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Supplementary Data from TNFRSF19 Inhibits TGFβ Signaling through Interaction with TGFβ Receptor Type I to Promote Tumorigenesis

Genetic susceptibility underlies the pathogenesis of cancer. We and others have previously identified a novel susceptibility gene TNFRSF19, which encodes an orphan member of the TNF receptor superfamily known to be associated with nasopharyngeal carcinoma (NPC) and lung cancer risk. Here, we show that TNFRSF19 is highly expressed in NPC and is required for cell proliferation and NPC development. However, unlike most of the TNF receptors, TNFRSF19 was not involved in NFκB activation or associated with TRAF proteins. We identified TGFβ receptor type I (TβRI) as a specific binding partner for TNFRSF19. TNFRSF19 bound the kinase domain of TβRI in the cytoplasm, thereby blocking Smad2/3 association with TβRI and subsequent signal transduction. Ectopic expression of TNFRSF19 in normal epithelial cells conferred resistance to the cell-cycle block induced by TGFβ, whereas knockout of TNFRSF19 in NPC cells unleashed a potent TGFβ response characterized by upregulation of Smad2/3 phosphorylation and TGFβ target gene transcription. Furthermore, elevated TNFRSF19 expression correlated with reduced TGFβ activity and poor prognosis in patients with NPC. Our data reveal that gain of function of TNFRSF19 in NPC represents a mechanism by which tumor cells evade the growth-inhibitory action of TGFβ.Significance:TNFRSF19, a susceptibility gene for nasopharyngeal carcinoma and other cancers, functions as a potent inhibitor of the TGFβ signaling pathway.Graphical Abstract:http://cancerres.aacrjournals.org/content/canres/78/13/3469/F1.large.jpg. Cancer Res; 78(13); 3469–83. ©2018 AACR.

Supplementary Figure S4 from TNFRSF19 Inhibits TGFβ Signaling through Interaction with TGFβ Receptor Type I to Promote Tumorigenesis

Supplementary Table S1 from TNFRSF19 Inhibits TGFβ Signaling through Interaction with TGFβ Receptor Type I to Promote Tumorigenesis

During the outbreak of COVID-19 in Wuhan in 2020, we conducted a nationwide survey of 8170 respondents from 31 provinces/municipalities in China via Sojump to examine the relationship between the distance to respondents’ city of residence from Wuhan and their safety concerns and risk perception of the epidemic that occurred in Wuhan City. We found that (1) the farther (psychologically or physically) people were from Wuhan, the more concerned they were with the safety of the epidemic risk in Wuhan, which we dubbed the psychological typhoon eye (PTE) effect on responses to the outbreak of COVID-19; (2) agenda setting can provide a principled account for such effect: the risk information proportion mediated the PTE effect. The theoretical and managerial implications for the PTE effect and public opinion disposal were discussed, and agenda setting was identified to be responsible for the preventable overestimated risk perception.

Hydrogen-bonded organic frameworks (HOFs) have received tremendous attention in recent years due to the good designability. However, the pure organic nature of HOFs sometimes limits the application development and performance improvement. Functionalizing is an effective strategy to control and modulate material properties, which can achieve properties that cannot be achieved by a pristine material. Herein, a series of HOF-76⊃DSMI were synthesized through functionalizing the stable AIE-based HOF-76 by incorporating a red dye which complements the deficiency of the red component of HOF-76. Then, a single matrix white light-emitting diode (WLED) was fabricated by coating the HOF-76⊃DSMI material on a 460 nm blue LED with CIE chromaticity coordinates of (0.333, 0.329), a correlated colour temperature (CCT) of 5490 K and a colour rendering index (CRI) of 80.

The establishment of highly permanent porosity in hydrogen-bonded organic frameworks (HOFs) is a long-standing challenge due to the fragile nature of hydrogen bonds, which delimits their broad appl...

We herein successfully realized the first example of using a stable HOF (ZJU-HOF-1) for highly efficient removal of both trace (1%) and bulk (50%) CO2 from CO2/CO mixtures under dry and humid conditions.

Epstein-Barr virus (EBV) is a γ-herpesvirus associated with the occurrence of several human malignancies. BBRF2 and BSRF1 are two EBV tegument proteins that have been suggested to form a hetero-complex and mediate viral envelopment, but the molecular basis of their interaction and the functional mechanism of this complex remains unknown. Here, we present crystal structures of BBRF2 alone and in complex with BSRF1. BBRF2 has a compact globular architecture featuring a central β-sheet that is surrounded by 10 helices, it represents a novel fold distinct from other known protein structures. The central portion of BSRF1 folds into two tightly associated antiparallel α-helices, forming a composite four-helix bundle with two α-helices from BBRF2 via a massive hydrophobic network. In vitro, a BSRF1-derived peptide binds to BBRF2 and reduces the number of viral genome copies in EBV-positive cells. Exogenous BBRF2 and BSRF1 co-localize at the Golgi apparatus. Furthermore, BBRF2 binds capsid and capsid-associated proteins, whereas BSRF1 associates with glycoproteins. These findings indicate that the BBRF2-BSRF1 complex tethers EBV nucleocapsids to the glycoprotein-enriched Golgi membrane, facilitating secondary envelopment., Epstein-Barr virus (EBV) tegument proteins BBRF2 and BSRF1 have been suggested to form a hetero-complex. Here, He et al. provide the crystal structures of BBRF2 alone and in complex with BSRF1 and suggest that the complex tethers EBV nucleocapsids to the Golgi membrane, facilitating secondary envelopment.

Interleukin6 (IL-6) is a key driver of hyperinflammation in COVID-19, and its level strongly correlates with disease progression. To investigate whether variability in COVID-19 severity partially results from differential IL-6 expression, functional single-nucleotide polymorphisms (SNPs) of IL-6 were determined in Chinese COVID-19 patients with mild or severe illness. An Asian-common IL-6 haplotype defined by promoter SNP rs1800796 and intronic SNPs rs1524107 and rs2066992 correlated with COVID-19 severity. Homozygote carriers of C-T-T variant haplotype were at lower risk of developing severe symptoms (odds ratio, 0.256; 95% confidence interval, 0.088 to 0.739; P = 0.007). This protective haplotype was associated with lower levels of IL-6 and its antisense long noncoding RNA IL-6-AS1 by cis-expression quantitative trait loci analysis. The differences in expression resulted from the disturbance of stimulus-dependent bidirectional transcription of the IL-6/IL-6-AS1 locus by the polymorphisms. The protective rs2066992-T allele disrupted a conserved CTCF-binding locus at the enhancer elements of IL-6-AS1, which transcribed antisense to IL-6 and induces IL-6 expression in inflammatory responses. As a result, carriers of the protective allele had significantly reduced IL-6-AS1 expression and attenuated IL-6 induction in response to acute inflammatory stimuli and viral infection. Intriguingly, this low-producing variant that is endemic to present-day Asia was found in early humans who had inhabited mainland Asia since ∼40,000 years ago but not in other ancient humans, such as Neanderthals and Denisovans. The present study suggests that an individual's IL-6 genotype underlies COVID-19 outcome and may be used to guide IL-6 blockade therapy in Asian patients. IMPORTANCE Overproduction of cytokine interleukin-6 (IL-6) is a hallmark of severe COVID-19 and is believed to play a critical role in exacerbating the excessive inflammatory response. Polymorphisms in IL-6 account for the variability of IL-6 expression and disparities in infectious diseases, but its contribution to the clinical presentation of COVID-19 has not been reported. Here, we investigated IL-6 polymorphisms in severe and mild cases of COVID-19 in a Chinese population. The variant haplotype C-T-T, represented by rs1800796, rs1524107, and rs2066992 at the IL-6 locus, was reduced in patients with severe illness; in contrast, carriers of the wild-type haplotype G-C-G had higher risk of severe illness. Mechanistically, the protective variant haplotype lost CTCF binding at the IL-6 intron and responded poorly to inflammatory stimuli, which may protect the carriers from hyperinflammation in response to acute SARS-CoV-2 infection. These results point out the possibility that IL-6 genotypes underlie the differential viral virulence during the outbreak of COVID-19. The risk loci we identified may serve as a genetic marker to screen high-risk COVID-19 patients.

We herein realize the first example of using a microporous HOF material (ZJU-HOF-1) with suitable pore cavities for highly efficient CO

Seventeen triterpenoids including four new lanostane triterpenoids (1-3 and 5) were isolated from the fruiting bodies of Ganoderma lucidum by various chromatographic techniques. Their chemical structures were determined by extensive spectroscopic data, including 1D-NMR, 2D-NMR, and HRESIMS. In addition, the spectral data of compound 4 was reported for the first time. In an in vitro bioassay, most isolated triterpenoids could inhibit the hydrolysis activity of fatty acid amide hydrolase (FAAH). Furthermore, there is no cytotoxicity observed for these isolated triterpenoids. Therefore, G. lucidum showed the potential application for anti-neuroinflammation and more FAAH inhibitors may be explored from G. lucidum.

Fibroblast growth factor 2 (FGF2), a member of FGF family, binds with FGF receptors (FGFR) to initiate biological functions in various somatic cells. However, little is known regarding the role of FGF2/FGFR on oocyte meiosis. In this study, we investigated expression patterns and functions of FGF2/FGFR during in vitro maturation (IVM) of mouse cumulus-oocyte complexes (COCs). Among four FGFRs, Ffgr1 was the most abundant in COCs. The transcripts for Fgf2 and Ffgr1 in COCs increased during IVM. Ffgr1 was present in oocytes and cumulus cells, while Fgf2 was present in only cumulus cells. Treatment of COCs with the selective FGFR inhibitor SU5402 blocked oocyte meiotic progression and downregulated expression of Bmp15 and Gdf9. In contrast, supplement of FGF2 promoted oocyte meiotic progression and upregulated Bmp15 and Gdf9 expression. Inhibition of FGFR with SU5402 reduced cumulus expansion and expressions of Ptx3, Has2 and Tnfaip6. Treatment with FGF2 increased Ptx3 and Has2 expression. Inhibition of FGFR had no effect on meiotic progression of denuded oocytes (DOs). However, co-culture of DOs with COCs or supplementation with FGF2 promoted meiotic progression of DOs. Inhibition of FGF2/FGFR signaling also downregulated Ffgr1 expression, while supplemental FGF2 upregulated Fgfr1 expression. Furthermore, inhibition of FGFR in COCs interrupted the c-Mos/MAPK pathway and maturation-promoting factor (MPF), as indicated by downregulation of oocyte c-mos and Ccnb1 transcripts, respectively. Overall, this study suggests that FGF2 produced by cumulus cells, activates a FGF2/FGFR autocrine/paracrine loop within COCs to regulate cumulus expansion and oocyte meiosis. These findings reveal a novel role for FGF2/FGFR signaling during in vitro maturation of COCs.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that has spread rapidly around the world. Previous studies have indicated that COVID-19 patients with diabetes are prone to having poor clinical outcomes. AIM: To systematically evaluate the prevalence of diabetes among COVID-19 patients in China and its impact on clinical outcomes, including ICU admission, progression to severe cases, or death. METHODS: We searched studies published in PubMed, Web of Science, and EMBASE from December 1, 2019 to March 31, 2020 to identify relevant observational study that investigated the prevalence of diabetes among COVID-19 patients or its impact on clinical outcomes. We used a random-effects or fixed-effects model to estimate the pooled prevalence of diabetes and risk ratio (RR) and its 95% confidence interval (CI) of diabetes on outcomes. Funnel plots were used to evaluate the publication bias and the heterogeneity was evaluated by I(2) statistic. RESULTS: Twenty-three eligible articles including 49564 COVID-19 patients (1573 with and 47991 without diabetes) were finally included. The pooled prevalence of diabetes was 10% (95%CI: 7%-15%) in COVID-19 patients. In the subgroup analyses, the pooled prevalence of diabetes was higher in studies with patients aged > 50 years (13%; 95%CI: 11%-16%) than in studies with patients aged ≤ 50 years (7%; 95%CI: 6%-8%), in severe patients (17%; 95%CI: 14%-20%) than in non-severe patients (6%; 95%CI: 5%-8%), and in dead patients (30%; 95%CI: 13%-46%) than in survivors (8%; 95%CI: 2%-15%) (P < 0.05 for all). Compared with patients without diabetes, the risk of severe cases was higher (RR = 2.13, 95%CI: 1.76-2.56, I(2) = 49%) in COVID-19 patients with diabetes. The risk of death was also higher in COVID-19 patients with diabetes (RR = 3.16, 95%CI: 2.64-3.78, I(2) = 34%). However, diabetes was not found to be significantly associated with admission to ICU (RR = 1.16, 95%CI: 0.15-9.11). CONCLUSION: Nearly one in ten COVID-19 patients have diabetes in China. Diabetes is associated with a higher risk of severe illness and death. The present study suggested that targeted early intervention is needed in COVID-19 patients with diabetes.

Epstein-Barr virus (EBV)-associated epithelial cancers, including nasopharyngeal carcinoma (NPC) and approximately 10% of gastric cancers, termed EBVaGC, represent 80% of all EBV-related malignancies. However, the exact role of EBV in epithelial cancers remains elusive. Here, we report that EBV functions in vasculogenic mimicry (VM). Epithelial cancer cells infected with EBV develop tumor vascular networks that correlate with tumor growth, which is different from endothelial-derived angiogenic vessels and is VEGF-independent. Mechanistically, activation of the PI3K/AKT/mTOR/HIF-1α signaling cascade, which is partly mediated by LMP2A, is responsible for EBV-induced VM formation. Both xenografts and clinical samples of NPC and EBVaGC exhibit VM histologically, which are correlated with AKT and HIF-1α activation. Furthermore, although anti-VEGF monotherapy shows limited effects, potent synergistic antitumor activities are achieved by combination therapy with VEGF and HIF-1α-targeted agents. Our findings suggest that EBV creates plasticity in epithelial cells to express endothelial phenotype and provides a novel EBV-targeted antitumor strategy., EBV latent infection contributes to the pathogenesis of epithelial malignancies by inducing angiogenesis. Here, the authors show EBV promotes vasculogenic mimicry in EBV associated epithelial cancers via AKT/HIF-1α pathway and combination therapy of HIF-1α and VEGF reduces tumour growth.

Genetic susceptibility underlies the pathogenesis of cancer. We and others have previously identified a novel susceptibility gene TNFRSF19, which encodes an orphan member of the TNF receptor superfamily known to be associated with nasopharyngeal carcinoma (NPC) and lung cancer risk. Here, we show that TNFRSF19 is highly expressed in NPC and is required for cell proliferation and NPC development. However, unlike most of the TNF receptors, TNFRSF19 was not involved in NFκB activation or associated with TRAF proteins. We identified TGFβ receptor type I (TβRI) as a specific binding partner for TNFRSF19. TNFRSF19 bound the kinase domain of TβRI in the cytoplasm, thereby blocking Smad2/3 association with TβRI and subsequent signal transduction. Ectopic expression of TNFRSF19 in normal epithelial cells conferred resistance to the cell-cycle block induced by TGFβ, whereas knockout of TNFRSF19 in NPC cells unleashed a potent TGFβ response characterized by upregulation of Smad2/3 phosphorylation and TGFβ target gene transcription. Furthermore, elevated TNFRSF19 expression correlated with reduced TGFβ activity and poor prognosis in patients with NPC. Our data reveal that gain of function of TNFRSF19 in NPC represents a mechanism by which tumor cells evade the growth-inhibitory action of TGFβ. Significance: TNFRSF19, a susceptibility gene for nasopharyngeal carcinoma and other cancers, functions as a potent inhibitor of the TGFβ signaling pathway. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3469/F1.large.jpg. Cancer Res; 78(13); 3469–83. ©2018 AACR.

Terrorist attacks can occur anywhere. As the threat of terrorism develops, the China-Eurasia Expo held in Ürümqi, China is attracting fewer potential visitors. A nationwide survey of 2034 residents from 31 provinces and municipalities in China was conducted to examine the relation between the distance to respondents’ city of residence from Ürümqi and their levels of concern for safety and security concerning the Expo. The two were found to be positively related: the closer the respondents lived to Ürümqi, the less concerned they were with the safety and security of the Expo. This is consistent with the “psychological typhoon eye” effect, which states that people living closer to the center of an unfortunate event (whether natural or man-made hazards) are less concerned with the event’s negative consequences. This effect appears to hold for terrorism. There are implications of this finding for international counter-terrorism practice, tourism, and research.

A Long Short Term Memory network technique is being applied in the anomaly detection at Huawei in IP Network Performance Monitor. LSTM networks are trained and used to predict instant network traffic at port level. The output is sent to an anomaly identifier to detect abnormal traffic events. Good precision and recall rate are achieved by using the traffic data from routers.

The management of advanced nasopharyngeal carcinoma (NPC) remains a challenge. The ubiquitous nature of Epstein–Barr virus (EBV) infection in nonkeratinizing NPC has forced us to investigate novel drugs for NPC in the presence of EBV. In this study, we performed a small-scale screening of a library of compounds that target epigenetic regulators in paired EBV-positive and EBV-negative NPC cell lines. We found that bromodomain and extra-terminal (BET) inhibitor JQ1 preferentially inhibits the growth of EBV-positive NPC cells. JQ1 induces apoptosis, decreases cell proliferation and enhances the radiosensitivity in NPC cells, especially EBV-positive cells. Significantly, JQ1-induced cell death is c-Myc-dependent. Notably, RNA-seq analysis demonstrated that JQ1 represses TP63, TP53 and their targets. JQ1 also lessens the expression of PD-L1 in NPC. Moreover, the high potency of JQ1 in NPC cells was further confirmed in vivo in CNE2-EBV+ tumor-bearing mice. These findings indicate that JQ1 is a promising therapeutic candidate for advanced NPC.

In this paper, a LOMB algorithm for Heart Rate Variability (HRV) analysis is realized using PPG sensor on a low-cost DSP processor at device node with an LoRaWAN IOT eco system. HRV analysis can reflect the activities of sympathetic and parasympathetic on a person health condition. In experiments, 20 candidates are selected to test three different HRV calculation methods. The Lomb algorithm based PPG sensor method can improve the accuracy from 50% error to 30% in average compared to FFT PPG method. The proposed solution is able to direct calculate the HRV analysis at local sensor node and upload patient information through LoRaWAN network to Cloud server, further allows the Medical center to monitor the patient statue in the metropolitan area.