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Chemical Science Jun 2024Efficient, economically viable n-type organic semiconductor materials suitable for solution-processed OFET devices with high electron mobility and ambient stability are...
Efficient, economically viable n-type organic semiconductor materials suitable for solution-processed OFET devices with high electron mobility and ambient stability are scarce. Merging these attributes into a single molecule remains a significant challenge and a careful molecular design is needed. To address this, synthetic viability (achievable in fewer than three steps) and using cost-effective starting materials are crucial. Our research presents a strategy that meets these criteria using naphthalene diimide (NDI) core structures. The approach involves a simple synthesis process with a cost of $ 5-10 per gram for the final products. This paper highlights our success in scaling up the production using affordable known reagents, creating ambient condition solution-processed OFET devices with impressive electron mobility, on-off current ratio (1 cm V s and / ∼ 10) and good ambient stability (more than 100 h). We conducted a comprehensive study on EHNDIBr, a material that demonstrates superior performance due to its unique supramolecular arrangement in its brickwork stack. This was compared with two similar structures to validate our findings. The superior performance of EHNDIBr is attributed to the effective interlocking of charge-hopping units within the NDI core in its brickwork stack. Our findings include detailed electronic, spectroscopic, and microscopic analyses of these layers.
PubMed: 38939134
DOI: 10.1039/d4sc02339k -
G-quadruplex-guided cisplatin triggers multiple pathways in targeted chemotherapy and immunotherapy.Chemical Science Jun 2024G-quadruplexes (G4s) are atypical nucleic acid structures involved in basic human biological processes and are regulated by small molecules. To date, pyridostatin and...
G-quadruplexes (G4s) are atypical nucleic acid structures involved in basic human biological processes and are regulated by small molecules. To date, pyridostatin and its derivatives [, PyPDS (4-(2-aminoethoxy)- , -bis(4-(2-(pyrrolidin-1-yl) ethoxy) quinolin-2-yl) pyridine-2,6-dicarboxamide)] are the most widely used G4-binding small molecules and considered to have the best G4 specificity, which provides a new option for the development of cisplatin-binding DNA. By combining PyPDS with cisplatin and its analogs, we synthesize three platinum complexes, named PyPDSplatins. We found that cisplatin with PyPDS (CP) exhibits stronger specificity for covalent binding to G4 domains even in the presence of large amounts of dsDNA compared with PyPDS either extracellularly or intracellularly. Multiomics analysis reveals that CP can effectively regulate G4 functions, directly damage G4 structures, activate multiple antitumor signaling pathways, including the typical cGAS-STING pathway and AIM2-ASC pathway, trigger a strong immune response and lead to potent antitumor effects. These findings reflect that cisplatin-conjugated specific G4 targeting groups have antitumor mechanisms different from those of classic cisplatin and provide new strategies for the antitumor immunity of metals.
PubMed: 38939132
DOI: 10.1039/d4sc00643g -
Chemical Science Jun 2024This article offers a broad overview of measurement methods in the field of molecular electronics, with a particular focus on the most common single-molecule junction... (Review)
Review
This article offers a broad overview of measurement methods in the field of molecular electronics, with a particular focus on the most common single-molecule junction fabrication techniques, the challenges in data analysis and interpretation of single-molecule junction current-distance traces, and a summary of simulations and predictive models aimed at establishing robust structure-property relationships of use in the further development of molecular electronics.
PubMed: 38939131
DOI: 10.1039/d4sc00488d -
Chemical Science Jun 2024Exploration of porous adsorbents with high CO/N selectivity is of great significance for reducing CO content in the atmosphere. In this study, a series of isoreticular...
Exploration of porous adsorbents with high CO/N selectivity is of great significance for reducing CO content in the atmosphere. In this study, a series of isoreticular ultramicroporous fluorinated metal-organic frameworks (MOFs) were prepared to explore the benefits of fluorinated ultramicropores in improving CO/N selectivity. Gas adsorption measurements revealed that the increase in the number of fluorine atoms in a ligand molecule leads to the increased CO uptakes and CO/N selectivity. Theoretical calculations indicate that the interaction between the fluorine atoms and adsorbed CO molecules enhances the CO-philicity, offering useful insight into the improvement of CO/N selectivity in isoreticular frameworks.
PubMed: 38939130
DOI: 10.1039/d4sc01525h -
Biochemistry and Biophysics Reports Sep 2024Zika virus represents the primary cause of infection during pregnancy and can lead to various neurological disorders such as microcephaly and Guillain-Barré syndrome...
Zika virus represents the primary cause of infection during pregnancy and can lead to various neurological disorders such as microcephaly and Guillain-Barré syndrome affecting both children and adults. This infection is also associated with urological and nephrological problems. So far, evidence of mosquito-borne Zika virus infection has been reported in a total of 89 countries and territories. However, surveillance efforts primarily concentrate on outbreaks that this virus can cause, yet the measures implemented are typically limited. Currently, there are no specific treatments or vaccines designed for the prevention or treatment of Zika virus infection or its associated disease. The development of effective therapeutic agents presents an urgent need. Importantly, an alternative for advancing the discovery of new molecules could be dermaseptins, a family of antimicrobial peptides known for their potential antiviral properties. In this study, we carried out the synthesis of dermaseptins and their analogs and subsequently assessed the bioactivity tests against Zika virus (ZIKV PF13) of dermaseptins B2 and S4 and their derivatives. The cytotoxicity of these peptides was investigated on HMC3 cell line and HeLa cells by CellTiter-Glo® Luminescent Cell Viability Assay. Thereafter, we evaluated the antiviral activity caused by the action of our dermaseptins on the viral envelope using the Fluorescence Activated Cell Sorting (FACS). The cytotoxicity of our molecules was concentration-dependent at microgram concentrations Expect for dermaseptin B2 and its derivative which present no toxicity against HeLa and HMC3 cell lines. It was observed that all tested analogs from S4 family exhibited antiviral activity with low concentrations ranging from 3 to 12.5 μg/ml , unlike the native B2 and its derivative which increased the infectivity. Pre-incubating of dermaseptins with ZIKV PF13 before infection revealed that these derivatives inhibit the initial stages of virus infection. In summary, these results suggest that dermaseptins could serve as novel lead structures for the development of potent antiviral agents against Zika virus infections.
PubMed: 38939125
DOI: 10.1016/j.bbrep.2024.101747 -
IScience Jun 2024Human leukocyte antigen (HLA) class-I molecules present fragments of the cellular proteome to the T cell receptor (TCR) of cytotoxic T cells to control infectious...
Human leukocyte antigen (HLA) class-I molecules present fragments of the cellular proteome to the T cell receptor (TCR) of cytotoxic T cells to control infectious diseases and cancer. The large number of combinations of HLA class-I allotypes and peptides allows for highly specific and dedicated low-affinity interactions to a diverse array of TCRs and natural killer (NK) cell receptors. Whether the divergent HLA class-I peptide complex is exclusive for interactions with these proteins is unknown. Using genome-wide CRISPR-Cas9 activation and knockout screens, we identified peptide-specific HLA-C∗07 combinations that can interact with the surface molecules CD55 and heparan sulfate. These interactions closely resemble the HLA class-I interaction with the TCR regarding both the affinity range and the specificity of the peptide and HLA allele. These findings indicate that various proteins can specifically bind HLA class-I peptide complexes due to their polymorphic nature, which suggests there are more interactions like the ones we describe here.
PubMed: 38939106
DOI: 10.1016/j.isci.2024.110120 -
Cureus Jun 2024Introduction Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), represent chronic progressive inflammatory gastrointestinal...
Introduction Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), represent chronic progressive inflammatory gastrointestinal disorders, without a single reference standard for their diagnosis. The histological assessment gained an important role in accurately measuring disease activity, and mucosal healing (MH) was recently proposed to be an ideal treatment goal for patients with IBD because of its favorable prognosis, with a lower risk of recurrence or surgical treatment. This paper aims to add to the histological classical findings for IBD patients the identification of the monomeric form of the C-reactive protein (mCRP) as a supplementary marker that could be stained at the level of tissue samples and could be correlated with the pathogenic mechanism. Methods Two groups of 10 patients were each selected for the study, for both UC and CD, together with a control group. All samples collected through digestive endoscopy were analyzed by using H&E-stained slides, followed by immunohistochemical examination with antibodies to mCRP (M8C10), and markers of inflammatory activity through CD3, CD45(leukocyte common antigen (LCA)), CD138/syndecan-1 and CD68. Results For the CD study group, all histological elements identified with H&E and afterward stained with CD138, CD68, CD3, and CD45/LCA were correlated with the standards imposed by the European Crohn's and Colitis Organization (ECCO). For the group of patients with UC, histological images obtained with H&E and IHC stainings also confirmed the recommendation of ECCO. The main cells considered in the literature as histological markers for IBD are neutrophils, lymphocytes, and plasmocytes, stained in our study with CD45/LCA, CD3, and CD138. For all 20 cases of IBD (UC and CD), the staining with anti-Ab8C10 antibodies for mCRP was positive, while negative results were noticed within the control group. An mCRP protein visualized with anti-Ab8C10 antibodies presented an intracytoplasmatic localization in the neutrophils, plasma cells, lymphocytes, and macrophages from the lamina propria and glandular epithelium, without expression in endothelial cells. Conclusions Our study represents one of the first papers that identifies the localization of mCRP molecules within the intestinal mucosa of patients with IBD (both UC and CD) by using immunohistochemistry (IHC) staining. This finding opens a new perspective for considering mCRP as a marker correlated with histological disease activity and/or definition of histological remission in IBD.
PubMed: 38938906
DOI: 10.7759/cureus.63200 -
Frontiers in Cellular and Infection... 2024Hand, foot, and mouth disease (HFMD) is a common infectious disease caused by enterovirus 71 (EV71) that frequently affects children, leading to severe infections in...
Hand, foot, and mouth disease (HFMD) is a common infectious disease caused by enterovirus 71 (EV71) that frequently affects children, leading to severe infections in some cases. In general, when infection occurs, the body upregulates inflammatory responses to eliminate pathogenic microorganisms to protect the host from infection. However, EV71 may inhibit host's innate immunity to promote virus infection. At present, it is not fully understood how EV71 hijack the host cells for its own replication. Toll-like receptor 4 (TLR4), a natural immune receptor, historically associated with bacterial endotoxin-induced inflammatory responses. However, it is still unclear whether and how TLR4 is altered during EV71 infection. In this study, we observed a reduction in both TLR4 protein and gene transcript levels in RD, GES-1, and Vero cells following EV71 infection, as detected by RT-qPCR, immunofluorescence staining and western blot. Furthermore, we observed that the TLR4 downstream molecules of MYD88, p-NF-κB p65, p-TBK1 and related inflammatory cytokines were also reduced, suggesting that antiviral innate immune and inflammatory response were suppressed. To determine the impact of TLR4 changes on EV71 infection, we interfered EV71-infected RD cells with TLR4 agonist or inhibitor and the results showed that activation of TLR4 inhibited EV71 replication, while inhibition of TLR4 promote EV71 replication. Besides, EV71 replication was also promoted in TLR4 siRNA-transfected and EV71-infected RD cells. This suggests that down-regulation the expression of TLR4 by EV71 can inhibit host immune defense to promote EV71 self-replication. This novel mechanism may be a strategy for EV71 to evade host immunity.
Topics: Toll-Like Receptor 4; Enterovirus A, Human; Humans; Virus Replication; Signal Transduction; Animals; Vero Cells; Chlorocebus aethiops; Immunity, Innate; Host-Pathogen Interactions; Inflammation; Myeloid Differentiation Factor 88; Cell Line; Protein Serine-Threonine Kinases; Cytokines; NF-kappa B; Hand, Foot and Mouth Disease
PubMed: 38938877
DOI: 10.3389/fcimb.2024.1393680 -
Journal of Extracellular Biology Apr 2024Extracellular vesicles (EVs) have been proposed to play dual roles in cellular homeostasis, functioning both to remove unwanted intracellular molecules, and to enable...
Extracellular vesicles (EVs) have been proposed to play dual roles in cellular homeostasis, functioning both to remove unwanted intracellular molecules, and to enable communication between cells as a means of modulating cellular responses in different physiological and pathological scenarios. EVs contain a broad range of cargoes, including multiple biotypes of RNA, which can vary depending on the cell status, and may function as signalling molecules. In this study, we carried out comparative transcriptomic analysis of EVs and cells, demonstrating that the RNA profile of EVs is distinct from cells and shows dose-dependent changes in response to oxidative stress. We identified a high abundance of snoRNAs in EVs, alongside an enrichment of intronic and untranslated regions (UTRs) of mRNAs under stress. We also observed an increase in the relative abundance of either aberrant or modified mRNAs under stress. These findings suggest that EVs may function both for the elimination of specific cellular RNAs, and for the incorporation of RNAs that may hold signalling potential.
PubMed: 38938847
DOI: 10.1002/jex2.150 -
JACS Au Jun 2024Sample efficiency is a fundamental challenge in molecular design. Ideally, molecular generative models should learn to satisfy a desired objective under minimal calls...
Sample efficiency is a fundamental challenge in molecular design. Ideally, molecular generative models should learn to satisfy a desired objective under minimal calls to oracles (computational property predictors). This problem becomes more apparent when using oracles that can provide increased predictive accuracy but impose significant computational cost. Consequently, designing molecules that are optimized for such oracles cannot be achieved under a practical computational budget. Molecular generative models based on simplified molecular-input line-entry system (SMILES) have shown remarkable sample efficiency when coupled with reinforcement learning, as demonstrated in the practical molecular optimization (PMO) benchmark. Here, we first show that experience replay drastically improves the performance of multiple previously proposed algorithms. Next, we propose a novel algorithm called Augmented Memory that combines data augmentation with experience replay. We show that scores obtained from oracle calls can be reused to update the model multiple times. We compare Augmented Memory to previously proposed algorithms and show significantly enhanced sample efficiency in an exploitation task, a drug discovery case study requiring both exploration and exploitation, and a materials design case study optimizing explicitly for quantum-mechanical properties. Our method achieves a new state-of-the-art in sample-efficient molecular design, outperforming all of the previously reported methods. The code is available at https://github.com/schwallergroup/augmented_memory.
PubMed: 38938817
DOI: 10.1021/jacsau.4c00066