Objective: To survey the health-related quality of life (HRQoL) and its influencing factors among patients with COVID-19 in their first medical follow up. Methods: All patients diagnosed with COVID-19 were discharged from 12 hospitals in Wenzhou, Zhejiang from Jan 17, 2020 to Mar 20, 2020. Prospectively collected and analyzed data included demographics, clinical symptoms, comorbidity, and chest CT imaging features at the first follow up, 1 month after discharge. All patients underwent the HRQoL evaluation with the Chinese version of Short-Form 36-item questionnaire (SF-36) as well as a general condition questionnaire. Factors associated with SF-36 were constructed using linear regression. Predictors of impaired physical component summary (PCS) and a mental component summary (MCS) were identified by logistic regression. Results: SF-36 demonstrated a significant difference in HRQoL in patients with COVID-19, except in physical function (PF), when compared to the general Chinese population (p<0.05). The multiple linear regressions demonstrated that age was negatively associated with PF, role physical (RP), but positively associated with vitality (VT) (p<0.05). PF, bodily pain (BP), and role-emotional (RE) were negatively associated with the female sex (p<0.05). For mental health, the clinical subtypes were significant associated factors (p < 0.05). Length of stay (LOS) was strongly negatively associated with RE and RP, and positively associated with VT (p< 0.05). Logistical regression revealed that non-obese overweight (OR 3.71) and obesity (OR 3.94) were risk factors for a low PCS and female sex (OR 2.22) was a risk factor for a low MCS. Conclusions: Health-related quality of life was poor among COVID-19 patients at the 1 month follow-up. Patients suffered from significant physical and psychological impairment. Therefore, prospective monitoring of individuals exposed to SARS-CoV-2 is needed in order to fully understand the long-term impact of COVID-19, as well as to inform prompt and efficient interventions to alleviate suffering.

Sp1-like proteins are defined by three highly homologous C 2 H 2 zinc finger motifs that bind GC-rich sequences found in the promoters of a large number of genes essential for mammalian cell homeostasis. Here we report that TIEG2, a transforming growth factor ␤-inducible Sp1-like protein with antiproliferative functions, represses transcription through recruitment of the mSin3A-histone deacetylase complex. The interaction of TIEG2 with mSin3A is mediated by an alpha-helical repression motif (␣-HRM) located within the repression domain (R1) of TIEG2. This ␣-HRM specifically associates with the second paired amphipathic helix (PAH2) domain of mSin3A. Mutations in the TIEG2 ␣-HRM domain that disrupt its helical structure abolish its ability to both bind mSin3A and repress transcription. Interestingly, the ␣-HRM is conserved in both the TIEG (TIEG1 and TIEG2) and BTEB (BTEB1, BTEB3, and BTEB4) subfamilies of Sp1-like proteins. The ␣-HRM from these proteins also mediates direct interaction with mSin3A and represses transcription. Surprisingly, we found that the ␣-HRM of the Sp1-like proteins characterized here exhibits structural and functional resemblance to the Sin3A-interacting domain previously described for the basic helix-loop-helix protein Mad1. Thus, our study defines a mechanism of transcriptional repression via the interactions of the ␣-HRM with the Sin3-histone deacetylase complex that is utilized by at least five Sp1-like transcriptional factors. More importantly, we demonstrate that a helical repression motif which mediates Sin3 interaction is not an exclusive structural and functional characteristic of the Mad1 subfamily but rather has a wider functional impact on transcriptional repression than previously demonstrated.The Sp1-like family of transcription factors is characterized by the presence of three highly homologous C-terminal zinc finger motifs that are capable of binding GC-rich DNA sequences. These GC-rich motifs are present in the promoters of more than a thousand different gene products (10,17,21,23). Currently, the Sp1-like proteins identified contain at least 16 members that can be classified into several subgroups, including Sp (Sp1, Sp2, Sp3, and Sp4), BTEB (BTEB1), KLF (BKLF, BKLF3, EKLF, GKLF, BTEB2/IKLF, and LKLF), CPBP (CPBP and UKLF), TIEG (TIEG1 and TIEG2), and Ap-2rep. The detailed nomenclature and classification of these proteins can be found in several recent reviews (7,8,26,34). Several new members, including BTEB3 (J. Kaczynski et al., unpublished data), BTEB4 (A. Conley et al., unpublished data), Sp5 (14), and SP6/KLF14 (27), have recently been added to this growing family of proteins. Because many of the genes essential for the regulation of cell growth (6, 18, 28, 30), differentiation (2, 9), and apoptosis (21, 32) contain Sp1-like binding sites, it is not surprising that members of the Sp1 family are important regulators of mammalian cell homeostasis. Additionally, Sp1-like proteins are critical for normal development. Studies with animal models have shown that disruption o...

The Hippo pathway is crucial in organ size control and tissue homeostasis, with deregulation leading to cancer. An extracellular nutrition signal, such as glucose, regulates the Hippo pathway activation. However, the mechanisms are still not clear. Here, we found that the Hippo pathway is directly regulated by the hexosamine biosynthesis pathway (HBP) in response to metabolic nutrients. Mechanistically, the core component of Hippo pathway (YAP) is O-GlcNAcylated by O-GlcNAc transferase (OGT) at serine 109. YAP O-GlcNAcylation disrupts its interaction with upstream kinase LATS1, prevents its phosphorylation, and activates its transcriptional activity. And this activation is not dependent on AMPK. We also identified OGT as a YAP-regulated gene that forms a feedback loop. Finally, we confirmed that glucose-induced YAP O-GlcNAcylation and activation promoted tumorigenesis. Together, our data establish a molecular mechanism and functional significance of the HBP in directly linking extracellular glucose signal to the Hippo-YAP pathway and tumorigenesis.

Macroautophagy is an evolutionarily conserved cellular process involved in the clearance of proteins and organelles. Although the cytoplasmic machinery that orchestrates autophagy induction during starvation, hypoxia, or receptor stimulation has been widely studied, the key epigenetic events that initiate and maintain the autophagy process remain unknown. Here we show that the methyltransferase G9a coordinates the transcriptional activation of key regulators of autophagosome formation by remodeling the chromatin landscape. Pharmacological inhibition or RNA interference (RNAi)-mediated suppression of G9a induces LC3B expression and lipidation that is dependent on RNA synthesis, protein translation, and the methyltransferase activity of G9a. Under normal conditions, G9a associates with the LC3B, WIPI1, and DOR gene promoters, epigenetically repressing them. However, G9a and G9a-repressive histone marks are removed during starvation and receptor-stimulated activation of naive T cells, two physiological inducers of macroautophagy. Moreover, we show that the c-Jun N-terminal kinase (JNK) pathway is involved in the regulation of autophagy gene expression during naive-T-cell activation. Together, these findings reveal that G9a directly represses genes known to participate in the autophagic process and that inhibition of G9a-mediated epigenetic repression represents an important regulatory mechanism during autophagy.A utophagy is an evolutionarily conserved catabolic process in eukaryotes that involves lysosomal degradation of cellular components, including long-lived proteins and organelles. There are four main forms of autophagy: macroautophagy (referred to here as autophagy), selective autophagy, microautophagy, and chaperone-mediated autophagy (1-4). Autophagy serves as an adaptive response to protect cells or organisms during periods of cellular stress, such as nutrient deprivation. In addition, autophagy can participate in several cellular and developmental processes, including homeostasis, clearance of intracellular pathogens, and immunity (1). Due to its fundamental importance for cellular survival, autophagy regulation has been implicated in several human diseases, such as cancer and neurodegenerative disorders (2, 5).Autophagy initiation involves the de novo synthesis of a double-membrane structure known as the phagophore, which ultimately elongates and closes to sequester cytoplasmic proteins and organelles, forming the autophagosome. The autophagosome subsequently undergoes a stepwise maturation process that culminates in its fusion with acidified endosomal/lysosomal vesicles, resulting in the degradation of its contents into useful biomolecules (2). A screen of yeast mutants unable to survive under nitrogen deprivation characterized a network of autophagy-related (ATG) genes (6). Mammalian homologues of these ATGs were later identified and shown to participate during distinct steps of autophagy. For example, microtubule-associated protein light chain 3 (LC3B) undergoes lipidation and is recruited to the pha...

Idiopathic pulmonary fibrosis (IPF) is a fatal disease in which the intricate alveolar network of the lung is progressively replaced by fibrotic scars. Myofibroblasts are the effector cells that excessively deposit extracellular matrix proteins thus compromising lung structure and function. Emerging literature suggests a correlation between fibrosis and metabolic alterations in IPF. In this study, we show that the first-line antidiabetic drug metformin exerts potent antifibrotic effects in the lung by modulating metabolic pathways, inhibiting TGFβ1 action, suppressing collagen formation, activating PPARγ signaling and inducing lipogenic differentiation in lung fibroblasts derived from IPF patients. Using genetic lineage tracing in a murine model of lung fibrosis, we show that metformin alters the fate of myofibroblasts and accelerates fibrosis resolution by inducing myofibroblast-to-lipofibroblast transdifferentiation. Detailed pathway analysis revealed a two-arm mechanism by which metformin accelerates fibrosis resolution. Our data report an antifibrotic role for metformin in the lung, thus warranting further therapeutic evaluation.

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Summary Idiopathic pulmonary fibrosis is a common form of interstitial lung disease resulting in alveolar remodeling and progressive loss of pulmonary function because of chronic alveolar injury and failure to regenerate the respiratory epithelium. Histologically, fibrotic lesions and honeycomb structures expressing atypical proximal airway epithelial markers replace alveolar structures, the latter normally lined by alveolar type 1 (AT1) and AT2 cells. Bronchial epithelial stem cells (BESCs) can give rise to AT2 and AT1 cells or honeycomb cysts following bleomycin-mediated lung injury. However, little is known about what controls this binary decision or whether this decision can be reversed. Here we report that inactivation of Fgfr2b in BESCs impairs their contribution to both alveolar epithelial regeneration and honeycomb cysts after bleomycin injury. By contrast overexpression of Fgf10 in BESCs enhances fibrosis resolution by favoring the more desirable outcome of alveolar epithelial regeneration over the development of pathologic honeycomb cysts.

BACKGROUND & AIMS Transcriptional silencing of the p15INK4b tumor suppressor pathway overcomes cellular protection against unrestrained proliferation in cancer. Here we show a novel pathway involving the oncogenic transcription factor nuclear factor of activated T cells (NFAT) c2 targeting a p15INK4b-mediated failsafe mechanism to promote pancreatic cancer tumor growth. METHODS Immunohistochemistry, real-time polymerase chain reaction, immunoblotting, and immunofluorescence microscopy were used for expression studies. Cancer growth was assessed in vitro by [3H]thymidine incorporation, colony formation assays, and in vivo using xenograft tumor models. Protein-protein interactions, promoter regulation, and local histone modifications were analyzed by immunoprecipitation, DNA pull-down, reporter, and chromatin immunoprecipitation assays. RESULTS Our study uncovered induction of NFATc2 in late-stage pancreatic intraepithelial neoplasia lesions with increased expression in tumor cell nuclei of advanced cancers. In the nucleus, NFATc2 targets the p15INK4b promoter for inducible heterochromatin formation and silencing. NFATc2 binding to its cognate promoter site induces stepwise recruitment of the histone methyltransferase Suv39H1, causes local H3K9 trimethylation, and allows docking of heterochromatin protein HP1γ to the repressor complex. Conversely, inactivation of NFATc2 disrupts this repressor complex assembly and local heterochromatin formation, resulting in restoration of p15INK4b expression and inhibition of pancreatic cancer growth in vitro and in vivo. CONCLUSIONS Here we describe a novel mechanism for NFATc2-mediated gene regulation and identify a functional link among its repressor activity, the silencing of the suppressor pathway p15INK4b, and its pancreatic cancer growth regulatory functions. Thus, we provide evidence that inactivation of oncogenic NFATc2 might be an attractive strategy in treatment of pancreatic cancer.