Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
6,147
result(s) for
"Tian, Min"
Sort by:
Structures and gating mechanism of human TRPM2
Adenosine diphosphate–ribose (ADPR) mediates calcium (Ca 2+ ) release by activating the transient receptor potential melastatin 2 (TRPM2) channel. Three structures now elucidate the conformational regulation mechanism of TRPM2 gating. Wang et al. describe cryo–electron microscopy structures of human TRPM2 in the apo, ADPR-bound, and ADPR- and Ca 2+ -bound states. In the apo state, both intra- and intersubunit interactions appeared to lock TRPM2 into a closed and autoinhibited state. ADPR binding disrupted some interactions and dramatically altered the TRPM2 conformation. Binding of Ca 2+ further primed the opening of the channel. Science , this issue p. eaav4809 Gating of the TRPM2 (transient receptor potential melastatin 2) cation channel involves transmembrane helix–linked conformational changes. Transient receptor potential (TRP) melastatin 2 (TRPM2) is a cation channel associated with numerous diseases. It has a C-terminal NUDT9 homology (NUDT9H) domain responsible for binding adenosine diphosphate (ADP)–ribose (ADPR), and both ADPR and calcium (Ca 2+ ) are required for TRPM2 activation. Here we report cryo–electron microscopy structures of human TRPM2 alone, with ADPR, and with ADPR and Ca 2+ . NUDT9H forms both intra- and intersubunit interactions with the N-terminal TRPM homology region (MHR1/2/3) in the apo state but undergoes conformational changes upon ADPR binding, resulting in rotation of MHR1/2 and disruption of the intersubunit interaction. The binding of Ca 2+ further engages transmembrane helices and the conserved TRP helix to cause conformational changes at the MHR arm and the lower gating pore to potentiate channel opening. These findings explain the molecular mechanism of concerted TRPM2 gating by ADPR and Ca 2+ and provide insights into the gating mechanism of other TRP channels.
Journal Article
Nanotechnology for Cancer Therapy Based on Chemotherapy
Chemotherapy has been widely applied in clinics. However, the therapeutic potential of chemotherapy against cancer is seriously dissatisfactory due to the nonspecific drug distribution, multidrug resistance (MDR) and the heterogeneity of cancer. Therefore, combinational therapy based on chemotherapy mediated by nanotechnology, has been the trend in clinical research at present, which can result in a remarkably increased therapeutic efficiency with few side effects to normal tissues. Moreover, to achieve the accurate pre-diagnosis and real-time monitoring for tumor, the research of nano-theranostics, which integrates diagnosis with treatment process, is a promising field in cancer treatment. In this review, the recent studies on combinational therapy based on chemotherapy will be systematically discussed. Furthermore, as a current trend in cancer treatment, advance in theranostic nanoparticles based on chemotherapy will be exemplified briefly. Finally, the present challenges and improvement tips will be presented in combination therapy and nano-theranostics.
Journal Article
Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway
The protein PTEN is a phosphatase and tumor suppressor whose activity is often decreased in human cancers. Thus, reactivating such a protein could potentially be an effective therapy against cancer. Lee et al. identified a ubiquitin E3 ligase (WWP1) as a PTEN-interacting protein that modifies PTEN and inhibits its tumor suppressive activity (see the Perspective by Parsons). Depletion of WWP1 increased dimerization and membrane recruitment of PTEN. A natural compound found to be a pharmacological inhibitor of WWP1 inhibited tumor growth in a mouse model of prostate cancer. Thus, reactivation of the tumor suppressor PTEN may provide a strategy for battling tumors. Science , this issue p. eaau0159 ; see also p. 633 Lee et al . bolster a tumor suppressor as a potential cancer therapy. Activation of tumor suppressors for the treatment of human cancer has been a long sought, yet elusive, strategy. PTEN is a critical tumor suppressive phosphatase that is active in its dimer configuration at the plasma membrane. Polyubiquitination by the ubiquitin E3 ligase WWP1 (WW domain–containing ubiquitin E3 ligase 1) suppressed the dimerization, membrane recruitment, and function of PTEN. Either genetic ablation or pharmacological inhibition of WWP1 triggered PTEN reactivation and unleashed tumor suppressive activity. WWP1 appears to be a direct MYC (MYC proto-oncogene) target gene and was critical for MYC-driven tumorigenesis. We identified indole-3-carbinol, a compound found in cruciferous vegetables, as a natural and potent WWP1 inhibitor. Thus, our findings unravel a potential therapeutic strategy for cancer prevention and treatment through PTEN reactivation.
Journal Article
ICE-CBF-COR Signaling Cascade and Its Regulation in Plants Responding to Cold Stress
Cold stress limits plant geographical distribution and influences plant growth, development, and yields. Plants as sessile organisms have evolved complex biochemical and physiological mechanisms to adapt to cold stress. These mechanisms are regulated by a series of transcription factors and proteins for efficient cold stress acclimation. It has been established that the ICE-CBF-COR signaling pathway in plants regulates how plants acclimatize to cold stress. Cold stress is perceived by receptor proteins, triggering signal transduction, and Inducer of CBF Expression (ICE) genes are activated and regulated, consequently upregulating the transcription and expression of the C-repeat Binding Factor (CBF) genes. The CBF protein binds to the C-repeat/Dehydration Responsive Element (CRT/DRE), a homeopathic element of the Cold Regulated genes (COR gene) promoter, activating their transcription. Transcriptional regulations and post-translational modifications regulate and modify these entities at different response levels by altering their expression or activities in the signaling cascade. These activities then lead to efficient cold stress tolerance. This paper contains a concise summary of the ICE-CBF-COR pathway elucidating on the cross interconnections with other repressors, inhibitors, and activators to induce cold stress acclimation in plants.
Journal Article
Robust optimization for multi-project scheduling via the critical chain method
The critical chain method is often used to improve robustness in single-project scheduling, but there are two challenges when applying it to multi-project scheduling. First, the existing robustness measure focuses on time elasticity within sub-projects but neglects elasticity across sub-projects, making it difficult to balance drum resource requirements. Second, the differential evolution (DE) algorithm is adopted to solve this problem, but continuous evolutionary operators have limited flexibility, leading to numerous transformations between the continuous solution space and the discrete problem space. Therefore, we adjust the critical chain multi-project scheduling model by incorporating the drum buffer and the capacity constraint buffer and propose a robustness measure that considers both time elasticity within and among sub-projects. Meanwhile, we design an enhanced discrete DE algorithm, which not only discretizes the encoding–decoding strategy and evolutionary operators but also uses a hill-climbing algorithm to enhance local search. Experiments are conducted to verify the effectiveness of the robustness measure and the algorithm. The results indicate that, averaged over the eight instances, the enhanced discrete DE algorithm achieves an improvement of more than 3.3% in robustness compared with the overall mean of the benchmark algorithms. Furthermore, our robustness measure strengthens the stability of the scheduling plan and reduces buffer consumption and overflow during multi-project scheduling.
Journal Article
Gasdermin D pore structure reveals preferential release of mature interleukin-1
As organelles of the innate immune system, inflammasomes activate caspase-1 and other inflammatory caspases that cleave gasdermin D (GSDMD). Caspase-1 also cleaves inactive precursors of the interleukin (IL)-1 family to generate mature cytokines such as IL-1β and IL-18. Cleaved GSDMD forms transmembrane pores to enable the release of IL-1 and to drive cell lysis through pyroptosis
1
–
9
. Here we report cryo-electron microscopy structures of the pore and the prepore of GSDMD. These structures reveal the different conformations of the two states, as well as extensive membrane-binding elements including a hydrophobic anchor and three positively charged patches. The GSDMD pore conduit is predominantly negatively charged. By contrast, IL-1 precursors have an acidic domain that is proteolytically removed by caspase-1
10
. When permeabilized by GSDMD pores, unlysed liposomes release positively charged and neutral cargoes faster than negatively charged cargoes of similar sizes, and the pores favour the passage of IL-1β and IL-18 over that of their precursors. Consistent with these findings, living—but not pyroptotic—macrophages preferentially release mature IL-1β upon perforation by GSDMD. Mutation of the acidic residues of GSDMD compromises this preference, hindering intracellular retention of the precursor and secretion of the mature cytokine. The GSDMD pore therefore mediates IL-1 release by electrostatic filtering, which suggests the importance of charge in addition to size in the transport of cargoes across this large channel.
A cryo-electron microscopy study of the gasdermin D pore reveals a model of pore assembly and a charge-based mechanism for the preferential release of mature cytokines.
Journal Article
Targeting stem-loop 1 of the SARS-CoV-2 5′ UTR to suppress viral translation and Nsp1 evasion
SARS-CoV-2 is a highly pathogenic virus that evades antiviral immunity by interfering with host protein synthesis, mRNA stability, and protein trafficking. The SARS-CoV-2 nonstructural protein 1 (Nsp1) uses its C-terminal domain to block the messenger RNA (mRNA) entry channel of the 40S ribosome to inhibit host protein synthesis. However, how SARS-CoV-2 circumvents Nsp1-mediated suppression for viral protein synthesis and if the mechanism can be targeted therapeutically remain unclear. Here, we show that N- and C-terminal domains of Nsp1 coordinate to drive a tuned ratio of viral to host translation, likely to maintain a certain level of host fitness while maximizing replication. We reveal that the stem-loop 1 (SL1) region of the SARS-CoV-2 5′ untranslated region (5′ UTR) is necessary and sufficient to evade Nsp1-mediated translational suppression. Targeting SL1 with locked nucleic acid antisense oligonucleotides inhibits viral translation and makes SARS-CoV-2 5′ UTR vulnerable to Nsp1 suppression, hindering viral replication in vitro at a nanomolar concentration, as well as providing protection against SARS-CoV-2–induced lethality in transgenic mice expressing human ACE2. Thus, SL1 allows Nsp1 to switch infected cells from host to SARS-CoV-2 translation, presenting a therapeutic target against COVID-19 that is conserved among immune-evasive variants. This unique strategy of unleashing a virus’ own virulence mechanism against itself could force a critical trade-off between drug resistance and pathogenicity.
Journal Article