Construction of various lipid carriers to study the transdermal penetration mechanism of sinomenine hydrochloride.

OBJECTIVE: To investigate the transdermal mechanisms and compare the differences in transdermal delivery of Sinomenine hydrochloride (SN) between solid lipid nanoparticles (SLN), liposomes (LS), and nanoemulsions (NE). METHODS: SN-SLN, SN-LS and SN-NE were prepared by ultrasound, ethanol injection and spontaneous emulsification, respectively. FTIR, DSC, in vitro skin penetration, activation energy (Ea) analysis were used to explore the mechanism of drug penetration across the skin. RESULTS: The particle size and encapsulation efficiency were 126.60 nm, 43.23 ± 0.48%(w/w) for SN-SLN, 224.90 nm, 78.31 ± 0.75%(w/w) for SN-LS, and 83.22 nm, 89.01 ± 2.16%(w/w) for SN-LS. FTIR and DSC showed the preparations had various levels of impacts on the stratum corneum's lipid structure which was in the order of SLN > NE > LS. Ea values of SN-SLN, SN-LS, and SN-NE crossing the skin were 2.504, 1.161, and 2.510 kcal/mol, respectively. CONCLUSION: SLN had a greater degree of alteration on the skin cuticle, which allows SN to permeate skin more effectively.

Fatigue Behavior of the FGH96 Superalloy under High-Temperature Cyclic Loading.

Strain-controlled low-cycle fatigue (LCF) tests and stress-controlled creep-fatigue interaction (CFI) tests on the FGH96 superalloy were carried out at 550 °C to obtain the cyclic softening/hardening characteristics at different strain amplitudes and ratcheting strain characteristics under different hold time. The failure mechanism of the FGH96 superalloy under different loading conditions was analyzed through fracture observations. The results show that the FGH96 superalloy exhibits different cyclic softening/hardening characteristics at different strain amplitudes, and the introduction of the hold time at peak stress exacerbates the ratcheting strain of the FGH96 superalloy under asymmetric stress cycles. Fracture observations show that the magnitude of the strain amplitude, high-temperature oxidation, and the introduction of the hold time will affect the mechanical properties of the FGH96 superalloy and change its fracture mode.

Multi-functionalized Metallo-Supramolecular Spoked Wheels: Their Emission-Tunable Hierarchically Assembled System with Dye Molecules.

Supramolecular architectures with multiple emissive units are especially appealing due to their desired properties, such as artificial light harvesting and white-light emission. But fully achieving multi-wavelength photoluminescence in a single supramolecular architecture remains a challenge. In this paper, functionalized supramolecular architectures containing twelve metal centers and six pyrene moieties were nearly quantitatively synthesized by multi-component self-assembly and fully characterized by 1D and 2D nuclear magnetic resonance, dynamic light scattering, electrospray ionization mass spectrometry, traveling-wave ion mobility mass spectrometry, and transmission electron microscopy. Moreover, the hierarchical nano-assemblies were prepared by introducing anionic dyes to the positively charged self-assembled framework, which contained three luminescence centers, namely, pyrene, tpy-Cd coordination parts, and Sulforhodamine B anions. Such a hierarchically assembled system displayed tunable emission by taking full advantage of aggregation-induced emission enhancement, aggregation-caused quenching, and fluorescence resonance energy transfer effects and showed the diverse emission colors. This research provides a new insight for constructing multiple emissive metallo-supramolecular assemblies.

Disheveled3 enhanced EMT and cancer stem-like cells properties via Wnt/ß-catenin/c-Myc/SOX2 pathway in colorectal cancer.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) and cancer stem-like cells (CSLCs) play crucial role in tumor metastasis and drug-resistance. Disheveled3 (DVL3) is involved in malignant behaviors of cancer. However, the role and potential mechanism of DVL3 remain elusive in EMT and CSLCs of colorectal cancer (CRC). METHODS: UALCAN and PrognoScan databases were employed to evaluate DVL3 expression in CRC tissues and its correlation with CRC prognosis, respectively. Transwell, sphere formation and CCK8 assay were used to assess metastasis, stemness and drug sensitivity of CRC cells, respectively. Western blotting and dual luciferase assay were performed to analyze the protein expression and Wnt/ß-catenin activation, respectively. Lentiviral transfection was used to construct the stable cell lines. Animal studies were performed to analyze the effect of silencing DVL3 on tumorigenicity and metastasis of CRC cells in vivo. RESULTS: DVL3 was overexpressed in CRC tissues and several CRC cell lines. DVL3 expression was also higher in CRC tissues with lymph node metastasis than tumor tissues without metastasis, and correlated with poor prognosis of CRC patients. DVL3 positively regulated the abilities of migration, invasion and EMT-like molecular changes in CRC cells. Moreover, DVL3 promoted CSLCs properties and multidrug resistance. We further identified that Wnt/ß-catenin was crucial for DVL3-mediated EMT, stemness and SOX2 expression, while silencing SOX2 inhibited DVL3-mediated EMT and stemness. Furthermore, c-Myc, a direct target gene of Wnt/ß-catenin, was required for SOX2 expression and strengthened EMT and stemness via SOX2 in CRC cells. Finally, knockdown of DVL3 suppressed tumorigenicity and lung metastasis of CRC cells in nude mice. CONCLUSION: DVL3 promoted EMT and CSLCs properties of CRC via Wnt/ß-catenin/c-Myc/SOX2 axis, providing a new strategy for successful CRC treatment.

Steric Hindrance Effect as a Decisive Factor for the Self-Assembly of Metallocages.

In the past decades, many supramolecular cages with different sizes and shapes have been achieved through coordination-driven self-assembly. However, the strategy of topology adjustment by using a steric hindrance effect has not been fully developed. In this Article, we report the synthesis of ligand LA with rotatable arms, ligand LB with restricted arms, and their precisely controlled self-assembly to tetramer cage T1 and dimer cage D1, respectively, under the same conditions. By utilizing the steric hindrance of the ligands, the shapes and sizes of metallosupramolecular cages have been successfully adjusted. The metallocages were characterized by NMR spectroscopy (1H, 13C, COSY, NOESY, and DOSY), mass spectrometry (ESI-MS, TWIM-MS), transmission electron microscopy, and atomic force microscopy. This synthetic method would have the potential to be a general strategy for the design and self-assembly of diverse cages with tunable shape, size, and applicable properties.

A 5.3 nm giant metal-organic cage and its supramolecular gel for the formation of dye molecular ionic pairs.

A terpyridine-based supramolecular cage was successfully synthesized by the self-assembly of a hexapodal metal-organic ligand with Zn2+. This metallo-cage exhibited two large parallel planes on the top and bottom with diameters close to 6 nm and a face-to-face distance close to 3.5 nm, thus possessing a large cavity. Electrospray ionization mass spectrometry (ESI-MS), nuclear magnetic resonance (NMR), two-dimensional nuclear Overhauser (2D-NOESY), and diffusion-ordered (DOSY) spectroscopies as well as transmission electron microscopy (TEM) and atomic force microscopy (AFM) measurements, unambiguously supported the formation of a supramolecular cage. Furthermore, the corresponding metal-organic gel was felicitously prepared in CH3CN/H2O and displayed good adsorption performance for dye molecules.

Business Strategy and Environmental Information Disclosure Quality: Empirical Evidence from Chinese Heavy Pollution Listed Firms.

Using the data of listed firms in China's A-share heavy pollution industry between 2008 and 2020, based on organizational theory, this study examines the impact of prospector-type firms and defender-type firms on environmental information disclosure quality. Empirical evidence shows that prospector-type firms reduce environmental information disclosure quality, compared with defender-type firms. After a series of robustness tests, the conclusion is still valid. This paper tests the impact mechanism of business strategy on environmental information disclosure quality and finds that financing constraints play a mediating effect in the relationship between business strategy and environmental information disclosure quality. This paper enriches and expands the literature in the field of influencing factors of environmental information disclosure quality and economic consequences of business strategy. At the same time, the conclusion of this paper has important reference significance for regulators to formulate policies to improve environmental information disclosure quality according to the heterogeneity of business strategy.

Monitoring or Colluding? Institutional Investors' Heterogeneity and Environmental Information Disclosure Behavior.

High-quality environmental information disclosure is not only an effective way for the firm to fulfill its environmental responsibility and promote green development, but also an important governance mechanism to reduce the degree of information asymmetry between the firm's management and shareholders and alleviate the agency conflict. As an important shareholder of a firm, there are two different hypotheses about the influence of institutional investors on firm decision-making and behavior: monitor and collusion. Institutional investors are not homogeneous, and there are significant differences in the impact of different types of institutional investors on firm decision-making and behavior. We divide institutional investors into the stable institutional investors and the unstable institutional investors, using the data of listed firms in China's A-share heavy pollution industry between 2008 and 2020, and this study explores the effect of institutional investors' heterogeneity on environmental information disclosure behavior from the perspective of environmental information disclosure quality. Empirical evidence shows that institutional investors as a whole have a positively significant impact on environmental information disclosure quality. Further analysis shows that the stable institutional investors have positive impact on environmental information disclosure quality compared with the unstable institutional investors. After a series of robustness tests, the conclusion is still valid. The results of this paper show that institutional investors, especially the stable institutional investors, can effectively reduce the degree of information asymmetry, alleviate the agency conflict of the firm, play an active role in corporate governance, strengthen the main responsibility of firm ecological environment protection, and promote the green development of firm. The conclusion of this paper has important reference significance for the regulators to formulate policies to improve environmental information disclosure quality and promote green development according to the heterogeneity of institutional investors.

Study on Influencing Factors of Construction Workers' Unsafe Behavior Based on Text Mining.

The unsafe behavior of construction workers is the key cause of safety accidents. The accident investigation report contains rich experience and lessons, which can be used to prevent and reduce the occurrence of safety accidents. In order to draw lessons from the accident and realize knowledge sharing and reuse, this paper uses text mining technology to analyze the data of 500 construction accident investigation reports in Shenzhen, China. Firstly, a Latent Dirichlet Allocation (LDA) topic model is used to identify the unsafe behavior of construction workers and its influencing factors. Then, with the help of Social Network Analysis, the importance of influencing factors and the relationship between them are identified. The results show that weak safety awareness, operating regulations, supervision dereliction of duty, equipment resources, and inadequate supervision of the construction party are the key and important factors. It is also found that there are correlations between weak safety awareness and supervision dereliction of duty, between equipment resources and poor construction environment, between organization and coordination and inadequate supervision of the construction party, and between operating regulations and hidden dangers investigation. This study not only helps to improve the theoretical system in the field of construction workers' unsafe behavior but also helps managers to find the key control direction of construction safety, so as to effectively curb unsafe behavior of construction workers and improve the level of safety management.

Psychoacoustic modelling of rotor noise.

The aviation sector is rapidly evolving with more electric propulsion systems and a variety of new technologies of vertical take-off and landing manned and unmanned aerial vehicles. Community noise impact is one of the main barriers for the wider adoption of these new vehicles. Within the framework of a perception-driven engineering approach, this paper investigates the relationship between sound quality and first order physical parameters in rotor systems to aid design. Three case studies are considered: (i) contra-rotating versus single rotor systems, (ii) varying blade diameter and thrust in both contra-rotating and single rotor systems, and (iii) varying rotor-rotor axial spacing in contra-rotating systems. The outcomes of a listening experiment, where participants assessed a series of sound stimuli with varying design parameters, allow a better understanding of the annoyance induced by rotor noise. Further to this, a psychoacoustic annoyance model optimised for rotor noise has been formulated. The model includes a novel psychoacoustic function to account for the perceptual effect of impulsiveness. The significance of the proposed model lies in the quantification of the effects of psychoacoustic factors, such as loudness as the dominant factor, and also tonality, high frequency content, temporal fluctuations, and impulsiveness on rotor noise annoyance.

TRDMT1 exhibited protective effects against LPS-induced inflammation in rats through TLR4-NF-κB/MAPK-TNF-α pathway.

BACKGROUND: Inflammation is a complex physiological and pathological process. Although many types of inflammation are well characterized, their physiological functions are largely unknown. tRNA aspartic acid methyltransferase 1 (TRDMT1) has been implicated as a stress-related protein, but its intrinsic biological role is unclear. METHODS: We constructed a Trdmt1 knockout rat and adopted the LPS-induced sepsis model. Survival curve, histopathological examination, expression of inflammatory factors, and protein level of TLR4 pathway were analyzed. RESULTS: Trdmt1 deletion had no obvious impact on development and growth. Trdmt1 deletion slightly increased the mortality during aging. Our data showed that Trdmt1 strongly responded in LPS-treated rats, and Trdmt1 knockout rats were vulnerable to LPS treatment with declined survival rate. We also observed more aggravated tissue damage and more cumulative functional cell degeneration in LPS-treated knockout rats compared with control rats. Further studies showed upregulated TNF-α level in liver, spleen, lung, and serum tissues, which may be explained by enhanced p65 and p38 phosphorylation. CONCLUSIONS: Our data demonstrated that Trdmt1 plays a protective role in inflammation by regulating the TLR4-NF-κB/MAPK-TNF-α pathway. This work provides useful information to understand the TRDMT1 function in inflammation.

Probiotic Bacillus subtilis LF11 Protects Intestinal Epithelium Against Salmonella Infection.

Enteric diseases caused by Salmonella are prevalent in poultry farming. With the forbiddance of antibiotics in feedstuff industry, Bacillus subtilis (B. subtilis) preparation as antibiotic alternatives against Salmonella infection has gained increasing attention recently. However, the protection modes of B. subtilis against Salmonella infection in broilers are strain-specific. In this study, probiotic B. subtilis LF11 significantly reduced diarrhea and mortality of broilers caused by Salmonella braenderup (S. braenderup) in spite of no inhibition effect on it in vitro. Here, the intestinal epithelial cells NCM460 were incubated to explore the protection of B. subtilis LF11 on intestinal epithelium against Salmonella. The results revealed that B. subtilis LF11 showed obvious exclusion activity with the decrease of adhesion and invasion of S. braenderup to NCM460 cells, accordingly with the increase of NCM460 cell survival compared with S. braenderup challenge alone. Meanwhile, RT-PCR and Western blot proved that the gene transcription and expression levels of four tight junction proteins in NCM 460 cells were upregulated, which was further confirmed by immunofluorescence observation. Besides, B. subtilis LF11 downregulated the gene transcription levels of the proinflammatory cytokines IL-6, IL-8, and TNF-α induced by S. braenderup H9812. ELISA analysis also verified that B. subtilis LF11 reduced the IL-8 production significantly. In general, B. subtilis LF11 has the ability to protect the intestinal epithelium against Salmonella infection by reducing the Salmonella adhesion and invasion, enhancing the intestinal barrier and attenuating the enterocyte inflammatory responses, and has the potential as probiotics to prevent enteric diseases in broilers.

DocR-BERT: Document-Level R-BERT for Chemical-Induced Disease Relation Extraction via Gaussian Probability Distribution.

Chemical-induced disease (CID) relation extraction from biomedical articles plays an important role in disease treatment and drug development. Existing methods are insufficient for capturing complete document level semantic information due to ignoring semantic information of entities in different sentences. In this work, we proposed an effective document-level relation extraction model to automatically extract intra-/inter-sentential CID relations from articles. Firstly, our model employed BERT to generate contextual semantic representations of the title, abstract and shortest dependency paths (SDPs). Secondly, to enhance the semantic representation of the whole document, cross attention with self-attention (named cross2self-attention) between abstract, title and SDPs was proposed to learn the mutual semantic information. Thirdly, to distinguish the importance of the target entity in different sentences, the Gaussian probability distribution was utilized to compute the weights of the co-occurrence sentence and its adjacent entity sentences. More complete semantic information of the target entity is collected from all entities occurring in the document via our presented document-level R-BERT (DocR-BERT). Finally, the related representations were concatenated and fed into the softmax function to extract CIDs. We evaluated the model on the CDR corpus provided by BioCreative V. The proposed model without external resources is superior in performance as compared with other state-of-the-art models (our model achieves 53.5%, 70%, and 63.7% of the F1-score on inter-/intra-sentential and overall CDR dataset). The experimental results indicate that cross2self-attention, the Gaussian probability distribution and DocR-BERT can effectively improve the CID extraction performance. Furthermore, the mutual semantic information learned by the cross self-attention from abstract towards title can significantly influence the extraction performance of document-level biomedical relation extraction tasks.

Psychoacoustic analysis of contra-rotating propeller noise for unmanned aerial vehicles.

Unmanned aerial vehicle (UAV) technologies are rapidly advancing due to the unlimited number of applications from parcel delivery to people transportation. As the UAV market expands, community noise impact will become a significant problem for public acceptance. Compact drone architectures based on contra-rotating propellers bring significant benefits in terms of aerodynamic performance and redundancy to ensure vehicle control in case of component failure. However, contra-rotating propellers are severely noisy if not designed appropriately. In the framework of a perception-influenced design approach, this paper investigates the optimal rotor spacing distance configuration to minimise noise annoyance. On the basis of a series of psychoacoustic metrics (i.e., loudness, fluctuation strength, roughness, sharpness, and tonality) and psychoacoustic annoyance (PA) models, the optimal rotor axial separation distance (expressed as a function of propeller blade diameter) is at a range from 0.2 to 0.4. This paper also discusses the performance of currently available psychoacoustic models to predict propeller noise annoyance and defines further work to develop a PA model optimised for rotating systems.

Russian-Doll-Like Molecular Cubes.

Nanosized cage-within-cage compounds represent a synergistic molecular self-assembling form of three-dimensional architecture that has received particular research focus. Building multilayered ultralarge cages to simulate complicated virus capsids is believed to be a tough synthetic challenge. Here, we synthesize two large double-shell supramolecular cages by facile self-assembly of presynthesized metal-organic hexatopic terpyridine ligands with metal ions. Differing from the mixture of prisms formed from the inner tritopic ligand, the redesigned metal-organic hexatopic ligands bearing high geometric constraints that led to the exclusive formation of discrete double-shell structures. These two unique nested cages are composed of inner cubes (5.1 nm) and outer huge truncated cubes (12.0 and 13.2 nm) with six large bowl-shape subcages distributed on six faces. The results with molecular weights of 75 232 and 77 667 Da were among the largest synthetic cage-in-cage supramolecules reported to date. The composition, size and shape were unambiguously characterized by a combination of 1H NMR, DOSY, ESI-MS, TWIM-MS, TEM, AFM, and SAXS. This work provides an interesting model for functional recognition, delivery, and detection of various guest molecules in the field of supramolecular materials.

Giant Truncated Metallo-Tetrahedron with Unexpected Supramolecular Aggregation Induced Emission Enhancement.

The artificial synthesis of giant, three-dimensional, and shell-like architectures with growing complexity and novel functionalities is an especially challenging task for chemists. Fullerenes and self-assembled cages are remarkable examples that are proven milestones in the field of functional materials. Herein, we present another unique system: a giant terpyridine-based truncated metallo-tetrahedral architecture that includes densely-packed ionic pairs with a significant internal cavity. This huge metallo-tetrahedron with a molecular weight up to 70 000 Da was self-assembled simultaneously with 64 components: 12 large antler-shaped ligands (5), 4 star-shaped ligands (6), and 48 Cd2+ ions. Surprisingly, the giant tetrahedron shows broad visible emission (400-640 nm) and aggregation induced emission enhancement (AIEE) via a hierarchical assembly into highly-ordered nanoaggregates. A tunable emission color and near white-light emission in mixed solvent systems were also achieved. The present work not only affords an effective approach to the creation of giant shell-like architectures that can be used to mimic biological viruses and chemical frameworks but also provides a new class of functional metallo-architectures.

Tetraphenylethylene(TPE)-Containing Metal-Organic Nanobelt and Its Turn-on Fluorescence for Sulfide (S2-).

A metal-organic supramolecular nanobelt was synthesized by quantitative self-assembling terpyridine-functionized tetraphenylethylene (TPE) and Cd2+, which only showed a weak emission both in solution or aggregated state. Nevertheless, nanobelt complex could be transferred to a fluorescence turn-on sensor to S2- by taking advantage of the structural transformation from nanobelt to its fluorescent ligand.

Dynamic expressions of hypothalamic genes regulate seasonal breeding in a natural rodent population.

Seasonal breeding is a universal reproductive strategy in many animals. Hypothalamic genes, especially type 2 and 3 iodothyronine deiodinases (Dio2/3), RFamide-related peptide 3 (Rfrp-3), kisspeptin (Kiss-1) and gonadotropin-releasing hormone (GnRH), are involved in a photoperiodic pathway that encodes seasonal signals from day length in many vertebrate species. However, the seasonal expression patterns of these genes in wild mammals are less studied. Here, we present a four-year field investigation to reveal seasonal rhythm and age-dependent reproductive activity in male Brandt's voles (Lasiopodomys brandtii) and to detect relationships among seasonal expression profiles of hypothalamic genes, testicular activity, age and annual day length. From breeding season (April) to nonbreeding season (October), adult male voles displayed a synchronous peak in gonadal activity with annual day length around summer solstice, which was jointly caused by age structure shifts and age-dependent gonadal development patterns. Overwintered males maintained reproductive activity until late in the breeding season, whereas most newborn males terminated gonadal development completely, except for a minority of males born early in spring. Consistently, the synchronous and opposite expression profiles of Dio2/3 suggest their central function to decode photoperiodic signals and to predict the onset of the nonbreeding season. Moreover, changes in Dio2/3 signals may guide the actions of Kiss-1 and Rfrp-3 to regulate the age-dependent divergence of reproductive strategy in wild Brandt's vole. Our results provide evidence on how hypothalamic photoperiod genes regulate seasonal breeding in a natural rodent population.

The Effect of Prescription on the Framework of Lipid Matrix and In Vitro Properties.

PURPOSE: To clarify the inner framework and relative properties in vitro of Lyotropic liquid crystal (LLC) based on various prescriptions by using hydrophilic sinomenine hydrochloride (SH) and lipophilic cinnamaldehyde (CA) as model drugs. METHODS: Phase structures were checked by polarized light microscopy (PLM) and small-angle X-ray scattering (SAXS). Rheological studies and Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) analysis were carried out to reveal their molecular interactions. In vitro release and skin permeation were conducted by Franz diffusion cell. RESULTS: PLM and SAXS showed double diamond cubic crystal. All the samples displayed characteristics of non-Newtonian fluid, and the molecular interactions increased with the reducing water. ATRFTIR showed that the strongest strength of hydrogen bond emerged in the formulation with 32% water. Released SH of S2 and S3 arrived over 80%, while S1 only reached 45%, and that of CA was about 23%. Water-rich prescription gave higher percutaneous penetration for hydrophilic drugs, whereas no significant difference existed in CA permeation. CONCLUSION: Proportion of Phytantriol to water determined the LLC assembling and affected the dissolving status of hydrophilic substance, thereby impacting on the location sites of guest molecular interactions among the substances, rheology properties, and finally the release and penetration behavior in vitro. Adjusting the basic prescription was the key to obtain satisfactory percutaneous delivery and stability for LLC carrying multi-therapeutic agents.