and female mice. These changes are associated with enhanced inhibitory synaptic transmission and reduced intrinsic neuronal excitability. Chemogenetic inhibition of AgRP neurons increases susceptibility to subthreshold unpredictable stress. Conversely, chemogenetic activation of AgRP neurons completely reverses anhedonic and despair behaviors induced by chronic unpredictable stress. These results indicate that chronic stress induces maladaptive synaptic and intrinsic plasticity, leading to hypoactivity of AgRP neurons and subsequently causing behavioral changes. Our findings suggest that AgRP neurons in the ARC are a key component of neural circuitry involved in mediating depression-related behaviors and that increasing AgRP neuronal activity coule be a novel and effective treatment for depression.