최근 중국의 웹예능 프로그램에서는 예능 콘텐츠 및 IP를 확장하기 위해 다양한 스핀오프(spin-off) 예능 시리즈의 제작에 나서고 있다. 스핀오프 예능은 새로운 유형과 패턴을 바탕으로 독자적인 스토리월드와 IP까지 형성시키며 오리지널 예능과 함께 "오리지널-스핀오프 예능"이라는 IP 사슬을 형성시키는 것으로 더 큰 가치를 창출할 수 있다. 본고는 망고TV 〈명성대정탐(明星大偵探)〉과 〈밀실대탈출(密室大逃脫)〉 두 추리 예능에서 파생된 스핀오프 예능의 유형을 정리하여, 스핀오프 예능에서 오리지널 예능의 IP를 확장하는 새로운 방식을 탐색하였다. 그 결과, 중국 스핀오프 예능은 주로 원작 보완형, 출연자의 캐릭터지향형, 미션게임형, 플롯체험형 등 4가지 유형으로 나눌 수 있었다. 동시에 이는 파편화 전파, 멀티 프로그램 연동, 무대 전후의 장벽 해소 등 전파 특징을 가지고 있으며 게임 역할 중시, 오리지널 예능 세계관에 입각한 IP 확장, 팬들의 콘텐츠 생산참여를 통한 융합문화 집단 창조 등 내용적 특징을 보였다. In recent years, Chinese web variety programs have been producing various spin-off variety series to expand their variety content and IP. Spin-off shows create their own storyworlds and IP based on new types and patterns, and can create greater value by forming an IP chain of "original and spin-off shows" with the original shows. This paper summarizes the types of spin-off shows derived from two mystery shows, Mango TV"s 〈Who’s the Murderer〉 and 〈Great Escape〉, and explores new ways to extend the IP of original shows in spin-off shows. The results show that Chinese spin-off shows are mainly divided into four types: original complementary, character-oriented, mission game, and plot experience. They are characterized by fragmented dissemination, multi-program integration, and the elimination of barriers before and after the stage, while content features include emphasis on the role of games, IP expansion based on the original entertainment worldview, and the creation of convergence culture groups through fans" participation in content production.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an effective chemotherapeutic agent that specifically impairs cancer cells while sparing normal cells; however, some cancer cells develop resistance to TRAIL.Here, we identified Andrographolide, a diterpenoid lactone derived from a traditional herbal medicine Andrographis paniculata, as an ideal sensitizer for TRAIL to overcome bladder cancer.Our results showed that combination treatment of Andro and TRAIL retarded growth, attenuated proliferation, decreased colony formation, inhibited migration and promoted caspases-mediated apoptosis in T24 cells.Additionally, the sensitization by Andro is achieved through up-regulation of death receptors (DR4 and DR5) of TRAIL in a p53-dependent manner.Crucially, Andro is also capable of inactivating NF-κB signaling pathway via transcriptional down-regulation p65/RelA, which is further contributed to enhancement of TRAIL-mediated cytotoxicity.These results indicated that non-toxic doses of Andrographolide sensitized bladder cancer cells to TRAIL-mediated apoptosis, suggesting it as an effective therapeutic agent for TRAIL resistant human bladder cancers.
Enterovirus D68 (EV-D68) is a globally re-emerging respiratory pathogen implicated in outbreaks of severe respiratory illnesses and associated with acute flaccid myelitis. However, effective vaccines or treatments for EV-D68 infections remain scarce. We demonstrated that the active constituent of blueberries, pterostilbene (Pte), and its major metabolite, pinostilbene (Pin), facilitated innate immune responses in EV-D68-infected human respiratory cells. Pte and Pin treatment clearly relieved EV-D68-triggered cytopathic effects. Importantly, both Pte and Pin disrupted viral RNA replication (EC 50 rank from 1.336 to 4.997 µM) and infectious virion production in a dose-dependent manner, without cytotoxicity at virucidal concentrations. Pte- or Pin-treated respiratory cells did not show any influences on EV-D68 entry but showed substantially decreased viral RNA replication and protein synthesis. Finally, we showed that Pte and Pin broadly suppressed the replication capacity of circulating EV-D68 strains isolated from recent pandemics. In summary, our results suggest that Pte and its derivative, Pin, enhance host immune recognition of EV-D68 and suppress EV-D68 replication, which represents a promising strategy for antiviral drug development.
Recent studies have identified human myxovirus resistance protein 2 (MxB or Mx2) as an interferon induced inhibitor of HIV-1 replication. However, whether HIV-1 can overcome MxB restriction without compromise of viral fitness has been undefined. Here, we have discovered that naturally occurring capsid (CA) variants can render HIV-1 resistant to the activity of MxB without losing viral infectivity or the ability to escape from interferon induction. Moreover, these MxB resistant HIV-1 variants do not lose MxB recognition. Surprisingly, MxB resistant CA variants are most commonly found in the Clade C HIV-1 that is the most rapidly expanding Clade throughout the world. Accumulation of MxB resistant mutations is also observed during HIV-1 spreading in human populations. These findings support a potential role for MxB as a selective force during HIV-1 transmission and evolution.
The discovery of magnetism in van der Waals (vdW) materials has established unique building blocks for the research of emergent spintronic phenomena. In particular, owing to their intrinsically clean surface without dangling bonds, the vdW magnets hold the potential to construct a superior interface that allows for efficient electrical manipulation of magnetism. Despite several attempts in this direction, it usually requires a cryogenic condition and the assistance of external magnetic fields, which is detrimental to the real application. Here, we fabricate heterostructures based on Fe3GaTe2 flakes that possess room-temperature ferromagnetism with excellent perpendicular magnetic anisotropy. The current-driven non-reciprocal modulation of coercive fields reveals a high spin-torque efficiency in the Fe3GaTe2/Pt heterostructures, which further leads to a full magnetization switching by current. Moreover, we demonstrate the field-free magnetization switching resulting from out-of-plane polarized spin currents by asymmetric geometry design. Our work could expedite the development of efficient vdW spintronic logic, memory and neuromorphic computing devices.
The lentiviral accessory proteins Vpx and Vpr are known to utilize CRL4 (DCAF1) E3 ligase to induce the degradation of the host restriction factor SAMHD1 or host helicase transcription factor (HLTF), respectively. Selective disruption of viral CRL4 (DCAF1) E3 ligase could be a promising antiviral strategy. Recently, we have determined that posttranslational modification (neddylation) of Cullin-4 is required for the activation of Vpx-CRL4 (DCAF1) E3 ligase. However, the mechanism of Vpx/Vpr-CRL4 (DCAF1) E3 ligase assembly is still poorly understood. Here, we report that zinc coordination is an important regulator of Vpx-CRL4 E3 ligase assembly. Residues in a conserved zinc-binding motif of Vpx were essential for the recruitment of the CRL4 (DCAF1) E3 complex and Vpx-induced SAMHD1 degradation. Importantly, altering the intracellular zinc concentration by treatment with the zinc chelator N,N,N'-tetrakis-(2'-pyridylmethyl)ethylenediamine (TPEN) potently blocked Vpx-mediated SAMHD1 degradation and inhibited wild-type SIVmac (simian immunodeficiency virus of macaques) infection of myeloid cells, even in the presence of Vpx. TPEN selectively inhibited Vpx and DCAF1 binding but not the Vpx-SAMHD1 interaction or Vpx virion packaging. Moreover, we have shown that zinc coordination is also important for the assembly of the HIV-1 Vpr-CRL4 E3 ligase. In particular, Vpr zinc-binding motif mutation or TPEN treatment efficiently inhibited Vpr-CRL4 (DCAF1) E3 ligase assembly and Vpr-mediated HLTF degradation or Vpr-induced G2 cell cycle arrest. Collectively, our study sheds light on a conserved strategy by the viral proteins Vpx and Vpr to recruit host CRL4 (DCAF1) E3 ligase, which represents a target for novel anti-human immunodeficiency virus (HIV) drug development.IMPORTANCE The Vpr and its paralog Vpx are accessory proteins encoded by different human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) lentiviruses. To facilitate viral replication, Vpx has evolved to induce SAMHD1 degradation and Vpr to mediate HLTF degradation. Both Vpx and Vpr perform their functions by recruiting CRL4 (DCAF1) E3 ligase. In this study, we demonstrate that the assembly of the Vpx- or Vpr-CRL4 E3 ligase requires a highly conserved zinc-binding motif. This motif is specifically required for the DCAF1 interaction but not for the interaction of Vpx or Vpr with its substrate. Selective disruption of Vpx- or Vpr-CRL4 E3 ligase function was achieved by zinc sequestration using N,N,N'-tetrakis-(2'-pyridylmethyl)ethylenediamine (TPEN). At the same time, zinc sequestration had no effect on zinc-dependent cellular protein functions. Therefore, information obtained from this study may be important for novel anti-HIV drug development.
High-risk Human papillomaviruses (HPVs) types are associated with more than 90% of premalignant and malignant squamous lesions of the uterine cervix. The E6 oncoprotein of high-risk HPVs is a key determinant in cell transformation because it induces the degradation of the host pro-apoptotic tumor suppressor p53. E6 recruits the intracellular ubiquitin ligase E6AP and subsequently induces proteasome-dependent p53 degradation. Neither E6 nor E6AP alone interact with p53; however, the precise mechanism of the functional regulation of the E6/E6AP/p53 complex is unclear. Here, we showed that the high-risk HPV E6 proteins are ubiquitinated during E6/E6AP/p53 complex assembly and degraded by the proteasome system. Increasing p53 expression enhanced E6/E6AP/p53 assembly and facilitated E6 ubiquitination and degradation. The dominant negative mutant of p53 R175H, which does not efficiently bind E6, decreased E6 ubiquitination and increased stability. Furthermore, we showed that the ubiquitin ligase E6AP is essential for E6 ubiquitination, and downregulation of E6AP expression increased E6 stability. We also showed that p53 R175H inhibited E6-mediated p53 degradation. Consistently, the host deubiquitinating enzyme USP15 removed ubiquitin chains from E6 proteins and inhibited E6-mediated p53 degradation. Crucially, ectopic expression of either p53 R175H or USP15 promoted p53-triggered apoptosis in human cervical cancer cells. Considering the importance of ubiquitinated E6 on p53 degradation, the disruption of E6 ubiquitination represents an attractive pharmacological intervention against HPV-positive human cervical cancer.Virtually 100% of cervical cancers are linked to HPV infection. Commercial HPV vaccines are estimated to prevent up to 90% of HPV-associated cancers, while they do not eliminate persistent HPV infections and have no effect on the progression to malignancy. Hence, the development of novel therapeutic interventions against HPV is urgently required. The HPV oncoprotein E6 binds to the intracellular E3 ubiquitin ligase E6AP and p53 resulting in the degradation of p53. In this study, we demonstrate that HPV E6 is ubiquitinated by E6AP in presence of p53. Crucially, ubiquitination of E6 is important for p53 degradation and blockage of E6 ubiquitination negatively interferes with E6-mediated p53 degradation and enhances the apoptotic effects of p53 and the cytotoxicity of DNA damage in HPV-positive cervical cancer cells. Importantly, our data suggest that the HPV oncogene E6 might be an optimal pharmacologic.
Endothelial cells play important roles in neurodegenerative diseases caused by diabetes, therefore, we aimed at investigating the mechanisms through which endothelial cells are involved in diabetes development.Single cell analysis was performed to identify the major endothelial cell subtypes in cardiovascular tissues that are involved in diabetes development. A cell-cell communication approach was then used to identify ligand-receptor interaction pairs between these cell types. Differential expression analysis between the two experimental groups [standard chow diet group and diabetogenic diet with cholesterol (DDC) group] was used to identify diabetes-related differentially expressed genes (DEGs). The upregulated genes were used to identify candidate ligands or receptors, as well as the corresponding cell types. Cell trajectory inference was performed to identify the stage of cell development and changes in expression of candidate ligands or receptors during cell development. Gene set enrichment analysis (GSEA) was conducted to investigate the biological functions of genes of purpose. Finally, molecular dynamics simulations (MDSs) were used to predict potential drugs with the ability to target the proteins of purpose.Seven cell types, including five endothelial cell subtypes (EC_1, EC_2, EC_3, EC_4, and EC_EndMT), were identified from endothelial cell-enriched single cell samples from the heart and aorta of mice. Cell-cell communication analysis revealed the potential ligand-receptor interactions between these cell types while five important ligand-receptor-associated genes, including Fn1, Vcam1, Fbn1, Col4a1, and Col4a2, were established by differential expression analysis. Among them, Vcam1 is mainly expressed in EC_EndMT and is involved in interactions between EC_EndMT and other cells. Cell trajectory extrapolation analysis revealed a shift from EC_2/EC_4 to EC_EndMT and a shift from EC_EndMT to EC_3/EC_1 during the progression of diabetes. GSEA analysis revealed that upregulation of VCAM1 may have inhibitory effects on cell growth and energy metabolism.EC_EndMT subtypes have a complex role in neurodegenerative diseases caused by diabetes. Through mechanisms involved in cell-cell communication, Vcam1 may play an important role in dysregulation of biological functions of EC_ EndMT. Molecular docking results of the quercetin-VCAM1 complex suggest that quercetin may be an effective drug for targeting this protein.
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