Ga-chabazite zeolites (Ga-CHA) have been found to efficiently catalyze propane dehydrogenation with high propylene selectivity (96%). In situ Fourier transform infrared spectroscopy and pulse ...titrations are employed to determine that upon reduction, surface Ga2O3 is reduced and diffuses into the zeolite pores, displacing the Brønsted acid sites and forming extra-framework Ga+ sites. This isolated Ga+ site reacts reversibly with H2 to form GaH x (2034 cm–1) with an enthalpy of formation of ∼−51.2 kJ·mol–1, a result supported by density functional theory calculations. The initial C3H8 dehydrogenation rates decrease rapidly (40%) during the first 100 min and then decline slowly afterward, while the C3H6 selectivity is stable at ∼96%. The reduction in the reaction rate is correlated with the formation of polycyclic aromatics inside the zeolite (using UV–vis spectroscopy) indicating that the accumulation of polycyclic aromatics is the main cause of the deactivation. The carbon species formed can be easily oxidized at 600 °C with complete recovery of the PDH catalytic properties. The correlations between GaH x vs Ga/Al ratio and PDH rates vs Ga/Al ratio show that extra-framework Ga+ is the active center catalyzing propane dehydrogenation. The higher reaction rate on Ga+ than In+ in CHA zeolites, by a factor of 43, is the result of differences in the stabilization of the transition state due to the higher stability of Ga3+ vs In3+. The uniformity of the Ga+ sites in this material makes it an excellent model for the molecular understanding of metal cation-exchanged hydrocarbon interactions in zeolites.
Ubiquitination plays a major role in protein degradation. Although phosphorylation-dependent ubiquitination is well known for the regulation of protein stability, methylation-dependent ubiquitination ...machinery has not been characterized. Here, we provide evidence that methylation-dependent ubiquitination is carried out by damage-specific DNA binding protein 1 (DDB1)/cullin4 (CUL4) E3 ubiquitin ligase complex and a DDB1-CUL4-associated factor 1 (DCAF1) adaptor, which recognizes monomethylated substrates. Molecular modeling and binding affinity studies reveal that the putative chromo domain of DCAF1 directly recognizes monomethylated substrates, whereas critical binding pocket mutations of the DCAF1 chromo domain ablated the binding from the monomethylated substrates. Further, we discovered that enhancer of zeste homolog 2 (EZH2) methyltransferase has distinct substrate specificities for histone H3K27 and nonhistones exemplified by an orphan nuclear receptor, RORα. We propose that EZH2-DCAF1/DDB1/CUL4 represents a previously unrecognized methylation-dependent ubiquitination machinery specifically recognizing “methyl degron”; through this, nonhistone protein stability can be dynamically regulated in a methylation-dependent manner.
► EZH2-mediated RORα monomethylation destabilizes RORα ► EZH2-DCAF1/DDB1/CUL4 as a methylation-dependent ubiquitination machine ► Molecular basis for the recognition of “methyl degron” by DCAF1 ► RORα ubiquitination leads to the transcriptional repression of RORα target genes
Semiconductor heterostructures are backbones for solid-state-based optoelectronic devices. Recent advances in assembly techniques for van der Waals heterostructures have enabled the band engineering ...of semiconductor heterojunctions for atomically thin optoelectronic devices. In two-dimensional heterostructures with type II band alignment, interlayer excitons, where Coulomb bound electrons and holes are confined to opposite layers, have shown promising properties for novel excitonic devices, including a large binding energy, micron-scale in-plane drift-diffusion, and a long population and valley polarization lifetime. Here, we demonstrate interlayer exciton optoelectronics based on electrostatically defined lateral p–n junctions in a MoSe2–WSe2 heterobilayer. Applying a forward bias enables the first observation of electroluminescence from interlayer excitons. At zero bias, the p–n junction functions as a highly sensitive photodetector, where the wavelength-dependent photocurrent measurement allows the direct observation of resonant optical excitation of the interlayer exciton. The resulting photocurrent amplitude from the interlayer exciton is about 200 times smaller than the resonant excitation of intralayer exciton. This implies that the interlayer exciton oscillator strength is 2 orders of magnitude smaller than that of the intralayer exciton due to the spatial separation of electron and hole to the opposite layers. These results lay the foundation for exploiting the interlayer exciton in future 2D heterostructure optoelectronic devices.
Post-translational modifications of DNA and histones are epigenetic mechanisms, which affect the chromatin structure, ultimately leading to gene expression changes. A number of different epigenetic ...enzymes are actively involved in the addition or the removal of various covalent modifications, which include acetylation, methylation, phosphorylation, ubiquitination, and sumoylation. Deregulation of these processes is a hallmark of cancer. For instance, G9a, a histone methyltransferase responsible for histone H3 lysine 9 (H3K9) mono- and dimethylation, has been observed to be upregulated in different types of cancer and its overexpression has been associated with poor prognosis. Key roles played by these enzymes in various diseases have led to the hypothesis that these molecules represent valuable targets for future therapies. Several small molecule inhibitors have been developed to specifically block the epigenetic activity of these enzymes, representing promising therapeutic tools in the treatment of human malignancies, such as cancer. In this review, the role of one of these epigenetic enzymes, G9a, is discussed, focusing on its functional role in regulating gene expression as well as its implications in cancer initiation and progression. We also discuss important findings from recent studies using epigenetic inhibitors in cell systems in vitro as well as experimental tumor growth and metastasis assays in vivo.
The Canadian Earth System Model version 5 (CanESM5) is a global
model developed to simulate historical climate change and variability, to
make centennial-scale projections of future climate, and to ...produce
initialized seasonal and decadal predictions. This paper describes the model
components and their coupling, as well as various aspects of model
development, including tuning, optimization, and a reproducibility strategy.
We also document the stability of the model using a long control simulation,
quantify the model's ability to reproduce large-scale features of the
historical climate, and evaluate the response of the model to external
forcing. CanESM5 is comprised of three-dimensional atmosphere (T63 spectral
resolution equivalent roughly to 2.8∘) and ocean (nominally 1∘) general
circulation models, a sea-ice model, a land surface scheme, and explicit
land and ocean carbon cycle models. The model features relatively coarse
resolution and high throughput, which facilitates the production of large
ensembles. CanESM5 has a notably higher equilibrium climate sensitivity
(5.6 K) than its predecessor, CanESM2 (3.7 K), which we briefly discuss, along
with simulated changes over the historical period. CanESM5 simulations
contribute to the Coupled Model Intercomparison Project phase 6 (CMIP6)
and will be employed for climate science and service applications in Canada.
The coronavirus disease 2019 (COVID-19) pandemic has led to accelerated efforts to develop therapeutics and vaccines. A key target of these efforts is the spike (S) protein, which is metastable and ...difficult to produce recombinantly. We characterized 100 structure-guided spike designs and identified 26 individual substitutions that increased protein yields and stability. Testing combinations of beneficial substitutions resulted in the identification of HexaPro, a variant with six beneficial proline substitutions exhibiting higher expression than its parental construct (by a factor of 10) as well as the ability to withstand heat stress, storage at room temperature, and three freeze-thaw cycles. A cryo-electron microscopy structure of HexaPro at a resolution of 3.2 angstroms confirmed that it retains the prefusion spike conformation. High-yield production of a stabilized prefusion spike protein will accelerate the development of vaccines and serological diagnostics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Identification of any mechanism for microbiologically influenced corrosion (MIC) requires an understanding of the specificity of metal/microbe/electrolyte interactions. Recent advancements in our ...understanding of MIC are related to recognition of the implications of this specificity. For example, under some circumstances, nutrients can accelerate rates of corrosion. In other cases the oxyanions in nutrients can inhibit localised corrosion. In some environments the absence of oxidisable carbon can force a shift in electron donor and may result in more aggressive corrosion than in the presence of oxidisable carbon. Non-corrosive biofilms can become corrosive with subtle changes in the environment, e.g., addition of electron shuttle compounds. The list of electron donors and acceptors related to MIC has been expanded in recognition of the metabolic flexibility that has been demonstrated for microorganisms. Recent research on microbial fuel cells and microbial batteries has added to our understanding of microbial/metal interactions.
Abstract
Colorectal cancer (CRC) remains a leading cause of cancer-related deaths in the United States. Although immunotherapy has dramatically changed the landscape of treatment for many advanced ...cancers, the benefit in CRC has thus far been limited to patients with microsatellite instability high (MSI-H):DNA mismatch repair–deficient (dMMR) tumors. Recent studies in the refractory CRC setting have led to US Food and Drug Administration approvals for pembrolizumab as well as nivolumab (with or without ipilimumab) for tumors harboring an MSI-H:dMMR molecular profile. Several randomized controlled trials are underway to move immunotherapy into the frontline for metastatic cancer (with or without chemotherapy) and the adjuvant setting. Awareness of these studies is critical given the relatively low incidence (approximately 3%–5%) of MSI-H:dMMR in advanced or metastatic CRC to support study completion, because the results could be potentially practice changing. The real challenge in this disease is related to demonstrating the benefit of immunotherapy for the vast majority of patients with CRC not harboring MSI-H:dMMR. Given the rapid pace of scientific changes, this article provides a narrative review regarding the current landscape of immunotherapy for CRC. Particular attention is paid to the currently available data that inform today’s clinical practice along with upcoming randomized controlled trials that may soon dramatically change the treatment landscape for CRC.
Osteogenic sarcoma (OS) is a deadly skeletal malignancy whose cause is unknown. We report here a mouse model of OS based on conditional expression of the intracellular domain of Notch1 (NICD). ...Expression of the NICD in immature osteoblasts was sufficient to drive the formation of bone tumors, including OS, with complete penetrance. These tumors display features of human OS; namely, histopathology, cytogenetic complexity, and metastatic potential. We show that Notch activation combined with loss of p53 synergistically accelerates OS development in mice, although p53-driven OS is not Rbpj dependent, which demonstrates a dual dominance of the Notch oncogene and p53 mutation in the development of OS. Using this model, we also reveal the osteoblasts as the potential sources of OS.
•Notch 1 intracellular domain induces bone tumors in mice with 100% penetrance•Mouse osteosarcoma initiated by Notch activation mimics the human disease•Notch activation and p53 loss independently and synergistically induce osteosarcoma•Committed osteoblasts are a potential source of tumor cells in osteosarcomagenesis
Tao et al. show that Notch activation in osteoblasts is sufficient to initiate osteogenic sarcoma (OS)-like tumors that mimic human OS and demonstrate a dual dominance for Notch activation and p53 mutation in the development of OS.
Background Respiratory viral infection, including respiratory syncytial virus (RSV) and rhinovirus, has been linked to respiratory disease in pediatric patients, including severe acute bronchiolitis ...and asthma exacerbation. Objective The study examined the role of the epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) in the response to RSV infection. Methods Infection of human airway epithelial cells was used to examine TSLP induction after RSV infection. Air–liquid interface cultures from healthy children and children with asthma were also tested for TSLP production after infection. Finally, a mouse model was used to directly test the role of TSLP signaling in the response to RSV infection. Results Infection of airway epithelial cells with RSV led to the production of TSLP via activation of an innate signaling pathway that involved retinoic acid induced gene I, interferon promoter-stimulating factor 1, and nuclear factor-κB. Consistent with this observation, airway epithelial cells from asthmatic children a produced significantly greater levels of TSLP after RSV infection than cells from healthy children. In mouse models, RSV-induced TSLP expression was found to be critical for the development of immunopathology. Conclusion These findings suggest that RSV can use an innate antiviral signaling pathway to drive a potentially nonproductive immune response and has important implications for the role of TSLP in viral immune responses in general.
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