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Liquid-liquid phase separation (LLPS) underlies diverse biological processes. Because most LLPS studies were performed in vitro using recombinant proteins or in cells that overexpress protein, the physiological relevance of LLPS for endogenous protein is often unclear. PERIOD, the intrinsically disordered domain-rich proteins, are central mammalian circadian clock components and interact with other clock proteins in the core circadian negative feedback loop. Different core clock proteins were previously shown to form large complexes. Circadian clock studies often rely on experiments that overexpress clock proteins. Here, we show that when Per2 transgene was stably expressed in cells, PER2 protein formed nuclear phosphorylation-dependent slow-moving LLPS condensates that recruited other clock proteins. Super-resolution microscopy of endogenous PER2, however, revealed formation of circadian-controlled, rapidly diffusing nuclear microbodies that were resistant to protein concentration changes, hexanediol treatment, and loss of phosphorylation, indicating that they are distinct from the LLPS condensates caused by protein overexpression. Surprisingly, only a small fraction of endogenous PER2 microbodies transiently interact with endogenous BMAL1 and CRY1, a conclusion that was confirmed in cells and in mice tissues, suggesting an enzyme-like mechanism in the circadian negative feedback process. Together, these results demonstrate that the dynamic interactions of core clock proteins are a key feature of mammalian circadian clock mechanism and the importance of examining endogenous proteins in LLPS and circadian clock studies.
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Relógios Circadianos , Camundongos , Animais , Relógios Circadianos/genética , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Separação de Fases , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Ritmo Circadiano/genética , Microcorpos/metabolismo , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Mamíferos/metabolismoRESUMO
The catalytic removal of chlorinated VOCs (CVOCs) in gas-solid reactions usually suffers from chlorine-containing byproduct formation and catalyst deactivation. AOP wet scrubber has recently attracted ever-increasing interest in VOC treatment due to its advantages of high efficiency and no gaseous byproduct emission. Herein, the low-valence Co nanoparticles (NPs) confined in a N-doped carbon nanotube (Co@NCNT) were studied to activate peroxymonosulfate (PMS) for efficient CVOC removal in a wet scrubber. Co@NCNT exhibited unprecedented catalytic activity, recyclability, and low Co ion leakage (0.19 mg L-1) for chlorobenzene degradation in a very wide pH range (3-11). The chlorobenzene removal efficiency was kept stable above 90% over Co@NCNT, much higher than that of nonconfined Co@NCNS (45%). The low-valence Co NPs achieved a continuous electron redox cycling (Co0/Co2+ â Co3+ â Co0/Co2+) and greatly promoted the O-O bond dissociation of PMS with the least energy (0.83 eV) inside the channel of Co@NCNT to form abundant HO⢠and SO4â¢-. Thus, the deep oxidation of chlorobenzene was achieved without any biphenyl byproducts from the coupling reaction. This study provided a new avenue for designing novel nanoconfined catalysts with outstanding activity, paving the way for the deep oxidation of CVOC waste gas via AOP wet scrubber.
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Nanotubos de Carbono , Peróxidos/química , Oxirredução , ClorobenzenosRESUMO
Advanced oxidation process (AOP) wet scrubber is a powerful and clean technology for organic pollutant treatment but still presents great challenges in removing the highly toxic and hydrophobic volatile organic compounds (VOCs). Herein, we elaborately designed a bifunctional cobalt sulfide (CoS2)/activated carbon (AC) catalyst to activate peroxymonosulfate (PMS) for efficient toxic VOC removal in an AOP wet scrubber. By combining the excellent VOC adsorption capacity of AC with the highly efficient PMS activation activity of CoS2, CoS2/AC can rapidly capture VOCs from the gas phase to proceed with the SO4â¢- and HO⢠radical-induced oxidation reaction. More than 90% of aromatic VOCs were removed over a wide pH range (3-11) with low Co ion leaching (0.19 mg/L). The electron-rich sulfur vacancies and low-valence Co species were the main active sites for PMS activation. SO4â¢- was mainly responsible for the initial oxidation of VOCs, while HO⢠and O2 acted in the subsequent ring-opening and mineralization processes of intermediates. No gaseous intermediates from VOC oxidation were detected, and the highly toxic liquid intermediates like benzene were also greatly decreased, thus effectively reducing the health toxicity associated with byproduct emissions. This work provided a comprehensive understanding of the deep oxidation of VOCs via AOP wet scrubber, significantly accelerating its application in environmental remediation.
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Oxirredução , Compostos Orgânicos Voláteis , Compostos Orgânicos Voláteis/química , Catálise , Carvão Vegetal/química , Cobalto/química , Adsorção , Carbono/químicaRESUMO
Hypernetwork is a useful way to depict multiple connections between nodes, making it an ideal tool for representing complex relationships in network science. In recent years, there has been a marked increase in studies on hypernetworks; however, the comparison of the difference between two hypernetworks has received less attention. This paper proposes a hyper-distance (HD)-based method for comparing hypernetworks. The method is based on higher-order information, i.e, the higher-order distance between nodes and Jensen-Shannon divergence. Experiments carried out on synthetic hypernetworks have shown that HD is capable of distinguishing between hypernetworks generated with different parameters, and it is successful in the classification of hypernetworks. Furthermore, HD outperforms current state-of-the-art baselines to distinguish empirical hypernetworks when hyperedges are randomly perturbed.
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Ozone (O3) pollution is highly detrimental to human health and the ecosystem due to it being ubiquitous in ambient air and industrial processes. Catalytic decomposition is the most efficient technology for O3 elimination, while the moisture-induced low stability represents the major challenge for its practical applications. Here, activated carbon (AC) supported δ-MnO2 (Mn/AC-A) was facilely synthesized via mild redox in an oxidizing atmosphere to obtain exceptional O3 decomposition capacity. The optimal 5Mn/AC-A achieved nearly 100% of O3 decomposition at a high space velocity (1200 L g-1 h-1) and remained extremely stable under entire humidity conditions. The functionalized AC provided well-designed protection sites to inhibit the accumulation of water on δ-MnO2. Density functional theory (DFT) calculations confirmed that the abundant oxygen vacancies and a low desorption energy of intermediate peroxide (O22-) can significantly boost O3 decomposition activity. Moreover, a kilo-scale 5Mn/AC-A with low cost (â¼1.5 $/kg) was used for the O3 decomposition in practical applications, which could quickly decompose O3 pollution to a safety level below 100 µg m-3. This work offers a simple strategy for the development of moisture-resistant and inexpensive catalysts and greatly promotes the practical application of ambient O3 elimination.
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Ozônio , Humanos , Óxidos , Carvão Vegetal , Umidade , Compostos de Manganês , Ecossistema , Oxigênio , CatáliseRESUMO
Hypergraphs that can depict interactions beyond pairwise edges have emerged as an appropriate representation for modeling polyadic relations in complex systems. With the recent surge of interest in researching hypergraphs, the centrality problem has attracted much attention due to the challenge of how to utilize higher-order structure for the definition of centrality metrics. In this paper, we propose a new centrality method (HGC) on the basis of the gravity model as well as a semi-local HGC, which can achieve a balance between accuracy and computational complexity. Meanwhile, two comprehensive evaluation metrics, i.e., a complex contagion model in hypergraphs, which mimics the group influence during the spreading process and network s-efficiency based on the higher-order distance between nodes, are first proposed to evaluate the effectiveness of our methods. The results show that our methods can filter out nodes that have fast spreading ability and are vital in terms of hypergraph connectivity.
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Hydrogen peroxide (H2O2) is commonly used as an oxidizing, bleaching, or antiseptic agent. It is also hazardous at increased concentrations. It is therefore crucial to monitor the presence and concentration of H2O2, particularly in the vapor phase. However, it remains a challenge for many state-of-the-art chemical sensors (e.g., metal oxides) to detect hydrogen peroxide vapor (HPV) because of the interference of moisture in the form of humidity. Moisture, in the form of humidity, is guaranteed to be present in HPV to some extent. To meet this challenge, herein, we report a novel composite material based on poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) doped with ammonium titanyl oxalate (ATO). This material can be fabricated as a thin film on electrode substrates for use in chemiresistive sensing of HPV. The adsorbed H2O2 will react with ATO, causing a colorimetric response in the material body. Combining colorimetric and chemiresistive responses resulted in a more reliable dual-function sensing method that improved the selectivity and sensitivity. Moreover, the composite film of PEDOT:PSS-ATO could be coated with a layer of pure PEDOT via in situ electrochemical synthesis. The pure PEDOT layer was hydrophobic, shielding the sensor material underneath from coming into contact with moisture. This was shown to mitigate the interference of humidity when detecting H2O2. A combination of these material properties makes the double-layer composite film, namely PEDOT:PSS-ATO/PEDOT, an ideal sensor platform for the detection of HPV. For example, upon a 9 min exposure to HPV at a concentration of 1.9 ppm, the electrical resistance of the film increased threefold, surpassing the bounds of the safety threshold. Meanwhile, the colorimetric response observed was 2.55 (defined as the color change ratio), a ratio at which the color change could be easily seen by the naked eye and quantified. We expect that this reported dual-mode sensor will find extensive practical applications in the fields of health and security with real-time, onsite monitoring of HPV.
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Vacuum ultraviolet (VUV) photolysis is a facile method for volatile organic compounds (VOCs) elimination, but is greatly limited by the relatively low removal efficiency and the possible secondary pollution. To overcome above drawbacks, we developed an efficient method for VOCs elimination via VUV photolysis coupled with wet scrubbing process. In this coupled process, volatile toluene, a representative of VOCs, was oxidized by the gas-phase VUV photolysis, and then scrubbed into water for further oxidation by the liquid-phase VUV photolysis. More than 96% of toluene was efficiently removed by this coupled process, which was 2 times higher than that in the gas-phase VUV photolysis. This improvement was attributed to the synergistic effect between gas-phase and liquid-phase VUV photolysis. O3 and HO⢠are the predomination reactive species for the toluene degradation in this coupled process, and the generation of O3 in gas-phase VUV photolysis can efficiently enhance the HO⢠production in liquid-phase VUV photolysis. The result from in-situ proton transfer reaction ionization with mass analyzer (PTR-MS) further suggested that most intermediates were trapped by the wet scrubbing process and efficiently oxidized by the liquid-phase VUV photolysis, showing a high performance for controlling the secondary pollution. Furthermore, the result of stability test and the reuse of solution demonstrated that this coupled process has a highly stable and sustainable performance for toluene degradation. This study presents an environmentally benign and highly efficient VUV photolysis for gaseous VOCs removal in the wet scrubbing process.
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Compostos Orgânicos Voláteis , Fotólise , Vácuo , Oxirredução , Gases , ToluenoRESUMO
Thermally induced reversible up/down migration of poly(ionic liquid)s (PILs) in aqueous two-phase systems (ATPSs) was achieved for the first time in this study. Novel ATPSs were fabricated using azobenzene (Azo)- and benzyl (Bn)-modified PILs, and their upper and lower phases could be easily tuned using the grafting degree (GD) of the Azo and Bn groups. Bn-PIL with higher GDBn could go up into the upper phase and Azo-PIL come down to the lower phase when the temperature increased (>65 °C); this behavior was reversed at lower temperatures. Moreover, a reversible two-phase/single-phase transition was realized under UV irradiation. Experimental and simulation results revealed that the difference in the hydration capacity between Bn-PIL and Azo-PIL accounted for their unique phase-separation behavior. A versatile platform for fabricating ATPSs with tunable stimuli-responsive behavior can be realized based on our findings, which can broaden their applications in the fields of smart separation systems and functional material development.
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In this study, a wet scrubber coupled with a persulfate-based advanced oxidation process [carbocatalysts/peroxymonosulfate (PMS)] was demonstrated to efficiently remove gaseous volatile organic compounds (VOCs). The removal efficiency of a representative VOC, styrene, was stable at above 98%, and an average mineralization rate was achieved at 76% during 2 h. The removal efficiency of the carbocatalysts/PMS wet scrubber for styrene was much higher than that of pure water, carbocatalysts/water, or PMS/water systems. Quenching experiments, electron spin resonance spectroscopy, in-situ Raman spectroscopy and density functional theory (DFT) calculations indicated that singlet oxygen (1O2) and oxidative complexes are the main reactive oxygen species and that both contributed to styrene removal. In particular, carbonyl groups (CâO) in the carbocatalyst were found to be the active sites for activating PMS during styrene oxidation. The role of 1O2 was discovered to be benzene ring breaking and a possible non-radical oxidation pathway of styrene was proposed based on time-of-flight mass spectroscopy which was further verified by DFT calculations. In particular, the electron transfer process of multi world carbon nanotubes-PMS* in styrene oxidation was further studied in-depth by experiments and DFT calculations. The unstable vinyl on styrene was simultaneously degraded by the oxidative complexes and 1O2 into benzene, and finally oxidized by 1O2 into H2O and CO2. This study provides an effective method for VOC removal and clearly illustrates the complete degradation mechanism of styrene in a nonradical PMS-based process by a wet scrubber.
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Nanotubos de Carbono , Compostos Orgânicos Voláteis , Benzeno , Dióxido de Carbono , Gases , Peróxidos/química , Espécies Reativas de Oxigênio , Oxigênio Singlete , Estirenos , ÁguaRESUMO
Drought is the main limiting factor of maize productivity, therefore improving drought tolerance in maize has potential practical importance. Cloning and functional verification of drought-tolerant genes is of great importance to understand molecular mechanisms under drought stress. Here, we employed a bioinformatic pipeline to identify 42 ZmHDZ drought responsive genes using previously reported maize transcriptomic datasets. The coding sequences, exon-intron structure and domain organization of all the 42 genes were identified. Phylogenetic analysis revealed evolutionary conservation of members of the ZmHDZ genes in maize. Several regulatory elements associated with drought tolerance were identified in the promoter regions of ZmHDZ genes, indicating the implication of these genes in plant response to drought stress. 42 ZmHDZ genes were distributed unevenly on 10 chromosomes, and 24 pairs of gene duplications were the segmental duplication. The expression of several ZmHDZ genes was upregulated under drought stress, and ZmHDZ9 overexpressing transgenic plants exhibited higher SOD and POD activities and higher accumulation of soluble proteins under drought stress which resulted in enhanced developed phenotype and improved resistance. The present study provides evidence for the evolutionary conservation of HD-ZIP transcription factors homologs in maize. The results further provide a comprehensive insight into the roles of ZmHDZ genes in regulating drought stress tolerance in maize.
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Atrazine contamination of water is of considerable concern because of the potential hazard to human health. In this study, a magnetic molecularly imprinted polymer for atrazine was prepared by the surface-imprinting technique using Fe3 O4 as the core, mesoporous silica as the carrier, atrazine as the template, and itaconic acid as the functional monomer. The magnetic molecularly imprinted polymer was characterized by Fourier-transform infrared spectroscopy, scanning electron microscopy, X-ray diffraction, and vibration-sample magnetometry. The binding properties of the magnetic molecularly imprinted polymer toward atrazine were investigated by adsorption isotherms, kinetics, and competitive adsorption. It was found that the adsorption equilibrium was achieved within 2 h, the maximum adsorption capacity of atrazine was 8.8 µmol/g, and the adsorption process could be well described by the Langmuir isotherm model and pseudo-second-order kinetic model. The magnetic molecularly imprinted polymer exhibited good adsorption selectivity for atrazine with respect to structural analogues, such as cyanazine, simetryne, and prometryn. The reusability of the magnetic molecularly imprinted polymer was demonstrated for at least five repeated cycles without a significant decrease in adsorption capacity. These results suggested that the magnetic molecularly imprinted polymer could be used as an efficient material for the selective adsorption and removal of atrazine from water samples.
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Drought is a significant abiotic stressor that limits maize (Zea mays L.) growth and development. Thus, enhancing drought tolerance is critical for promoting maize production. Our findings demonstrated that ZmMYB39 is an MYB transcription factor with transcriptional activation activity. Drought stress experiments involving ZmMYB39 overexpression and knockout lines indicated that ZmMYB39 positively regulated drought stress tolerance in maize. DAP-Seq, EMSA, dual-LUC, and RT-qPCR provided initial insights into the molecular regulatory mechanisms by which ZmMYB39 enhances drought tolerance in maize. ZmMYB39 directly promoted the expression of ZmP5CS1, ZmPOX1, ZmSOD2, ZmRD22, ZmNAC49, and ZmDREB2A, which are involved in stress resistance. ZmMYB39 enhanced drought tolerance by interacting with and promoting the expression of ZmFNR1, ZmHSP20, and ZmDOF6. Our study offers a theoretical basis for understanding the molecular regulatory networks involved in maize drought stress response. Furthermore, ZmMYB39 serves as a valuable genetic resource for breeding drought-resistant maize.
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Secas , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas , Fatores de Transcrição , Zea mays , Zea mays/genética , Zea mays/fisiologia , Zea mays/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Plântula/genética , Plântula/fisiologia , Estresse Fisiológico , Plantas Geneticamente Modificadas , Resistência à SecaRESUMO
Programmed cell death is intricately linked to various physiological phenomena such as growth, development, and metabolism, as well as the proper function of the pancreatic ß cell and the migration and invasion of trophoblast cells in the placenta during pregnancy. Traditional and recently identified programmed cell death include apoptosis, autophagy, pyroptosis, necroptosis, and ferroptosis. In addition to cancer and degenerative diseases, abnormal activation of cell death has also been implicated in pregnancy related diseases like preeclampsia, gestational diabetes mellitus, intrahepatic cholestasis of pregnancy, fetal growth restriction, and recurrent miscarriage. Excessive or insufficient cell death and pregnancy related diseases may be mutually determined, ultimately resulting in adverse pregnancy outcomes. In this review, we systematically describe the characteristics and mechanisms underlying several types of cell death and their roles in pregnancy related diseases. Moreover, we discuss potential therapeutic strategies that target cell death signaling pathways for pregnancy related diseases, hoping that more meaningful treatments will be applied in clinical practice in the future.
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Morte Celular , Complicações na Gravidez , Humanos , Gravidez , Feminino , Morte Celular/fisiologia , Animais , Complicações na Gravidez/metabolismo , Complicações na Gravidez/patologia , Transdução de Sinais , Apoptose/fisiologia , Autofagia/fisiologiaRESUMO
BACKGROUND: As one of the most effective biologic treatments for psoriasis, the short-term effectiveness of ustekinumab has yet to be studied extensively. OBJECTIVE: The purpose of this study was to evaluate the short-term effectiveness and potential factors within four weeks after the first-dose ustekinumab treatment based on real-world data. METHODS: The study enrolled 98 patients with moderate-to-severe psoriasis, given ustekinumab 45 mg at week 0, week 4, and then every 12 weeks. Based on clinical data collected at baseline and week 4, we investigated the short-term effectiveness of ustekinumab after the first dose and potential factors associated with the treatment. For evaluation, we collected demographic information, body data, medical history, laboratory examination results, Psoriasis Area and Severity Index (PASI), body surface area (BSA), and dermatology life quality index (DLQI). Response rates were calculated based on the number of patients that achieved a 75/90/100% reduction in PASI (PASI 75/90/100), and the primary treatment goal was to achieve PASI 75. RESULTS: The response rates for PASI 75/90/100 at week 4 were 30.5%, 18.9%, and 16.8%, respectively. For PASI 75, the response rate was higher in patients without metabolic syndrome (MS) (without MS vs. with MS: 36.9% vs. 5.9%, p = 0.013); the serum triglyceride (TG) level was significantly lower in patients achieving PASI 75 (expressed as mean ± standard deviation, achieved vs. unachieved: 1.82 ± 1.79 vs. 3.59 ± 8.89, p = 0.010). For PASI 100, the response rates were higher in female patients (female vs. male: 26.3% vs. 10.5%, p = 0.044) and patients with a family history of psoriasis (with family history vs. without family history: 44.4% vs. 13.9%, p = 0.042). In addition, the possibility of achieving PASI 75/90/100 went up along with the serum high-density lipoprotein cholesterol (HDL-C) level (expressed as adjusted odds ratio < 95% confidence interval>: PASI 75: 28.484 < 2.035-248.419>, p = 0.011; PASI 90: 28.226 < 2.828-281.729>, p = 0.004; PASI 100: 12.175 < 1.876-79.028>, p = 0.009). CONCLUSION: In this study, nearly one-third of patients achieved PASI 75 after only the first-dose ustekinumab treatment. Sex, family history of psoriasis, MS, serum TG level might affect the short-term effectiveness, and serum HDL-C level may be a potential factor. The possibility of achieving treatment goals (PASI 75/90/100) at week 4 increased along with serum HDL-C levels.
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Psoríase , Ustekinumab , Humanos , Masculino , Feminino , Ustekinumab/uso terapêutico , Resultado do Tratamento , Psoríase/tratamento farmacológico , China , Índice de Gravidade de DoençaRESUMO
Drought stress is one of the most limiting factors of maize productivity and can lead to a sharp reduction in the total biomass when it occurs at the seedling stage. Improving drought tolerance at the seedling stage is of great importance for maize breeding. The AP2/ERF transcription factor family plays a critical role in plant response to abiotic stresses. Here, we used a preliminary previously-generated ranscriptomic dataset to identify a highly drought-stress-responsive AP2 gene, i.e., ZmEREB24. Compared to the wild type, the overexpression of ZmEREB24 in maize significantly promotes drought tolerance of transgenic plants at the seedling stage. CRISPR/Cas9-based ZmEREB24-knockout mutants showed a drought-sensitive phenotype. RNA-seq analysis and EMSA assay revealed AATGG.CT and GTG.T.GCC motifs as the main binding sites of ZmEREB24 to the promoters of downstream target genes. DAP-seq identified four novel target genes involved in proline and sugar metabolism and hormone signal transduction of ZmEREB24. Our data indicate that ZmEREB24 plays important biological functions in regulating drought tolerance by binding to the promoters of drought stress genes and modulating their expression. The results further suggest a role of ZmEREB24 in regulating drought adaptation in maize, indicating its potential importance for employing molecular breeding in the development of high-yield drought-tolerant maize cultivars.
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Resistência à Seca , Plântula , Plântula/metabolismo , Zea mays/metabolismo , Melhoramento Vegetal , Secas , Estresse Fisiológico/genética , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMO
Cancer mutations can create neomorphic protein-protein interactions to drive aberrant function 1 . As a substrate receptor of the CULLIN3-RBX1 E3 ubiquitin ligase complex, KBTBD4 is recurrently mutated in medulloblastoma (MB) 2 , the most common embryonal brain tumor in children, and pineoblastoma 3 . These mutations impart gain-of-function to KBTBD4 to induce aberrant degradation of the transcriptional corepressor CoREST 4 . However, their mechanism of action remains unresolved. Here, we elucidate the mechanistic basis by which KBTBD4 mutations promote CoREST degradation through engaging HDAC1/2, the direct neomorphic target of the substrate receptor. Using deep mutational scanning, we systematically map the mutational landscape of the KBTBD4 cancer hotspot, revealing distinct preferences by which insertions and substitutions can promote gain-of-function and the critical residues involved in the hotspot interaction. Cryo-electron microscopy (cryo-EM) analysis of two distinct KBTBD4 cancer mutants bound to LSD1-HDAC1-CoREST reveals that a KBTBD4 homodimer asymmetrically engages HDAC1 with two KELCH-repeat propeller domains. The interface between HDAC1 and one of the KBTBD4 propellers is stabilized by the MB mutations, which directly insert a bulky side chain into the active site pocket of HDAC1. Our structural and mutational analyses inform how this hotspot E3-neo-substrate interface can be chemically modulated. First, our results unveil a converging shape complementarity-based mechanism between gain-of-function E3 mutations and a molecular glue degrader, UM171. Second, we demonstrate that HDAC1/2 inhibitors can block the mutant KBTBD4-HDAC1 interface, the aberrant degradation of CoREST, and the growth of KBTBD4-mutant MB models. Altogether, our work reveals the structural and mechanistic basis of cancer mutation-driven neomorphic protein-protein interactions and pharmacological strategies to modulate their action for therapeutic applications.
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UM171 is a potent small molecule agonist of ex vivo human hematopoietic stem cell (HSC) self-renewal, a process that is tightly controlled by epigenetic regulation. By co-opting KBTBD4, a substrate receptor of the CULLIN3-RING E3 ubiquitin ligase complex, UM171 promotes the degradation of members of the CoREST transcriptional corepressor complex, thereby limiting HSC attrition. However, the direct target and mechanism of action of UM171 remain unclear. Here, we reveal that UM171 acts as a molecular glue to induce high-affinity interactions between KBTBD4 and HDAC1 to promote the degradation of select HDAC1/2 corepressor complexes. Through proteomics and chemical inhibitor studies, we discover that the principal target of UM171 is HDAC1/2. Cryo-electron microscopy (cryo-EM) analysis of dimeric KBTBD4 bound to UM171 and the LSD1-HDAC1-CoREST complex unveils an unexpected asymmetric assembly, in which a single UM171 molecule enables a pair of KBTBD4 KELCH-repeat propeller domains to recruit HDAC1 by clamping on its catalytic domain. One of the KBTBD4 propellers partially masks the rim of the HDAC1 active site pocket, which is exploited by UM171 to extend the E3-neo-substrate interface. The other propeller cooperatively strengthens HDAC1 binding via a separate and distinct interface. The overall neomorphic interaction is further buttressed by an endogenous cofactor of HDAC1-CoREST, inositol hexakisphosphate, which makes direct contacts with KBTBD4 and acts as a second molecular glue. The functional relevance of the quaternary complex interaction surfaces defined by cryo-EM is demonstrated by in situ base editor scanning of KBTBD4 and HDAC1. By delineating the direct target of UM171 and its mechanism of action, our results reveal how the cooperativity offered by a large dimeric CRL E3 family can be leveraged by a small molecule degrader and establish for the first time a dual molecular glue paradigm.
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Introduction: Universities in non-Anglophone countries are increasingly implementing English as the medium of instruction (EMI) lectures. There seems to be an assumption that students' performance on standardized English examinations can be equated with the lexical knowledge needed to comprehend EMI lectures regardless of discipline. For unknown words students encounter, it is assumed that they can be picked up through listening to these lectures. This potential for students to acquire unknown words incidentally while listening to these lectures has yet to be fully explored. Methods: This study addresses the potential of students incidentally acquiring vocabulary from listening to EMI lectures through corpus analyses of computer science lectures at one public university in Macau. Taking into consideration frequency, range, and lecturer explanation, corpus analyses of the transcripts of 28 computer science lectures (40 h 36 min) were conducted to determine the lexical knowledge needed for students to comprehend the lectures. The potential number of words these students could acquire through listening to the lectures was also uncovered through further analyses. Results: Results showed that L2 students need to have receptive knowledge of the most frequent 3,000 word families plus proper nouns and marginal words to reach beyond 95% lexical coverage. To reach 98% lexical coverage, 5,000 word families are needed. Considering frequency, range, and teacher explanation, we concluded that 30 new words could reasonably be incidentally acquired after listening to the 28 lectures. Discussion: These results indicate a need for EMI lecturers to consider the lexical knowledge of students and whether additional pedagogical techniques (i.e., vocabulary explanation) should be employed in content classrooms when lectures are delivered in English, especially for specialized fields such as computer science. Our results also draw attention to the importance of field specific vocabulary and the potential pitfalls of using blanket English language admissions criteria when admitting students to different academic programs.
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Stimulus-responsive ionic liquids have gained significant attention for their applications in various areas. Herein, three kinds of azobenzimidazole ionic liquids with reversible photo-induced conductivity regulation were designed and synthesized. The change of electrical conductivity under UV/visible light irradiation in aqueous solution was studied, and the effect of chemical structure and concentration of ionic liquids containing azobenzene to the regulation of photoresponse conductivity were discussed. The results showed that exposing the ionic liquid aqueous solution to ultraviolet light significantly increased its conductivity. Ionic liquids with longer alkyl chains exhibited an even greater increase in conductivity, up to 75.5%. Then under the irradiation of visible light, the electrical conductivity of the solution returned to its initial value. Further exploration of the mechanism of the reversible photo-induced conductivity regulation of azobenzene ionic liquids aqueous solution indicated that this may attributed to the formation/dissociation of ionic liquids aggregates in aqueous solution induced by the isomerization of azobenzene under UV/visible light irradiation and resulted the reversible conductivity regulation. This work provides a way for the molecular designing and performance regulation of photo-responsive ionic liquid and were expected to be applied in devices with photoconductive switching and micro photocontrol properties.