Deficiency of Histone Methyltransferase SET Domain-Containing 2 in Liver Leads to Abnormal Lipid Metabolism and HCC.

BACKGROUND AND AIMS: Trimethylation of Lys36 on histone 3 (H3K36me3) catalyzed by histone methyltransferase SET domain-containing 2 (SETD2) is one of the most conserved epigenetic marks from yeast to mammals. SETD2 is frequently mutated in multiple cancers and acts as a tumor suppressor. APPROACH AND RESULTS: Here, using a liver-specific Setd2 depletion model, we found that Setd2 deficiency is sufficient to trigger spontaneous HCC. Meanwhile, Setd2 depletion significantly increased tumor and tumor size of a diethylnitrosamine-induced HCC model. The mechanistic study showed that Setd2 suppresses HCC not only through modulating DNA damage response, but also by regulating lipid metabolism in the liver. Setd2 deficiency down-regulated H3K36me3 enrichment and expression of cholesterol efflux genes and caused lipid accumulation. High-fat diet enhanced lipid accumulation and promoted the development of HCC in Setd2-deficient mice. Chromatin immunoprecipitation sequencing analysis further revealed that Setd2 depletion induced c-Jun/activator protein 1 (AP-1) activation in the liver, which was trigged by accumulated lipid. c-Jun acts as an oncogene in HCC and functions through inhibiting p53 in Setd2-deficient cells. CONCLUSIONS: We revealed the roles of Setd2 in HCC and the underlying mechanisms in regulating cholesterol homeostasis and c-Jun/AP-1 signaling.

Fabrication of Protonated Two-Dimensional Metal-Organic Framework Nanosheets for Highly Efficient Iodine Capture from Water.

Radioactive iodine (129I and 131I), produced or released from nuclear-related activities, posed severe effects on both human health and environment. The efficient removal of radioiodine from aqueous medium and vapor phase is of paramount importance for the sustainable development of nuclear energy. Herein, a metal-organic framework (MOF) nanosheet with a positive charge was constructed for the capture of iodine for the first time. The as-synthesized ultrathin nanosheets, with a thickness of 4.4 ± 0.1 nm, showed a record-high iodine adsorption capacity (3704.08 mg g-1) from aqueous solution, which is even higher than that from the vapor phase (3510.05 mg g-1). It can be ascribed to the fully interactions between the extensive accessible active sites on the largely exposed surface of 2D MOF nanosheets and the target pollutants, which also gave rise to fast adsorption kinetics with relative high removal efficiencies in the low concentrations, even in seawater. Moreover, a facile recyclability with fast desorption kinetics can also be achieved for the MOF nanosheets. The excellent iodine removal performance in aqueous solution demonstrated that the electrostatic attraction between MOF nanosheets with a positive charge and the negatively charged triiodide (I3-, the dominant form of iodine in aqueous solution) is the driving force in adsorption, which endows the adsorbents with the characteristics of fast adsorption and desorption kinetics. The adsorption mechanism was systematically verified by the studies of ζ potential, Fourier transform infrared, X-ray photoelectron spectroscopy, and Raman spectra.

Enhancing bacterial cellulose production with hypoxia-inducible factors.

Komagataeibacter xylinus is an aerobic strain that produces bacterial cellulose (BC). Oxygen levels play a critical role in regulating BC synthesis in K. xylinus, and an increase in oxygen tension generally means a decrease in BC production. Fumarate nitrate reduction protein (FNR) and aerobic respiration control protein A (ArcA) are hypoxia-inducible factors, which can signal whether oxygen is present in the environment. In this study, FNR and ArcA were used to enhance the efficiency of oxygen signaling in K. xylinus, and globally regulate the transcription of the genome to cope with hypoxic conditions, with the goal of improving growth and BC production. FNR and ArcA were individually overexpressed in K. xylinus, and the engineered strains were cultivated under different oxygen tensions to explore how their overexpression affects cellular metabolism and regulation. Although FNR overexpression did not improve BC production, ArcA overexpression increased BC production by 24.0% and 37.5% as compared to the control under oxygen tensions of 15% and 40%, respectively. Transcriptome analysis showed that FNR and ArcA overexpression changed the way K. xylinus coped with oxygen tension changes, and that both FNR and ArcA overexpression enhanced the BC synthesis pathway. The results of this study provide a new perspective on the effect of oxygen signaling on growth and BC production in K. xylinus and suggest a promising strategy for enhancing BC production through metabolic engineering. KEY POINTS: • K. xylinus BC production increased after overexpression of ArcA • The young's modulus is enhanced by the ArcA overexpression • ArcA and FNR overexpression changed how cells coped with changes in oxygen tension.

Tailoring bacterial cellulose structure through CRISPR interference-mediated downregulation of galU in Komagataeibacter xylinus CGMCC 2955.

Diverse applications of bacterial cellulose (BC) have different requirements in terms of its structural characteristics. culturing Komagataeibacter xylinus CGMCC 2955, BC structure changes with alterations in oxygen tension. Here, the K. xylinus CGMCC 2955 transcriptome was analyzed under different oxygen tensions. Transcriptome and genome analysis indicated that BC structure is related to the rate of BC synthesis and cell growth, and galU is an essential gene that controls the carbon metabolic flux between the BC synthesis pathway and the pentose phosphate (PP) pathway. The CRISPR interference (CRISPRi) system was utilized in K. xylinus CGMCC 2955 to control the expression levels of galU. By overexpressing galU and interfering with different sites of galU sequences using CRISPRi, we obtained strains with varying expression levels of galU (3.20-3014.84%). By testing the characteristics of BC, we found that the porosity of BC (range: 62.99-90.66%) was negative with galU expression levels. However, the crystallinity of BC (range: 56.25-85.99%) was positive with galU expression levels; galU expression levels in engineered strains were lower than those in the control strains. Herein, we propose a new method for regulating the structure of BC to provide a theoretical basis for its application in different fields.

TTLL12 Inhibits the Activation of Cellular Antiviral Signaling through Interaction with VISA/MAVS.

Upon virus infection, host cells use retinoic-acid-inducible geneI I (RIG-I)-like receptors to recognize viral RNA and activate type I IFN expression. To investigate the role of protein methylation in the antiviral signaling pathway, we screened all the SET domain-containing proteins and identified TTLL12 as a negative regulator of RIG-I signaling. TTLL12 contains SET and TTL domains, which are predicted to have lysine methyltransferase and tubulin tyrosine ligase activities, respectively. Exogenous expression of TTLL12 represses IFN-ß expression induced by Sendai virus. TTLL12 deficiency by RNA interference and CRISPR-gRNA techniques increases the induced IFN-ß expression and inhibits virus replication in the cell. The global gene expression profiling indicated that TTLL12 specifically inhibits the expression of the downstream genes of innate immunity pathways. Cell fractionation and fluorescent staining indicated that TTLL12 is localized in the cytosol. The mutagenesis study suggested that TTLL12's ability to repress the RIG-I pathway is probably not dependent on protein modifications. Instead, TTLL12 directly interacts with virus-induced signaling adaptor (VISA), TBK1, and IKKε, and inhibits the interactions of VISA with other signaling molecules. Taken together, our findings demonstrate TTLL12 as a negative regulator of RNA-virus-induced type I IFN expression by inhibiting the interaction of VISA with other proteins.

Low birth weight contributed to increased serum IL-6 levels in infantile respiratory syncytial virus infection.

BACKGROUND: To evaluate the role of serum cytokines in the pathogenesis of respiratory syncytial virus (RSV) infection in infants with low birth weight (LBW). METHODS: A prospective observational study was performed, and hospitalized children with lower respiratory tract infection (LRTI) were recruited. Three hundred fifty-eight patients < 1 year met the inclusion criteria: 116 patients had only RSV infection (RSV group); 242 patients had no RSV or other specific pathogen (non-RSV group). Serum interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) were detected through flow cytometry. RESULTS: No significant differences in serum IL-2, 4, 6, 10, and IFN-γ levels were observed between the RSV and non-RSV groups. For RSV infected infants with or without wheezing, delivery mode had no obvious effect on the changes of serum cytokine levels. However, the level of IL-6 in the RSV-infected infants with LBW was significantly higher than that in infants with normal birth weight. CONCLUSIONS: Serum IL-6 level was significantly increased in RSV infected infants with LBW. It is likely that the specific serum cytokine pattern will contribute to our understanding of the pathogenesis of RSV infections, especially in RSV-infected infants with LBW.

Serum cytokine profile contributes to discriminating M. pneumoniae pneumonia in children.

BACKGROUND: To evaluate the role of serum cytokines in discriminating M. pneumoniae infection in children with community-acquired pneumonia (CAP). METHODS: A prospective observational study was conducted. 385 hospitalized patients with CAP had only M. pneumoniae (MP group) infection; 321 hospitalized patients with CAP had no M. pneumoniae and other specific pathogen (control group) infections. Serum interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) were detected by flow cytometry. RESULTS: In children younger than 5years, serum IL-6, TNF-α, and IFN-γ levels from MP group were significantly higher than those from control group. However in children 5-15years, serum IL-6, IL-10, and IFN-γ levels from MP group were significantly higher than those from control group. In the final multivariate logistic regression model for serum cytokine, moderately elevated IL-6, IL-10, and IFN-γ shows a higher prediction of development of M. pneumoniae pneumonia among CAP patients. CONCLUSIONS: A specific cytokine pattern showed a higher prediction of M. pneumoniae pneumonia among CAP patients, further suggesting that serum cytokine pattern might be useful in differentiating infectious causative agents in children.

Understanding the regioselective hydrolysis of ginkgolide B under physiological environment based on generation, detection, identification, and semi-quantification of the hydrolyzed products.

A liquid chromatography-mass spectrometry (LC-MS) method coupled with specialized sample-preparation strategies was developed to investigate the hydrolysis of ginkgolide B (GB) in physiological environments in comparison with that of ginkgolide A (GA). The rapid hydrolysis processes were captured by the direct injection of samples prepared in the volatile buffers. The LC-MS behavior of the hydrolyzed products, including three monocarboxylates and three dicarboxylates, was acquired. The monocarboxylates were identified by fragmentation analysis, and the dicarboxylates were accordingly tentatively identified by reaction sequences. The base-catalyzed hydrolysis of GB and GA was characterized at 4 °C within pH 7.0-10.7. The regioselective reactions on the lactone-C and lactone-F were revealed by thermodynamic studies at pH 6.8 and 7.4. It was revealed that the 1-hydroxyl group on the skeleton of GB blocks the reactivity of the lactone-E. On the basis of these results, a distinctive hydrolysis phenomenon of GB was confirmed in plasma of humans, rats, and dogs as a rapid degradation of the trilactone along with the only production of the lactone-F-hydrolyzed product. This phenomenon is also closely associated with the 1-hydroxyl group, because it was not observed in GA. More interestingly, the underlying mechanism was revealed not to be associated with any typical enzyme-catalyzed process, but to be potentially involved with a selective reaction of the intact or broken lactone-C moiety with endogenous small-molecule reactants in plasma. This in-depth knowledge of the hydrolysis of GB versus GA not only facilitated understanding of their pharmacological mechanisms but also provided potential routes to study the structure-activity relationships of ginkgolides. Graphical Abstract Regioselective hydrolysis of ginkgolide B in pH 7.4 buffers and plasma.

Semi-quantitative determination of monocarboxylate forms of ginkgolide B in plasma by UPLC-MS.

Ginkgolide B (GB) has a unique structure incorporating three γ-lactones that may be hydrolyzed in aquae as carboxylate forms. However, the determinations of them are challenging because there is no way to prepare the standards of any hydrolyzed products of GB in the solid state. In this report, a semi-quantitative method was developed to determine the monocarboxylate forms of GB in plasma. UPLC coupled with selected ion monitoring (SIR) of m/z 423 and m/z 441 were employed to detect the trilactone and monocarboxylates in assistances with the frozen method and the recovered method, which were, respectively, used to stabilize the hydrolyzed states and fully recover the monocarboxylates as the trilactone in samples. Two monocarboxylates were detected in pH 7.4 potassium phosphate buffers (PPB) after incubations, while only one was found in plasma in vitro and in vivo. The identifications of them require further studies. Following the bioanalytical validation of the trilactone, critical issues of the relative responses of the monocarboxylates in contrast to the trilactone, matrix effects, and stabilities were carefully investigated with subtly designed measures. The validation results supported the quantifications of monocarboxylates in PPB or plasma directly by using the corresponding calibration curve of the trilactone. The applications of this method presented a clear disparity between the hydrolysis kinetics of GB in plasma and PPB. Based on the quantification results and method applications, it was concluded that the present method was suitable to study the complex hydrolysis mechanisms of GB in vitro and in vivo.

[Taohong Siwu Decoction regulated functions of endothelial cells and treated arteriosclerosis obliterans: an experimental study].

OBJECTIVE: To discuss the effect of Taohong Siwu Decoction (TSD) in regulating functions of endothelial cells and treating arteriosclerosis obliterans (ASO). METHODS: The ASO model was prepared by using high-fat diet plus intimal injury. They were randomly divided into the model group (n = 10), the normal control group (n = 9), the low dose TSD group (group A, n = 12), the middle dose TSD group (group B, n = 10), and the high dose TSD group (group C, n = 9). Eight weeks after modeling, the limb blood perfusion was observed using laser Doppler flowmetry. The arterial morphology was observed using light microscope and transmission electron microscope. The number of circulating endothelial cells (CECs) was determined using Percoll density gradient centrifugation method. Serum levels of TNF-alpha, IL-1, ET-1, and NO were detected using double antibody sandwich assay of enzyme linked immunosorbent assay (ELISA). RESULTS: The ASO rat model was successfully established. Blood lipids levels significantly increased, the blood perfusion of left hind limbs significantly decreased, the number of CECs in the peripheral blood significantly increased, the arterial lumen was irregularly narrowed, the ultra-structure of vessel walls was damaged, serum levels of TNF-alpha, IL-1, and ET-1 significantly increased, and the serum level of NO significantly decreased in the model group, showing statistical difference when compared with the normal control group (P < 0.01). Compared with the model group, significant improvement in the aforesaid indices was shown in group B and C (P < 0.05, P < 0.01). CONCLUSIONS: The injury and abnormal functions of endothelial cells is an important pathological process of ASO. As an effective recipe for treating ASO, TSD could protect vascular endothelial cells and improve the secretion function of vascular endothelial cells.

Advancements in endoscopic hemostasis for non-variceal upper gastrointestinal bleeding.

Non-variceal upper gastrointestinal (GI) bleeding is a significant cause of morbidity and mortality. Traditionally, through-the-scope (TTS) clips, thermal therapy, and injection therapies are used to treat GI bleeding. In this review, we provide an overview of novel endoscopic treatments that can be used to achieve hemostasis. Specifically, we discuss the efficacy and applicability of over-the-scope clips, hemostatic agents, TTS doppler ultrasound, and endoscopic ultrasound, each of which offer an effective method of reducing rates of GI rebleeding.

Successful Treatment of Rituximab-Induced Crohn's Disease With Ustekinumab.

Autoimmune optic papillitis is a rare disorder that causes progressive visual loss, often treated with rituximab (RTX). However, its use is not without risks. Here, we present a 51-year-old man who experienced vision loss because of autoimmune optic papillitis, which was well-controlled with RTX. Four years later, the patient developed abdominal pain and diarrhea and was found to have RTX-induced Crohn's disease (CD). The patient failed treatment with azathioprine, but was subsequently able to achieve clinical and endoscopic remission of his CD with ustekinumab, while continuing RTX therapy for autoimmune optic papillitis. This case report describes the efficacy of the anti-interleukin 12/23 monoclonal antibody in inducing remission of RTX-induced CD.

Lymphocytic Colitis With Enterocolic Lymphocytic Phlebitis.

Enterocolic lymphocytic phlebitis is a rare lymphocytic vasculitis afflicting the gastrointestinal veins without involving the arterial system. Lymphocytic colitis is a more common pathology described as lymphocytic inflammation of the colonic epithelium. Concurrence of both these pathologies is extremely rare. We describe a 53-year-old man presenting with chronic watery diarrhea, abdominal pain, and weight loss. Colonoscopic examination revealed normal-appearing mucosa, but biopsy findings revealed lymphocytic colitis with coexisting enterocolic lymphocytic phlebitis. The patient was started on oral budesonide and responded to the treatment with symptomatic and histopathological resolution.

[Screening for EXT1 and EXT2 gene mutations in a ethnic Han Chinese family from Shanxi with hereditary multiple exostoses].

OBJECTIVE: To screen for potential mutations in an ethnic Han Chinese family from Shanxi with hereditary multiple exostoses. METHODS: Polymerase chain reaction and DNA sequencing were used to screen potential mutations in EXT1 and EXT2 genes. RESULTS: For EXT1 gene, two synonymous mutations (P477P and E587E), three intronic mutations (c.1537 -48A>G, c.1721 +203A>G and c.1722 -103C>G) were detected. For EXT2 gene, five intronic mutations (c.-29 -148A>T, c.1080 -18T>A, c.1336 -93C>T, c.1526 -166C>T, and c.1526 -195C>T) were identified. Among these, EXT1 P477P, EXT1 E587E and EXT2 c.1080 -18T>A are polymorphisms listed by Multiple Osteochondroma Mutation Database, whilst the other 7 sites have not been reported. CONCLUSION: No mutations have been found among all exons of the EXT1 and EXT2 genes in this family. Linkage analysis is necessary for identifying the cause of this disease.

[The clinical outcomes of idiopathic optic neuritis with no light perception in 21 eyes].

OBJECTIVE: To evaluate the treatment outcomes of idiopathic optic neuritis with no light perception in 21 eyes. METHODS: This is a retrospective study. The hospital data of 17 patients (21 eyes) with idiopathic optic neuritis whose visual acuity were no light perception from August 2003 to April 2011 were retrospectively analyzed. These patients were treated with steroid pulse and other drugs. The clinical features, the time of appearance light perception, the best corrected visual acuity and VEP were measured. The follow-up was at least three months. RESULTS: Before the treatment, the average time of occurring no light perception were 1.0 ∼ 90.0 days, except 1 eye was 90.0 days while the other 20 eyes was (12.5 ± 10.6) days. After the treatment, vision improved in 14 eyes (66.7%) from Hand Move/30 cm to 20/20, the average time of appearance light perception was (9.9 ± 7.9) days. The best corrected vision acuity were 1 eye Hand Move, 2 eyes Finger Count, 1 eye 20/2000, 3 eyes 20/1000, 2 eyes 20/800, 1 eye 20/500, 1 eye 20/320, 1 eye 20/125, 1 eye 20/32, 1 eye 20/20. 5 eyes with no VEP wave pattern emerge P(100) after therapy, the other 2 eyes which had P(100) was flatten after therapy. The follow-up found that except 1 eye vision improve outside, the rest eye vision remained stable. CONCLUSIONS: The patients with optic neuritis who initially were no light perception should be treated promptly. The prognostic of vision can not be evaluated only by the duration time of no light perception, the appearing-time of light perception and the pattern of VEP.

[Study on the chemical constituents from the leaf of Hydnocarpus hainanensis].

OBJECTIVE: To study the chemical constituents from the leaf of Hydnocarpus hainanensis. METHODS: Compounds were isolated and purified by silica gel and Sephadex LH-20 column chromatography, their structures were identified by spectroscopic analysis. RESULTS: Nine compounds were isolated and identified as glutinol (I), fernenol (II), lupeol (III), a-armyrin (IV), 2, 9-dimethyldeca-2, 8-diene (V), phytenal (VI), phytol (VII), 3, 7, 11,15-tetramethylhexadecane-1,2-diol ( VI), 3, 5-dimethoxy-4-hydroxybenzaldehyde (IX). CONCLUSION: All the compounds are isolated from this plant for the first time.

Macular hole following phakic intraocular lens implantation: A case report.

BACKGROUND: Phakic intraocular lens (pIOL) implantation has been commonly prescribed and is considered as a safe and effective option for correcting high myopia. However, it is associated with multiple complications. CASE SUMMARY: This report describes a case of full-thickness macular hole (MH) in a patient with a history of bilateral pIOL implantation for the correction of myopia of -12.00 diopters in both eyes 7 mo ago. The MH closed after pars plana vitrectomy with internal limiting membrane removal and the best-corrected visual acuity improved to 20/40 in the left eye. CONCLUSION: In rare cases, MH can occur following pIOL. In this present case report, we analyzed the formation process of MH following the surgery and emphasized that it is important to inform highly myopic patients about the risk of MH occurrence while being aware of the symptoms of this complication.

Sesquiterpene and norsesquiterpene derivatives from Sanicula lamelligera and their biological evaluation.

Fourteen sesquiterpene and norsesquiterpene derivatives, comprising six different carbon skeletons, were isolated from Sanicula lamelligera. Saniculamoid A1 (1a) is an oxidation product of saniculamoid A (1), created by the transition of a formyl group to a carboxylic acid group after a period of storage in air. The known compounds 5-14 were identified in Sanicula plants for the first time. The compounds were evaluated for their anti-HIV-1, cytostatic, and nitric-oxide-production-inhibiting activities using in vitro cellular assays. The results showed that 1,5-naphthalenediol inhibited nitric oxide production in lipopolysaccharide-stimulated RAW 264.7 cells with an IC50 value of 28.1 µM and was active toward five cancer cell lines with IC50 values in the 31.1-41.6 µM range.

Arousing Electrochemiluminescence Out of Non-Electroluminescent Monomers within Covalent Organic Frameworks.

Covalent organic frameworks (COFs) with stable long-range ordered arrangements are promising materials for organic optoelectronics. However, their electrochemiluminescence (ECL) from non-ECL active monomers has not been realized. Here, we report a design strategy for ECL-emitting COF family. The donors and acceptors co-crystallized and stacked into the highly aligned array of olefin-linked COFs, so that electrons can be transported freely. By this means, a tunable ECL is activated from non-ECL molecules with the maximum efficiency of 32.1% in water with the dissolved oxygen as an inner coreactant, and no additional noxious co-reactant is needed any more. Quantum chemistry calculations further demonstrate that this design reduces the COFs' band gaps and the overlap of electrons and holes in the excited state for better photoelectric properties and stronger ECL signals. This work exploits a basis to envisage the broad application potential of ECL-COFs for various biosensors and light-emitting display.