Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer.

Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi1-5. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice6, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions7-9 and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported10,11, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment10-13. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-07514. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.

Machine Learning on Microstructure-Property Relationship of Lithium-Ion Conducting Oxide Solid Electrolytes.

Understanding the structure-property relationship of lithium-ion conducting solid oxide electrolytes is essential to accelerate their development and commercialization. However, the structural complexity of nonideal materials increases the difficulty of study. Here, we develop an algorithmic framework to understand the effect of microstructure on the properties by linking the microscopic morphology images to their ionic conductivities. We adopt garnet and perovskite polycrystalline oxides as examples and quantify the microscopic morphologies via extracting determined physical parameters from the images. It directly visualizes the effect of physical parameters on their corresponding ionic conductivities. As a result, we can determine the microstructural features of a Li-ion conductor with high ionic conductivity, which can guide the synthesis of highly conductive solid electrolytes. Our work provides a novel approach to understanding the microstructure-property relationship for solid-state ionic materials, showing the potential to extend to other structural/functional ceramics with various physical properties in other fields.

Multiomics blueprint of PANoptosis in deciphering immune characteristics and prognosis stratification of glioma patients.

BACKGROUND: As the most prevalent primary brain tumor in adults, glioma accounts for the majority of all central nervous system malignant tumors. The concept of PANoptosis is a relatively new, underlining the interconnection and synergy among three distinct pathways: pyroptosis, apoptosis and necroptosis. METHODS: We performed single-cell annotations of glioma cells and determined crucial signaling pathways through cell chat analysis. Using least absolute shrinkage and selection operator (LASSO) and Cox analyses, we identified a gene set with prognostic values. Our model was validated using independent external cohort. In addition, we employed single-sample gene set enrichment analysis and xCell analyses to describe the detailed profile of infiltrated immune cells and depicted the gene mutation landscape in the two groups. RESULTS: We identified seven distinct cell clusters in glioma samples, including oligodendrocyte precursor cells (OPCs), myeloid cells, tumor cells, oligodendrocytes, astrocytes, vascular cells and neuronal cells. We found that myeloid cells showed the highest PANoptosis activity. An intense mutual cell communication pattern between the tumor cells and OPCs and oligodendrocytes was observed. Differentially expressed genes between the high-PANoptosis and low-PANoptosis cell groups were obtained, which were enriched to actin cytoskeleton, cell adhesion molecules and gamma R-mediated phagocytosis pathways. We determined a set of five genes of prognostic significance: SAA1, SLPI, DCX, S100A8 and TNR. The prognostic differences between the two groups in the internal and external sets were found to be statistically significant. We found a marked correlation between S100A8 and activated dendritic cell, macrophage, mast cell, myeloid derived suppressor cell and Treg infiltration. Moreover, we have observed a significant increase of PTEN mutation in the high risk (HR) group of glioma patients. CONCLUSIONS: In the present study, we have constructed a prognostic model that is based on the PANoptosis, and we have demonstrated its significant efficacy in stratifying patients with glioma. This innovative prognostic model offers novel insights into precision immune treatments that could be used to combat this disease and improve patient outcomes, thereby providing a new avenue for personalized treatment options.

Associations of Lower-Carbohydrate and Lower-Fat Diets with Mortality among People with Cardiovascular Disease.

BACKGROUND: Although low-carbohydrate and low-fat diets have been shown to have short-term metabolic benefits, the associations of these dietary patterns, particularly different food sources and macronutrient quality, with mortality in people with cardiovascular disease (CVD) remain unclear. OBJECTIVES: To examine the associations of different types of lower-carbohydrate diets (LCDs) and lower-fat diets (LFDs) with mortality in individuals with CVD. METHODS: This study included 3971 adults with CVD from the NHANES 1999-2014. Mortality status was linked to National Death Index mortality data through 31 December 2019. Overall, unhealthy and healthy LCD and LFD scores were determined based on the percentages of energy from total and subtypes of carbohydrate, fat, and protein. Cox proportional hazards regression models were applied to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Higher healthy LCD score was associated with favorable blood lipids and higher homeostasis model assessment of insulin resistance, whereas higher unhealthy LFD score was associated with lower high-density lipoprotein and higher C-reactive protein at baseline (all P-trend < 0.05). During 35,150 person-years of follow-up, 2163 deaths occurred. For per 20-percentile increment in dietary scores, the multivariate-adjusted HRs of all-cause mortality were 0.91 (95% CI: 0.86, 0.96) for healthy LCD score (P < 0.001), 0.94 (95% CI: 0.89, 1.00) for healthy LFD score (P = 0.04), and 1.07 (95% CI: 1.00, 1.14) for unhealthy LFD score (P = 0.04). CONCLUSIONS: Overall LCD and LFD scores are not associated with total mortality. Unhealthy LFD scores are associated with higher total mortality, whereas healthy LCD and LFD scores are associated with lower mortality in people with CVD.

DeepST: identifying spatial domains in spatial transcriptomics by deep learning.

Recent advances in spatial transcriptomics (ST) have brought unprecedented opportunities to understand tissue organization and function in spatial context. However, it is still challenging to precisely dissect spatial domains with similar gene expression and histology in situ. Here, we present DeepST, an accurate and universal deep learning framework to identify spatial domains, which performs better than the existing state-of-the-art methods on benchmarking datasets of the human dorsolateral prefrontal cortex. Further testing on a breast cancer ST dataset, we showed that DeepST can dissect spatial domains in cancer tissue at a finer scale. Moreover, DeepST can achieve not only effective batch integration of ST data generated from multiple batches or different technologies, but also expandable capabilities for processing other spatial omics data. Together, our results demonstrate that DeepST has the exceptional capacity for identifying spatial domains, making it a desirable tool to gain novel insights from ST studies.

AKT from dental epithelium to papilla promotes odontoblast differentiation.

Epithelial-mesenchymal interactions occur during tooth development. The dental epithelium (DE) is regarded as the signal center that regulates tooth morphology. However, the mechanism by which DE regulates the differentiation of mesenchyme-derived dental papilla (DP) into odontoblasts remains unclear. Using miniature pigs as a model, we analyzed the expression profiles of the DE and DP during odontoblast differentiation using high-throughput RNA sequencing. The phosphatidylinositol-3-kinase (PI3K)/AKT pathway is one of the most enriched pathways in both DE and DP. The PI3K/AKT pathway was first activated in the inner enamel epithelium but not in the DP on embryonic day 50. This pathway was then activated in the odontoblast layer on embryonic day 60. We showed that AKT activation promoted odontoblast differentiation of DP cells. We further demonstrated that activation of PI3K/AKT signaling in the DE effectively increased the expression levels of AKT and dentin sialophosphoprotein in DP cells. Additionally, we found that DE cells secreted collagen type IV alpha 6 chain (COL4A6) downstream of epithelial AKT signaling to positively regulate mesenchymal AKT levels. Therefore, our data suggest that PI3K/AKT signaling from the DE to the DP promotes odontoblast differentiation via COL4A6 secretion.

Observations of Charge-Density-Wave States in W6Te6 Wires.

Determining the electronic ground state of a one-dimensional system is crucial to understanding the underlying physics of electronic behavior. Here, we demonstrate the discovery of charge-density wave states in few-wire W6Te6 arrays using scanning tunneling microscopy/spectroscopy. We directly visualize incommensurate charge orders, energy gaps with prominent coherence peaks, and the picometer-scale lattice distortion in nearly disorder-free double-wire systems, thereby demonstrating the existence of Peierls-type charge density waves. In the presence of disorder-induced charge order fluctuations, the coherence peaks resulting from phase correlation disappear and gradually transform the system into the pseudogap states. The power-law zero-bias anomaly and quasi-particle interference analysis further suggest the Tomonaga-Luttinger liquid behavior in such pseudogap region. In addition, we explicitly determined the evolution of the CDW energy gap as a function of stacking-wire numbers. The present study demonstrates the existence of electron-phonon interactions in few-wire W6Te6 that can be tuned by disorders and van der Waals stacking.

Realization of Multiple Charge-Density Waves in NbTe2 at the Monolayer Limit.

Layered transition-metal dichalcogenides down to the monolayer (ML) limit provide a fertile platform for exploring charge-density waves (CDWs). Here, we experimentally unveil the richness of the CDW phases in ML-NbTe2 for the first time. Not only the theoretically predicted 4 × 4 and 4 × 1 phases but also two unexpected 28×28 and 19×19 phases are realized. For such a complex CDW system, we establish an exhaustive growth phase diagram via systematic efforts in the material synthesis and scanning tunneling microscope characterization. Moreover, the energetically stable phase is the larger-scale order (19×19), which is surprisingly in contradiction to the prior prediction (4 × 4). These findings are confirmed using two different kinetic pathways: i.e., direct growth at proper growth temperatures (T) and low-T growth followed by high-T annealing. Our results provide a comprehensive diagram of the "zoo" of CDW orders in ML-NbTe2.

Natural Carrier-Free Binary Small Molecule Self-Assembled Hydrogel Synergize Antibacterial Effects and Promote Wound Healing by Inhibiting Virulence Factors and Alleviating the Inflammatory Response.

Methicillin-resistant Staphylococcus aureus (MRSA)-infected skin wounds have caused a variety of diseases and seriously endanger global public health. Therefore, multidimensional strategies are urgently to find antibacterial dressings to combat bacterial infections. Antibacterial hydrogels are considered potential wound dressing, while their clinical translation is limited due to the unpredictable risks and high costs of carrier excipients. it is found that the natural star antibacterial and anti-inflammatory phytochemicals baicalin (BA) and sanguinarine (SAN) can directly self-assemble through non-covalent bonds such as electrostatic attraction, π-π stacking, and hydrogen bonding to form carrier-free binary small molecule hydrogel. In addition, BA-SAN gel exhibited a synergistic inhibitory effect on MRSA. And its plasticity and injectability allowed it to be applied as a wound dressing. Due to the matched physicochemical properties and synergistic therapeutic effects, BA-SAN gel can inhibit bacterial virulence factors, alleviate wound inflammation, promote wound healing, and has good biocompatibility. The current study not only provided an antibacterial hydrogel with clinical value but also opened up new prospects that carrier-free hydrogels can be designed and originated from clinically used small-molecule phytochemicals.

Global characterization of B cell receptor repertoire in COVID-19 patients by single-cell V(D)J sequencing.

The world is facing a pandemic of Corona Virus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Adaptive immune responses are essential for SARS-CoV-2 virus clearance. Although a large body of studies have been conducted to investigate the immune mechanism in COVID-19 patients, we still lack a comprehensive understanding of the BCR repertoire in patients. In this study, we used the single-cell V(D)J sequencing to characterize the BCR repertoire across convalescent COVID-19 patients. We observed that the BCR diversity was significantly reduced in disease compared with healthy controls. And BCRs tend to skew toward different V gene segments in COVID-19 and healthy controls. The CDR3 sequences of heavy chain in clonal BCRs in patients were more convergent than that in healthy controls. In addition, we discovered increased IgG and IgA isotypes in the disease, including IgG1, IgG3 and IgA1. In all clonal BCRs, IgG isotypes had the most frequent class switch recombination events and the highest somatic hypermutation rate, especially IgG3. Moreover, we found that an IgG3 cluster from different clonal groups had the same IGHV, IGHJ and CDR3 sequences (IGHV4-4-CARLANTNQFYDSSSYLNAMDVW-IGHJ6). Overall, our study provides a comprehensive characterization of the BCR repertoire in COVID-19 patients, which contributes to the understanding of the mechanism for the immune response to SARS-CoV-2 infection.

Association of albumin levels with the risk of intracranial atherosclerosis.

OBJECTIVE: Intracranial artery stenosis from atherosclerosis is one of the etiologies of ischemic stroke. There is a correlation between serum albumin level and atherosclerosis. We aimed to investigate whether serum albumin level is related to intracranial atherosclerosis and its significance. METHODS: A retrospective analysis of 150 individuals who underwent cervical cerebral angiography after admission, including clinical data, imaging data, and laboratory data. Since atherosclerosis cannot be used as a good quantitative indicator, we choose the degree of arterial stenosis to reflect atherosclerosis. SPSS 24 software was used for data analysis, and P < .05 was considered statistically significant. RESULTS: Univariate analysis showed that age, diabetes, and serum albumin level were risk factors for intracranial atherosclerosis (P < .05). Multivariate analysis showed that diabetes and serum albumin levels were independent risk factors for intracranial atherosclerosis (P< 0.05). The average serum albumin level in the non-severe group was 39.80 g/L, and the average serum albumin level in the severe group was 37.60 g/L. The area under the ROC curve of serum albumin was 0.667 (95%CI 0.576-0.758, P = .001), the cutoff value was 0.332176, the sensitivity was 75.9%, and the specificity was 57.3%. CONCLUSION: Serum albumin level is an independent risk factor for intracranial atherosclerosis, and provides a new direction for clinical prevention and treatment.

Understanding metabolic alterations after SARS-CoV-2 infection: insights from the patients' oral microenvironmental metabolites.

BACKGROUND: Coronavirus disease 2019 is a type of acute infectious pneumonia and frequently confused with influenza since the initial symptoms. When the virus colonized the patient's mouth, it will cause changes of the oral microenvironment. However, few studies on the alterations of metabolism of the oral microenvironment affected by SARS-CoV-2 infection have been reported. In this study, we explored metabolic alterations of oral microenvironment after SARS-CoV-2 infection. METHODS: Untargeted metabolomics (UPLC-MS) was used to investigate the metabolic changes between oral secretion samples of 25 COVID-19 and 30 control participants. To obtain the specific metabolic changes of COVID-19, we selected 25 influenza patients to exclude the metabolic changes caused by the stress response of the immune system to the virus. Multivariate analysis (PCA and PLS-DA plots) and univariate analysis (students' t-test) were used to compare the differences between COVID-19 patients and the controls. Online hiplot tool was used to perform heatmap analysis. Metabolic pathway analysis was conducted by using the MetaboAnalyst 5.0 web application. RESULTS: PLS-DA plots showed significant separation of COVID-19 patients and the controls. A total of 45 differential metabolites between COVID-19 and control group were identified. Among them, 35 metabolites were defined as SARS-CoV-2 specific differential metabolites. Especially, the levels of cis-5,8,11,14,17-eicosapentaenoic acid and hexanoic acid changed dramatically based on the FC values. Pathway enrichment found the most significant pathways were tyrosine-related metabolism. Further, we found 10 differential metabolites caused by the virus indicating the body's metabolism changes after viral stimulation. Moreover, adenine and adenosine were defined as influenza virus-specific differential metabolites. CONCLUSIONS: This study revealed that 35 metabolites and tyrosine-related metabolism pathways were significantly changed after SARS-CoV-2 infection. The metabolic alterations of oral microenvironment in COVID-19 provided new insights into its molecular mechanisms for research and prognostic treatment.

Associations of serum vitamin C concentrations with risk of all-cause and cause-specific mortality among individuals with and without type 2 diabetes.

PURPOSE: Compared with people without diabetes, people with type 2 diabetes (T2D) are at higher risk of both subnormal vitamin C status and increased oxidative stress. We aimed to investigate the associations of serum vitamin C concentrations with all-cause and cause-specific mortality among adults with and without T2D. METHODS: The current analysis included 20,045 adults (2691 people with T2D and 17,354 without T2D) from the Third National Health and Nutrition Examination Survey (NHANES III) and NHANES 2003-2006. Cox proportional hazards regression models were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Restricted cubic spline analyses were used to examine the dose-response relationship. RESULTS: After a median follow-up of 17.3 years, 5211 deaths were documented. Individuals with T2D had a lower level of serum vitamin C concentrations compared with those without T2D (the median value: 40.1 vs. 44.9 µmol/L). Furthermore, the dose-response relationship between serum vitamin C and mortality showed different patterns between participants with and without T2D. In individuals without T2D, there was a nonlinear association of serum vitamin C concentrations with all-cause, cancer, and CVD mortality, with the lowest risk around a serum vitamin C concentration of 48.0 µmol/L (all Poverall < 0.05, Pnonlinearity < 0.05). In contrast, among those with T2D in the similar concentration range, higher serum vitamin C levels (ranged from 0.46 to 116.26 µmol/L) were linearly associated with lower all-cause and cancer mortality (both Poverall < 0.05, Pnonlinearity > 0.05). Significant additive interaction was observed between diabetes status and serum vitamin C levels with regard to all-cause and cancer mortality (P < 0.001). In addition, C-reactive protein, gamma-glutamyl transpeptidase, and HbA1c explained 14.08, 8.96, and 5.60% of the association between serum vitamin C and all-cause mortality among individuals with T2D, respectively. CONCLUSIONS: Higher serum vitamin C concentrations were significantly associated with lower risk of mortality in participants with T2D in a linear dose-response manner, while a nonlinear association was observed in participants without T2D, with an apparent threshold around 48.0 µmol/L. These findings suggest that the optimal vitamin C requirement may differ in individuals with and without T2D.

Design and synthesis of novel anti-multidrug-resistant staphylococcus aureus derivatives of glycyrrhetinic acid by blocking arginine biosynthesis, metabolic and H2S biogenesis.

With the soaring number of multidrug-resistant bacteria, it is imperative to develop novel efficient antibacterial agents and discovery new antibacterial pathways. Herein, we designed and synthesized a series of structurally novel glycyrrhetinic acid (GA) derivatives against multidrug-resistant Staphylococcus aureus (MRSA). The in vitro antibacterial activity of these compounds was evaluated using the microbroth dilution method, agar plate coating experiments and real-time growth curves, respectively. Most of the target derivatives showed moderate antibacterial activity against Staphylococcus aureus (S. aureus) and MRSA (MIC = 3.125-25 µM), but inactivity against Escherichia coli (E. Coli) and Pseudomonas aeruginosa (P. aeruginosa) (MIC > 200 µM). Among them, compound 11 had the strongest antibacterial activity against MRSA, with an MIC value of 3.125 µM, which was 32 times and 64 times than the first-line antibiotics penicillin and norfloxacin, respectively. Additionally, transcriptomic (RNA-seq) and quantitative polymerase chain reaction (qPCR) analysis revealed that the antibacterial mechanism of compound 11 was through blocking the arginine biosynthesis and metabolic and the H2S biogenesis. Importantly, compound 11 was confirmed to have good biocompatibility through the in vitro hemolysis tests, cytotoxicity assays and the in vivo quail chicken chorioallantoic membrane (qCAM) experiments. Current study provided new potential antibacterial candidates from glycyrrhetinic acid derivatives for clinical treatment of MRSA infections.

Flavokavain C Suppresses Breast Cancer Cell Viability and Induces Cell Apoptosis by Triggering DNA Damage.

Breast cancer, presented by multiple breast cancer subtypes that coexist within a diagnosed tumor in clinical, has ranked as the most common malignancy in women in recent years. Evidence suggested that limited effective drugs caused the unsatisfactory therapeutic efficacy of breast cancer. Flavokavain C exhibited anticancer activity on colon cancer cells HCT116. It is yet unknown if it can be used to treat breast cancer. This study aims to believe the mechanisms by which Flavokavain C suppresses cell proliferation and the pathways that impact on this effect in breast cancer. 3-(4,5-Dimethythiazol)-2,5-diphenyltetrazolium bromide assay was chosen to evaluate cell cytotoxicity. Colony formation and cell proliferation assays using 5-ethynyl-2'-deoxyuridine staining were performed. Cell cycle progression and apoptosis were examined via flow cytometry and Western blotting, respectively. Five methods (comet assay, immunofluorescence, Western blotting, agarose gel electrophoresis and molecular docking) were used to quantify DNA damage and its cellular response. Compared to cisplatin, Flavokavain C possessed a comparable or more substantial inhibitory effect on breast cancer cell viability while having lower cytotoxicity on human mammary cells. Breast cancer cells treated with Flavokavain C had their colony formation suppressed, DNA replication blocked, the G2/M phase cell cycle arrested, and apoptosis. Furthermore, the results indicated that Flavokavain C would directly interact with DNA and induce DNA cleavage, demonstrating that DNA is an attractive substrate for Flavokavain C. These results suggested that Flavokavain C had strong anticancer activity against multiple subtypes of breast cancer cells.

Tuning of the Valley Structures in Monolayer In2Se3/WSe2 Heterostructures via Ferroelectricity.

Recent findings of two-dimensional ferroelectric (FE) materials have enabled the integration of nonvolatile FE functions into device applications based on van der Waals (vdW) heterojunctions (HJs), resulting in versatile technological advances. In this paper, we report the results of direct probing of the electronic structures of In2Se3/WSe2 heterostructures at the single-layer limit, where monolayer (ML)-In2Se3 was found to be either antiferroelectric (AFE, ß') or ferroelectric (ß*) at sufficiently low temperatures. A general type-II band alignment was revealed for this heterostructure. Moreover, we observed significant modulations of the valley structures of WSe2, and in situ transformations between the FE and AFE In2Se3 phases demonstrated the dominant role of the polarizations in the top ML-In2Se3 layer. The observed phenomena can be attributed to the combination of both the linear and quadratic Stark shifts from the out-of-plane electric field, which has only been previously theoretically explored for ML-transition metal dichalcogenides (TMDs).

Biosynthesis of bionanomaterials using Bacillus cereus for the recovery of rare earth elements from mine wastewater.

The growing demand for rare earth elements (REEs) increasingly requires secondary resources such as mine wastewater containing high concentrations of REEs, to be used as a source of REEs. The current challenge is how to efficiently recover REEs from this feed source. In this paper, a functional bionanomaterial (FeNPs-EPS) was biosynthesized using Bacillus cereus as a possible means of recovering REEs. This composite was composed of both synthesized iron nanoparticles (FeNPs) and extracellular polymeric substances (EPS). Synthesis of the FeNPs-EPS composite via a one-step biosynthesis was confirmed by materials characterization. The peak in the material's UV-Vis spectra at 511 nm demonstrates the formation of FeNPs-EPS, where 3D-EEM showed that FeNPs-EPS was wrapped predominantly with tryptophan protein-like and humic acid-like substances. In addition, while FTIR indicated that the functional groups present in EPS where virtually identical to those observed in FeNPs-EPS, XPS demonstrated that Fe and O were the major elemental present as both FeO and Fe2O3. Zeta potential measurements indicated that FeNPs-EPS had good stability under different pH conditions, where BET analysis supported multilayer adsorption. Finally, on exposure to high concentrations of Eu(III) and Tb(III) in mine wastewater, the synthesized FeNPs-EPS demonstrated strong potential to remove two cations from the wastewater and hence a potentially practical way to efficiently recover REEs from such waste streams.

Multiple Impacts of Aerosols on O3 Production Are Largely Compensated: A Case Study Shenzhen, China.

Tropospheric ozone (O3) is a harmful gas compound to humans and vegetation, and it also serves as a climate change forcer. O3 is formed in the reactions of nitrogen oxides and volatile organic compounds (VOCs) with light. In this study, an O3 pollution episode encountered in Shenzhen, South China in 2018 was investigated to illustrate the influence of aerosols on local O3 production. We used a box model with comprehensive heterogeneous mechanisms and empirical prediction of photolysis rates to reproduce the O3 episode. Results demonstrate that the aerosol light extinction and NO2 heterogeneous reactions showed comparable influence but opposite signs on the O3 production. Hence, the influence of aerosols from different processes is largely counteracted. Sensitivity tests suggest that O3 production increases with further reduction in aerosols in this study, while the continued NOx reduction finally shifts O3 production to an NOx-limited regime with respect to traditional O3-NOx-VOC sensitivity. Our results shed light on the role of NOx reduction on O3 production and highlight further mitigation in NOx not only limiting the production of O3 but also helping to ease particulate nitrate, as a path for cocontrol of O3 and fine particle pollution.

Spatiotemporal Expression Patterns of Critical Genes Involved in FGF Signaling During Morphogenesis and Odontogenesis of Deciduous Molars in Miniature Pigs.

The fibroblast growth factor (FGF) pathway plays an important role in epithelial-mesenchymal interactions during tooth development. Nevertheless, how the ligands, receptors, and antagonists of the FGF pathway are involved in epithelial-mesenchymal interactions remains largely unknown. Miniature pigs exhibit tooth anatomy and replacement patterns like those in humans and hence can serve as large animal models. The present study investigated the spatiotemporal expression patterns of critical genes encoding FGF ligands (FGF3, FGF4, FGF7, and FGF9), antagonists (SPRY2 and SPRY4) and receptors (FGFR1, FGFR2, and FGFR3) in the third deciduous molars of miniature pigs at the cap (embryonic day 40, E40), early bell (E50), and late bell (E60) stages. The results of in situ hybridization (ISH) with tyramide signal amplification and of qRT-PCR analysis revealed increased expression of FGF7, FGFR1, FGFR2, and SPRY4 in dental epithelium and of FGF7 and FGFR1 in mesenchyme from E40 to E50. In contrast, the results revealed decreased expression of FGF3, FGF4, FGF9, and FGFR3 in dental epithelium and of FGF4, FGF9, FGFR2, and FGFR3 in the mesenchyme from E40 to E60. Mesenchyme signals of FGF3, FGF4, FGF7, SPRY2, FGFR2, and FGFR3 were concentrated in the odontoblast layer from E50 to E60. The distinct expression patterns of these molecules indicated elaborate regulation during dental morphogenesis. Our results provide a foundation for further investigation into fine-tuning dental morphogenesis and odontogenesis by controlling interactions between dental epithelium and mesenchyme, thus promoting tooth regeneration in large mammals.

Multi-functional self-assembly nanoparticles originating from small molecule natural product for oral insulin delivery through modulating tight junctions.

BACKGROUND: Oral administration of insulin (INS) could be absorbed into systemic circulation only if the carrier protected it from the hostile gastrointestinal conditions. However, traditional macromolecular carriers have not totally overcome challenges in addressing these biological barriers. RESULT: In this study, inspired by small molecule natural products (SMNPs), we demonstrate the multi-functional self-assembly nanoparticles (BA-Al NPs) originating from baicalin (BA) and AlCl3 through coordination bonds and hydrogen bonds. As a novel carrier for oral insulin delivery (INS@BA-Al NPs), it displayed effective capacity in pH stimuli-responsive insulin release, intestinal mucoadhesion and transepithelial absorption enhance. Meanwhile, BA improved the paracellular permeability for insulin absorption, because of its downregulation at both mRNA and protein level on internal tight junction proteins. In vivo experiments exhibited remarkable bioavailability of INS and an ideal glucose homeostasis in the type I diabetic rat model. CONCLUSION: This study offers a novel frontier of multi-functional carriers based on SMNPs with self-assembly character and bioactivity, which could be a promising strategy for diabetes therapy.