ABSTRACT
Extreme precipitation is a considerable contributor to meteorological disasters and there is a great need to mitigate its socioeconomic effects through skilful nowcasting that has high resolution, long lead times and local details1-3. Current methods are subject to blur, dissipation, intensity or location errors, with physics-based numerical methods struggling to capture pivotal chaotic dynamics such as convective initiation4 and data-driven learning methods failing to obey intrinsic physical laws such as advective conservation5. We present NowcastNet, a nonlinear nowcasting model for extreme precipitation that unifies physical-evolution schemes and conditional-learning methods into a neural-network framework with end-to-end forecast error optimization. On the basis of radar observations from the USA and China, our model produces physically plausible precipitation nowcasts with sharp multiscale patterns over regions of 2,048 km × 2,048 km and with lead times of up to 3 h. In a systematic evaluation by 62 professional meteorologists from across China, our model ranks first in 71% of cases against the leading methods. NowcastNet provides skilful forecasts at light-to-heavy rain rates, particularly for extreme-precipitation events accompanied by advective or convective processes that were previously considered intractable.
ABSTRACT
Epstein-Barr virus (EBV) is associated with multiple human malignancies. To evade immune detection, EBV switches between latent and lytic programs. How viral latency is maintained in tumors or in memory B cells, the reservoir for lifelong EBV infection, remains incompletely understood. To gain insights, we performed a human genome-wide CRISPR/Cas9 screen in Burkitt lymphoma B cells. Our analyses identified a network of host factors that repress lytic reactivation, centered on the transcription factor MYC, including cohesins, FACT, STAGA, and Mediator. Depletion of MYC or factors important for MYC expression reactivated the lytic cycle, including in Burkitt xenografts. MYC bound the EBV genome origin of lytic replication and suppressed its looping to the lytic cycle initiator BZLF1 promoter. Notably, MYC abundance decreases with plasma cell differentiation, a key lytic reactivation trigger. Our results suggest that EBV senses MYC abundance as a readout of B cell state and highlights Burkitt latency reversal therapeutic targets.
Subject(s)
Burkitt Lymphoma/pathology , Epstein-Barr Virus Infections/virology , Herpesvirus 4, Human/physiology , Host-Pathogen Interactions , Proto-Oncogene Proteins c-myc/metabolism , Virus Activation , Virus Latency , Animals , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , B-Lymphocytes/virology , Burkitt Lymphoma/metabolism , Burkitt Lymphoma/virology , Cell Proliferation , Epstein-Barr Virus Infections/genetics , Epstein-Barr Virus Infections/metabolism , Female , Gene Expression Regulation, Viral , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Promoter Regions, Genetic , Proto-Oncogene Proteins c-myc/genetics , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Prenylation is a post-translational modification (PTM) widely found in primary and secondary metabolism. This modification can enhance the lipophilicity of molecules, enabling them to interact with lipid membranes more effectively. The prenylation of peptides is often carried out by cyanobactin prenyltransferases (PTases) from cyanobacteria. These enzymes are of interest due to their ability to add prenyl groups to unmodified peptides, thus making them more effective therapeutics through the subsequent acquisition of increased membrane permeability and bioavailability. Herein we review the current knowledge of cyanobactin PTases, focusing on their discovery, biochemistry, and bioengineering, and highlight the potential application of them as peptide alkylation biocatalysts to generate peptide therapeutics.
Subject(s)
Dimethylallyltranstransferase , Dimethylallyltranstransferase/chemistry , Dimethylallyltranstransferase/metabolism , Peptides, Cyclic/chemistry , Peptides , BioengineeringABSTRACT
RNA splicing is a critical mechanism by which to modify transcriptome, and its dysregulation is the underlying cause of many human diseases. It remains challenging, however, to genetically modulate a splicing event in its native context. Here, we demonstrate that a CRISPR-guided cytidine deaminase (i.e., targeted-AID mediated mutagenesis [TAM]) can efficiently modulate various forms of mRNA splicing. By converting invariant guanines to adenines at either 5' or 3' splice sites (SS), TAM induces exon skipping, activation of alternative SS, switching between mutually exclusive exons, or targeted intron retention. Conversely, TAM promotes downstream exon inclusion by mutating cytidines into thymines at the polypyrimidine tract. Applying this approach, we genetically restored the open reading frame and dystrophin function of a mutant DMD gene in patient-derived induced pluripotent stem cells (iPSCs). Thus, the CRISPR-guided cytidine deaminase provides a versatile genetic platform to modulate RNA splicing and to correct mutations associated with aberrant splicing in human diseases.
Subject(s)
Clustered Regularly Interspaced Short Palindromic Repeats/genetics , Cytidine Deaminase/genetics , RNA Splicing/genetics , Amino Acid Sequence , Animals , Cell Line , Dystrophin/genetics , Exons/genetics , Gene Regulatory Networks , HEK293 Cells , Humans , Introns/genetics , Mice , Open Reading Frames/genetics , RNA Splice Sites/geneticsABSTRACT
Crystallographic control of crystals as catalysts with precise geometrical and chemical features is significantly important to develop sustainable chemistry, yet highly challenging. Encouraged by first principles calculations, precise structure control of ionic crystals could be realized by introducing an interfacial electrostatic field. Herein, we report an efficient in situ dipole-sourced electrostatic field modulation strategy using polarized ferroelectret, for crystal facet engineering toward challenging catalysis reactions, which avoids undesired faradic reactions or insufficient field strength by conventional external electric field. Resultantly, a distinct structure evolution from tetrahedron to polyhedron with different dominated facets of Ag3PO4 model catalyst was obtained by tuning the polarization level, and similar oriented growth was also realized by ZnO system. Theoretical calculations and simulation reveal that the generated electrostatic field can effectively guide the migration and anchoring of Ag+ precursors and free Ag3PO4 nuclei, achieving oriented crystal growth by thermodynamic and kinetic balance. The faceted Ag3PO4 catalyst exhibits high performance in photocatalytic water oxidation and nitrogen fixation for valuable chemicals production, validating the effectiveness and potential of this crystal regulation strategy. Such an electrically tunable growth concept by electrostatic field provides new synthetic insights and great opportunity to effectively tailor the crystal structures for facet-dependent catalysis.
ABSTRACT
BACKGROUND AND AIMS: Molecular classification is a promising tool for prognosis prediction and optimizing precision therapy for HCC. Here, we aimed to develop a molecular classification of HCC based on the fatty acid degradation (FAD) pathway, fully characterize it, and evaluate its ability in guiding personalized therapy. APPROACH AND RESULTS: We performed RNA sequencing (RNA-seq), PCR-array, lipidomics, metabolomics, and proteomics analysis of 41 patients with HCC, in which 17 patients received anti-programmed cell death-1 (PD-1) therapy. Single-cell RNA sequencing (scRNA-seq) was performed to explore the tumor microenvironment. Nearly, 60 publicly available multiomics data sets were analyzed. The associations between FAD subtypes and response to sorafenib, transarterial chemoembolization (TACE), immune checkpoint inhibitor (ICI) were assessed in patient cohorts, patient-derived xenograft (PDX), and spontaneous mouse model ls. A novel molecular classification named F subtype (F1, F2, and F3) was identified based on the FAD pathway, distinguished by clinical, mutational, epigenetic, metabolic, and immunological characteristics. F1 subtypes exhibited high infiltration with immunosuppressive microenvironment. Subtype-specific therapeutic strategies were identified, in which F1 subtypes with the lowest FAD activities represent responders to compounds YM-155 and Alisertib, sorafenib, anti-PD1, anti-PD-L1, and atezolizumab plus bevacizumab (T + A) treatment, while F3 subtypes with the highest FAD activities are responders to TACE. F2 subtypes, the intermediate status between F1 and F3, are potential responders to T + A combinations. We provide preliminary evidence that the FAD subtypes can be diagnosed based on liquid biopsies. CONCLUSIONS: We identified 3 FAD subtypes with unique clinical and biological characteristics, which could optimize individual cancer patient therapy and help clinical decision-making.
Subject(s)
Carcinoma, Hepatocellular , Chemoembolization, Therapeutic , Liver Neoplasms , Animals , Mice , Humans , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Sorafenib/therapeutic use , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Multiomics , Precision Medicine , Fatty Acids , Tumor MicroenvironmentABSTRACT
Fat grafting is a promising technique for correcting soft tissue abnormalities, but oil cyst formation and graft fibrosis frequently impede the therapeutic benefit of fat grafting. The lipolysis of released oil droplets after grafting may make the inflammation and fibrosis in the grafts worse; therefore, by regulating adipose triglyceride lipase (ATGL) via Atglistatin (ATG) and Forskolin (FSK), we investigated the impact of lipolysis on fat grafts in this study. After being removed from the mice and chopped into small pieces, the subcutaneous fat from wild-type C57BL/6J mice was placed in three different solutions for two hours: serum-free cell culture medium, culture medium+FSK (50 µM), and culture medium+ATG (100 µM). Following centrifugation to remove water and free oil droplets, 0.3 mL of the fat particles per mouse was subcutaneously injected into the back of mice. Additionally, the subcutaneous fat grafting area was immediately injected with PBS (control group), ATG (30 mg/kg), and FSK (15 mg/kg) following fat transplantation. Detailed cellular events after grafting were investigated by histological staining, real-time polymerase chain reaction, immunohistochemistry/immunofluorescent staining, and quantification. Two weeks after grafting, grafts treated with ATG showed lower expression of ATGL and decreased mRNA levels of TNFα and IL-6. In contrast, grafts treated with ATG showed elevated expression levels of IL-4 and IL-13 compared to the control grafts. In addition, fewer apoptotic cells and oil cysts were observed in ATG grafts. Meanwhile, a higher CD206+/CD68+ ratio of macrophages and more CD31+ vascular endothelial cells existed in the 2-month ATG grafts. In comparison to the control, ATG treatment improved the volume retention of grafts, and decreased graft fibrosis and oil cyst formation. By preventing oil droplet lipolysis, pharmacological suppression of ATGL shielded adipocytes from lipotoxicity following grafting. Additionally, ATG ameliorated the apoptosis and inflammation brought on by adipocyte death and oil droplet lipolysis in grafted fat. These all indicate that lipolysis inhibition improved transplanted fat survival and decreased the development of oil cysts and graft fibrosis, offering a potential postoperative pharmacological intervention for bettering fat grafting.
Subject(s)
Adipose Tissue , Cysts , Animals , Mice , Lipolysis , Endothelial Cells , Mice, Inbred C57BL , Fibrosis , InflammationABSTRACT
The development of low-temperature lithium metal batteries (LMBs) encounters significant challenges because of severe dendritic lithium growth during the charging/discharging processes. To date, the precise origin of lithium dendrite formation still remains elusive due to the intricate interplay between the highly reactive lithium metal anode and organic electrolytes. Herein, we unveil the critical role of interfacial defluorination kinetics of localized high-concentration electrolytes (LHCEs) in regulating lithium dendrite formation, thereby determining the performance of low-temperature LMBs. We investigate the impact of solvation structures of LHCEs on low-temperature LMBs by employing tetrahydrofuran (THF) and 2-methyltetrahydrofuran (2-MeTHF) as comparative solvents. The combination of comprehensive characterizations and theoretical simulations reveals that the THF-based LHCE featured with a strong solvation strength exhibits fast interfacial defluorination reaction kinetics, thus leading to the formation of an amorphous and inorganic-rich solid-electrolyte interphase (SEI) that can effectively suppress the growth of lithium dendrites. As a result, the highly reversible Li metal anode achieves an exceptional Coulombic efficiency (CE) of up to â¼99.63% at a low temperature of -30 °C, thereby enabling stable cycling of low-temperature LMB full cells. These findings underscore the crucial role of electrolyte interfacial reaction kinetics in shaping SEI formation and provide valuable insights into the fundamental understanding of electrolyte chemistry in LMBs.
ABSTRACT
Ferroptosis, a nonapoptotic form of cell death marked by iron-dependent peroxidation of phospholipids, is associated with the occurrence and progression of tumors. Erastin, a selective inhibitor of the cystine/glutamate transporter system Xc-, can induce the ferroptosis of cancer cells. Multiple myeloma (MM) has been reported to be insensitive to erastin-induced ferroptosis. However, we found the erastin sensitivity of different MM cells varied widely. Specifically, SLC7A11 abundance determined the sensitivity of MM cells to erastin-induced ferroptosis. MM cells expressing a high SLC7A11 level were more sensitive to erastin-induced ferroptosis than cells expressing a low level of SLC7A11. Moreover, the expression of SLC7A11 gradually increased with the progression of plasma cell dyscrasias. Survival analysis indicated that high levels of SLC7A11 predicted a poor prognosis for MM patients. Knocking down SLC7A11 expression significantly inhibited the proliferation of MM cells and induced ferroptotic cell death. Additionally, we revealed that the long noncoding RNA (lncRNA) SLC7A11-AS1 was a critical regulatory factor of SLC7A11 expression. SLC7A11-AS1 overexpression diminished SLC7A11 levels, leading to the ferroptosis of MM cells. In summary, our data show that heterogeneous SLC7A11 expression affects MM cell sensitivity to ferroptosis, providing a theoretical basis for improving the clinical treatment of MM.
Subject(s)
Ferroptosis , Multiple Myeloma , Piperazines , Humans , Apoptosis/genetics , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Ferroptosis/genetics , Cell Death , Amino Acid Transport System y+/genetics , Amino Acid Transport System y+/metabolismABSTRACT
Identification of degradation products and pathways is crucial for investigating emerging pollutants and evaluation of wastewater treatment methods. Nontargeted analysis is a powerful tool to comprehensively investigate the degradation pathways of organic pollutants in real-world wastewater samples but often generates large data sets, making it difficult to effectively locate the exact information on interests. Herein, to efficiently establish the linkages among compounds in the same degradation pathways, we introduce a compound similarity network (CSN) as a novel data mining strategy for LC-MS-based nontargeted analysis of complex wastewater samples. Different from molecular networks that cluster compounds based on MS/MS spectra similarity, our CSN strategy harnesses molecular fingerprints to establish linkages among compounds and thus is spectra-independent. The effectiveness of CSN was demonstrated by nontargeted identification of degradation pathways and products of organic pollutants in leather industrial wastewater that underwent laboratory-scale activated carbon adsorption (ACD) and ozonation treatments. Utilizing CSN in interpreting nontargeted data, we tentatively annotated 4324 compounds in the untreated leather industrial wastewater, 3246 after ACD, and 3777 after ACD/ozonation. We located 145 potential degradation pathways of organic pollutants in the ACD/ozonation process using CSN and validated 7 pathways with 15 chemical standards. CSN also revealed 5 clusters of emerging pollutants, from which 3 compounds were selected for in vitro cytotoxicity study to evaluate their potential biohazards as new pollutants. As CSN offers an efficient way to connect massive compounds and to find multiple degradation pathways in a high-throughput manner, we anticipate that it will find wide applications in nontargeted analysis of diverse environmental samples.
ABSTRACT
Bone mineralization is a ubiquitous process among vertebrates that involves a dynamic physical/chemical interplay between the organic and inorganic components of bone tissues. It is now well documented that carbonated apatite, an inorganic component of bone, is proceeded through transient amorphous mineral precursors that transforms into the crystalline mineral phase. Here, the evolution on mineral precursors from their sources to the terminus in the bone mineralization process is reviewed. How organisms tightly control each step of mineralization to drive the formation, stabilization, and phase transformation of amorphous mineral precursors in the right place, at the right time, and rate are highlighted. The paradigm shifts in biomineralization and biomaterial design strategies are intertwined, which promotes breakthroughs in biomineralization-inspired material. The design principles and implementation methods of mineral precursor-based biomaterials in bone graft materials such as implant coatings, bone cements, hydrogels, and nanoparticles are detailed in the present manuscript. The biologically controlled mineralization mechanisms will hold promise for overcoming the barriers to the application of biomineralization-inspired biomaterials.
Subject(s)
Biomimetics , Calcification, Physiologic , Animals , Minerals/chemistry , Bone and Bones , Biocompatible Materials/chemistryABSTRACT
A frozen-temperature (below -28 °C) laser tuning way is developed to optimize metal halide perovskite (MHP)'s stability and opto-electronic properties, for emitter, photovoltaic and detector applications. Here freezing can adjust the competitive laser irradiation effects between damaging and annealing/repairing. And the ligand shells on MHP surface, which are widely present for many MHP materials, can be frozen and act as transparent solid templates for MHP's re-crystallization/re-growth during the laser tuning. With model samples of different types of CsPbBr3 nanocube arrays,an attempt is made to turn the dominant exposure facet from low-energy [100] facet to high-energy [111], [-211], [113] and [210] ones respectively; selectively removing the surface impurities and defects of CsPbBr3 nanocubes to enhance the irradiation durability by 101 times; and quickly (tens of seconds) modifying a Ruddlesden-Popper (RP) boundary into another type of boundary like twinning, and so on. The laser tuning mechanism is revealed by an innovative in situ cryo-transmission electron microscope (cryo-TEM) exploration at atomic resolution.
ABSTRACT
Fibrinogen-like protein-1 (FGL1) is confirmed a major ligand of lymphocyte activation gene-3 which could inhibit antigen-mediated T-cell response and evade immune supervision. Although hepatocytes secrete large amounts of FGL1, its high expression also be detected in solid tumors such as lung cancer, leading to a poor efficacy of immune checkpoint inhibitors therapy. Here we reported that FGL1 was overexpressed in lung adenocarcinoma (LUAD) but not in lung squamous cell carcinoma. However, FGL1 in tissue and plasma can only distinguish LUAD patients from healthy donors and cannot correlate with clinical Tumor Node Metastasis (TNM) stage. Using lung cancer cell lines, we confirmed that FGL1 can be detected on extracellular vesicles (EVs) and we established a method using flow cytometry to detect FGL1 on the surface of EVs, which revealed that FGL1 could be secreted via EVs. Both animal model and clinical samples proved that plasma FGL1 in EVs would increase when the tumor was loaded. The level of FGL1 in plasma EVs was correlated with clinical TNM stage and tumor size, and a higher level indicated non-responsiveness to anti-programmed cell death ligand 1 (anti-PD-L1) immunotherapy. Its effect on tumor progression and immune evasion may be achieved by impairing the killing and proliferating capacities of CD8+ T cells. Our result demonstrates that FGL1 levels in plasma EVs, but not total plasma FGL1, could be a promising biomarker that plays an important role in predicting anti-PD-L1 immune therapy in LUAD and suggests a new strategy in LUAD immunotherapy.
Subject(s)
Adenocarcinoma of Lung , Carcinoma, Non-Small-Cell Lung , Extracellular Vesicles , Lung Neoplasms , Animals , Humans , Ligands , Lung Neoplasms/pathology , Carcinoma, Non-Small-Cell Lung/pathology , Extracellular Vesicles/metabolism , B7-H1 Antigen , Fibrinogen/metabolismABSTRACT
Diffuse large B-cell lymphoma (DLBCL) is the most common and aggressive type of B-cell lymphoma. Unfortunately, about one-third of patients either relapse after the initial treatment or are refractory to first-line therapy, indicating a need for new treatment modalities. PIM serine/threonine kinases are proteins that are associated with genetic mutations, overexpression, or translocation events in B-cell lymphomas. We conducted an integrative analysis of whole-exome sequencing in 52 DLBCL patients, and no amplification, mutation, or translocation of the PIM1 gene was detected. Instead, analyses of TCGA and GTEx databases identified that PIM1 expression was increased in DLBCL samples compared to normal tissue, and high expression levels were associated with poor overall survival. Moreover, interference of PIM1 significantly suppressed DLBCL cell proliferation. In addition, we identified anwulignan, a natural small-molecule compound, as a PIM1 inhibitor. Anwulignan directly binds to PIM1 and exerts antitumor effects on DLBCL in vitro and in vivo by inducing apoptosis, cell cycle arrest, and autophagic cell death. Furthermore, we identified an effective synergistic combination between anwulignan and chidamide. Our findings suggested that PIM1 could be a therapeutic target and prognostic factor for DLBCL, and anwulignan holds promise for future development as a natural product for treatment.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Proto-Oncogene Proteins c-pim-1 , Humans , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Proto-Oncogene Proteins c-pim-1/genetics , Proto-Oncogene Proteins c-pim-1/metabolism , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/genetics , Mice , Animals , Biological Products/therapeutic use , Cell Line, Tumor , Female , Xenograft Model Antitumor Assays , Male , Apoptosis/drug effects , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , Cell Proliferation/drug effects , Aminopyridines/therapeutic use , Aminopyridines/pharmacology , Molecular Targeted Therapy , Gene Expression Regulation, Neoplastic/drug effectsABSTRACT
In this study, researchers developed a novel composite material called NH2-MIL-53-Al/PAN, which consists of metal-organic frameworks (MOFs) grown on electrospun PAN nanofibers (NFs). The successful formation of the composite was confirmed by X-ray diffraction (XRD) and Fourier transform infrared (FTIR), and the hydrophilicity of NH2-MIL-53-Al/PAN was demonstrated by the water contact angle (WCA). Batch experiments were conducted to investigate the adsorption performance of Co(II) under different conditions. The maximum adsorption capacity reached 58.72 mg/g, and almost 95% of the adsorption was achieved within the first 6 h. The adsorption process was found to be spontaneous and endothermic and followed the pseudo-second-order kinetics and Langmuir models. Chemisorption and molecular layer adsorption are the main mechanisms of adsorption, and X-ray photoelectron spectroscopy (XPS) analysis further reveals that the interaction between the adsorbent and cobalt is a coordination interaction. In this study, NH2-MIL-53-Al was grown in situ on PAN to ensure effective loading of MOFs and prevent agglomeration during the NF mixing process. This approach successfully addressed the challenge of exposing active sites within the embedded MOF crystals. Additionally, it overcame the difficulty of recycling traditional MOF adsorbents. As a result, the exceptional performance of MOF NFs offers a promising solution for the efficient removal of cobalt-containing wastewater.
ABSTRACT
OBJECTIVES: The primary focus of this research is the proposition of a methodological framework for the clinical application of the long COVID symptoms and severity score (LC-SSS). This tool is not just a self-reported assessment instrument developed and validated but serves as a standardized, quantifiable means to monitor the diverse and persistent symptoms frequently observed in individuals with long COVID. METHODS: A 3-stage process was used to develop, validate, and establish scoring standards for the LC-SSS. Validation measures included correlations with other patient-reported measures, confirmatory factor analysis, Cronbach's α for internal consistency, and test-retest reliability. Scoring standards were determined using K-means clustering, with comparative assessments made against hierarchical clustering and the Gaussian Mixture Model. RESULTS: The LC-SSS showed correlations with EuroQol 5-Dimension 5-Level (rs = -0.55), EuroQol visual analog scale (rs = -0.368), Patient Health Questionnaire-9 (rs = 0.538), Beck Anxiety Inventory (rs = 0.689), and Insomnia Severity Index (rs = 0.516), confirming its construct validity. Structural validity was good with a comparative fit index of 0.969, with Cronbach's α of 0.93 indicating excellent internal consistency. Test-retest reliability was also satisfactory (intraclass correlation coefficient 0.732). K-means clustering identified 3 distinct severity categories in individuals living with long COVID, providing a basis for personalized treatment strategies. CONCLUSIONS: The LC-SSS provides a robust and valid tool for assessing long COVID. The severity categories established via K-means clustering demonstrate significant variation in symptom severity, informing personalized treatment and improving care quality for patients with long COVID.
Subject(s)
COVID-19 , Severity of Illness Index , Humans , COVID-19/diagnosis , Reproducibility of Results , Female , Psychometrics , Male , Middle Aged , Post-Acute COVID-19 Syndrome , Surveys and Questionnaires , SARS-CoV-2 , Adult , Quality of Life , Self Report , Aged , Factor Analysis, StatisticalABSTRACT
Micro(nano)plastics (MNPs) are emerging pollutants that can adsorb pollutants in the environment and biological molecules and ultimately affect human health. However, the aspects of adsorption of intracellular proteins onto MNPs and its biological effects in cells have not been investigated to date. The present study revealed that 100 nm polystyrene nanoplastics (NPs) could be internalized by THP-1 cells and specifically adsorbed intracellular proteins. In total, 773 proteins adsorbed onto NPs with high reliability were identified using the proteomics approach and analyzed via bioinformatics to predict the route and distribution of NPs following cellular internalization. The representative proteins identified via the Kyoto Encyclopedia of Genes and Genomes pathway analysis were further investigated to characterize protein adsorption onto NPs and its biological effects. The analysis revealed that NPs affect glycolysis through pyruvate kinase M (PKM) adsorption, trigger the unfolded protein response through the adsorption of ribophorin 1 (RPN1) and heat shock 70 protein 8 (HSPA8), and are chiefly internalized into cells through clathrin-mediated endocytosis with concomitant clathrin heavy chain (CLTC) adsorption. Therefore, this work provides new insights and research strategies for the study of the biological effects caused by NPs.
Subject(s)
Environmental Pollutants , Nanoparticles , Water Pollutants, Chemical , Humans , Polystyrenes , Microplastics , THP-1 Cells , Adsorption , Reproducibility of Results , Plastics , Environmental Pollutants/analysis , Water Pollutants, Chemical/analysisABSTRACT
Epidermal growth factor receptor (EGFR) is one of the most studied drug targets for treating non-small-cell lung cancer (NSCLC). However, there are no approved inhibitors for the C797S resistance mutation caused by the third-generation EGFR inhibitor (Osimertinib). Therefore, the development of fourth-generation EGFR inhibitors is urgent. In this study, we clarified the structure-activity relationship of several synthesized compounds as fourth-generation inhibitors against human triple (Del19/T790M/C797S) mutation. Representative compound 52 showed potent inhibitory activity against EGFRL858R/T790M/C797S with an IC50 of 0.55 nM and significantly inhibited the proliferation of the Ba/F3 cell line harboring EGFRL858R/T790M/C797S with an IC50 of 43.28 nM. Moreover, 52 demonstrated good pharmacokinetic properties and excellent in vivo efficacy. Overall, the compound 52 can be considered a promising candidate for overcoming EGFR C797S-mediated mutations.
Subject(s)
Acrylamides , Aniline Compounds , Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Cell Proliferation , Dose-Response Relationship, Drug , Drug Design , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , ErbB Receptors , Lung Neoplasms , Protein Kinase Inhibitors , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , ErbB Receptors/genetics , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Acrylamides/pharmacology , Acrylamides/chemistry , Acrylamides/chemical synthesis , Structure-Activity Relationship , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Aniline Compounds/pharmacology , Aniline Compounds/chemistry , Aniline Compounds/chemical synthesis , Aniline Compounds/therapeutic use , Cell Proliferation/drug effects , Drug Resistance, Neoplasm/drug effects , Molecular Structure , Animals , Mice , Cell Line, Tumor , Mutation , Indoles , PyrimidinesABSTRACT
In addition to describing sexual partner preferences, sexual self-labels in gay and bisexual (henceforth, sexual minority) men, such as top, bottom, and versatile, are associated with psychological characteristics (e.g., gendered personality traits). No research has explored the association between sexual self-labels and eating and body image disturbances in sexual minority men. Research in sexual minority men from China is particularly valuable and needed due to recent rises in rates of eating and body image disturbances and unique, minority-specific stressors experienced by Chinese sexual minority populations. We adopted an online, cross-sectional study in a sample of sexual minority men from China (N = 403; tops, n = 256, bottoms, n = 95, versatiles, n = 52). Bottoms reported higher thinness internalization, lower muscularity internalization, higher body fat dissatisfaction, and higher psychological distress than tops. Bottoms' weight bias internalization was higher than tops' and versatiles' reports and, compared to versatiles, bottoms also reported higher psychosocial impairment related to eating disorder psychopathology. Compared to versatiles, tops reported higher drive for muscularity and muscularity-oriented disordered eating. Adjusting for age, psychological distress, and psychosocial impairment, tops reported higher muscularity internalization than bottoms and higher drive for muscularity and muscularity-oriented disordered eating than both bottoms and versatiles. Findings suggested unique relations between sexual self-labels and eating and body image disturbances in Chinese sexual minority men. Replication and validation of the temporal order between sexual self-labels and eating and body image disturbances is needed, including assessment of social factors (e.g., femmephobia, minority stress) that may help explain the links between sexual self-labels and eating pathology.
ABSTRACT
Establishing an RNA-associated interaction repository facilitates the system-level understanding of RNA functions. However, as these interactions are distributed throughout various resources, an essential prerequisite for effectively applying these data requires that they are deposited together and annotated with confidence scores. Hence, we have updated the RNA-associated interaction database RNAInter (RNA Interactome Database) to version 4.0, which is freely accessible at http://www.rnainter.org or http://www.rna-society.org/rnainter/. Compared with previous versions, the current RNAInter not only contains an enlarged data set, but also an updated confidence scoring system. The merits of this 4.0 version can be summarized in the following points: (i) a redefined confidence scoring system as achieved by integrating the trust of experimental evidence, the trust of the scientific community and the types of tissues/cells, (ii) a redesigned fully functional database that enables for a more rapid retrieval and browsing of interactions via an upgraded user-friendly interface and (iii) an update of entries to >47 million by manually mining the literature and integrating six database resources with evidence from experimental and computational sources. Overall, RNAInter will provide a more comprehensive and readily accessible RNA interactome platform to investigate the regulatory landscape of cellular RNAs.