Neural cells respond to topographical cues with alterations in cell growth and neurite sprouting mediated by changes in cell behavior. The interaction of fiber topography with cell adhesion receptors ...affects how the cells adhere to the surface of fibers and defines cell fate through alterations in the biochemistry, physiology, and morphology of neural cells. Although previous studies suggest topographical features influence neural cell proliferation and neurite sprouting, only a few studies have attempted to assess the use of both electrical and topological cues in piezoelectric scaffolds for nerve regeneration. In this study, variations in the shape‐modified collectors enable tunable surface topographic constructs, from micropatterns to fiber bundle structure. The crystallinity, chemical composition, and quantitative analysis confirm that the interplay between the topological structures of the fibers and the blending of nanocomposite materials is critical for the formation of the β‐phase. It is found that the topographical features and induced electrical characteristics affect cell growth. Also, the intracellular signaling pathway is induced that can provide clues as to how neural cells respond to the topological gradient structure modulated piezoelectric scaffolds. An analysis of the neuron‐specific cytoskeletal related markers further reveals that the specific topographical features piezoelectric fibrous scaffold reinforces neuron‐specific cytoskeletal proteins and microtubule assembly.
Tunable topography modulated piezoelectric fibrous scaffolds are developed, which can regulate electrical cues and mechanotransduction to predict neural cell response. Yes‐associated protein (YAP) translocation in cells provides clues as to how the cells respond to topological gradient structure modulated piezoelectric scaffolds. Such pleiotropic regulations could fine‐tune the YAP transcriptional pathway, enabling the determination of cell fate including neural differentiation.
The applications of solution-exfoliated graphene oxide (GO) as an electrical/electrochemical conductor require rational design–based approaches. Herein, we show that reduced GO nanosheets with highly ...ordered or nanoporous structures can be fabricated by treatment of graphite oxide (GrO) having variable-oxidation-degree with hot KOH solution. As model systems, GrO powders fabricated by modified Brodie and Hummers methods (B-GrO and H-GrO, respectively) were exfoliated into GO in alkaline solutions (to afford B-KGO and H-KGO, respectively), followed by 2.5-h refluxing at 100 °C. Notably, B-KGO was exceptionally resistant to hot KOH solution, whereas H-KGO was partially reduced under these conditions, as confirmed by 13C solid-state NMR, X-ray photoelectron spectroscopy, and Fourier transform infrared spectroscopy analyses. Moreover, reduced B-KGO featured highly ordered structures, whereas reduced H-KGO contained nanopores resulting from low-temperature activation in KOH solution. These extraordinary reactions of KGO nanosheets were translated into different electrical properties of reduced KGO nanosheets and different rheological properties of the corresponding pastes.
High-quality or highly porous graphene nanosheets were rationally fabricated by oxidation degree–dependent transformations of graphene oxide in hot alkaline solution. These reactions were translated into exceptionally different electrical properties of reduced graphene oxide nanosheets and the different rheological properties of the corresponding pastes. Display omitted
•Sampling-based algorithms are commonly used in motion planning problems.•The RRT* algorithm incrementally builds a tree of motion to find a solution.•Taking a shortcut to the ancestry increases the ...convergence rate to the optimal.•Combination with sampling strategies further improves the performance.
The Rapidly-exploring Random Tree (RRT) algorithm is a popular algorithm in motion planning problems. The optimal RRT (RRT*) is an extended algorithm of RRT, which provides asymptotic optimality. This paper proposes Quick-RRT* (Q-RRT*), a modified RRT* algorithm that generates a better initial solution and converges to the optimal faster than RRT*. Q-RRT* enlarges the set of possible parent vertices by considering not only a set of vertices contained in a hypersphere, as in RRT*, but also their ancestry up to a user-defined parameter, thus, resulting in paths with less cost than those of RRT*. It also applies a similar technique to the rewiring procedure resulting in acceleration of the tendency that near vertices share common parents. Since the algorithm proposed in this paper is a tree extending algorithm, it can be combined with other sampling strategies and graph-pruning algorithms. The effectiveness of Q-RRT* is demonstrated by comparing the algorithm with existing algorithms through numerical simulations. It is also verified that the performance can be further enhanced when combined with other sampling strategies.
Background and Aims
Currently there is no Food and Drug Administration–approved drug to treat NAFLD and NASH, the rates of which are increasing worldwide. Although NAFLD/NASH are highly complex and ...heterogeneous conditions, most pharmacotherapy pipelines focus on a single mechanistic target. Considering the importance of the gut‐liver axis in their pathogenesis, we investigated the therapeutic effect of a long‐acting dual agonist of glucagon‐like peptide (GLP)‐1 and GLP‐2 receptors in mice with NAFLD/NASH.
Approach and Results
C57BL/6J mice were fed a choline‐deficient high‐fat diet/high fructose and sucrose solution. After 16 weeks, mice were randomly allocated to receive vehicle, GLP1‐Fc, GLP2‐Fc, or GLP1/2‐Fc fusion (GLP1/2‐Fc) subcutaneously every 2 days for 4 weeks. Body weight was monitored, insulin/glucose tolerance tests were performed, feces were collected, and microbiome profiles were analyzed. Immobilized cell systems were used to evaluate direct peptide effect. Immunohistochemistry, quantitative PCR, immunoblot analysis, tunnel assay, and biochemical assays were performed to assess drug effects on inflammation, hepatic fibrosis, cell death, and intestinal structures. The mice had well‐developed NASH phenotypes. GLP1/2‐Fc reduced body weight, glucose levels, hepatic triglyceride levels, and cellular apoptosis. It improved liver fibrosis, insulin sensitivity, and intestinal tight junctions, and increased microvillus height, crypt depth, and goblet cells of intestine compared with a vehicle group. Similar effects of GLP1/2‐Fc were found in in vitro cell systems. GLP1/2‐Fc also changed microbiome profiles. We applied fecal microbiota transplantation (FMT) gain further insight into the mechanism of GLP1/2‐Fc–mediated protection. We confirmed that FMT exerted an additive effect on GLP1‐Fc group, including the body weight change, liver weight, hepatic fat accumulation, inflammation, and hepatic fibrosis.
Conclusions
A long‐acting dual agonist of GLP‐1 and GLP‐2 receptors is a promising therapeutic strategy to treat NAFLD/NASH.
Aims: Familial hypercholesterolemia (FH) is currently a worldwide health issue. Understanding the characteristics of patients is important for proper diagnosis and treatment. This study aimed to ...analyze the phenotypic and genetic features, including threshold cholesterol levels, of Korean patients with FH.Methods: A total of 296 patients enrolled in the Korean FH registry were included, according to the following criteria: low-density lipoprotein-cholesterol (LDL-C) ＞190 mg/dL with tendon xanthoma or family history compatible with FH, or LDL-C ＞225 mg/dL. DNA sequences of three FH-associated genes were obtained using whole-exome or target exome sequencing. Threshold cholesterol levels for differentiating patients with FH/pathogenic variant (PV) carriers and predictors of PVs were identified.Results: Of the 296 patients, 104 had PVs and showed more obvious clinical findings, including higher cholesterol levels. PV rates ranged from 30% to 64% when patients were categorized by possible or definite type according to the Simon Broome criteria. Frequent PV types included missense variants and copy number variations (CNVs), while the most frequent location of PVs was p.P685L in LDLR. The threshold LDL-C levels for patient differentiation and PV prediction were 177 and 225 mg/dL, respectively. Younger age, tendon xanthoma, and higher LDL-C levels were identified as independent predictors of PVs, while traditional cardiovascular risk factors were predictors of coronary artery disease.Conclusions: Korean patients with FH had variable PV rates depending on diagnostic criteria and distinctive PV locations. The reported threshold LDL-C levels pave the way for efficient patient care in this population.
A desirability function approach has been widely used in multi‐response optimization due to its simplicity. Most of the existing desirability function‐based methods assume that the variability of the ...response variables is stable; thus, they focus mainly on the optimization of the mean of multiple responses. However, this stable variability assumption often does not apply in practical situations; thus, the quality of the product or process can be severely degraded due to the high variability of multiple responses. In this regard, we propose a new desirability function method to simultaneously optimize both the mean and variability of multiple responses. In particular, the proposed method uses a posterior preference articulation approach, which has an advantage in investigating tradeoffs between the mean and variability of multiple responses. It is expected that process engineers can use this method to better understand the tradeoffs, thereby obtaining a satisfactory compromise solution.
The plasma membrane, which is a phosphoglyceride bilayer at the outer edge of the cell, plays diverse and important roles in biological systems. Visualization of the plasma membrane in live samples ...is important for various applications in biological functions. We developed an amphiphilic two-photon (TP) fluorescent probe (THQ-Mem) to selectively monitor the plasma membrane in live samples. This probe exhibited red emission (620–700 nm), large TP absorption cross sections (δmax > 790 GM), and high selectivity to the plasma membrane. In cultured cells and in vivo hepatic tissue imaging, THQ-Mem showed bright TP-excited fluorescence (TPEF) and remarkable selectivity for the plasma membrane. Furthermore, simultaneous in vivo imaging with THQ-Mem and a TP lipid droplet probe could serve as an efficient tool to monitor morphological and physiological changes in the plasma membrane and lipid droplets.
Lipid droplets (LDs) store energy and supply fatty acids and cholesterol. LDs are a hallmark of chronic nonalcoholic fatty liver disease (NAFLD). Recently, studies have focused on the role of hepatic ...macrophages in NAFLD. Green fluorescent protein (GFP) is used for labeling the characteristic targets in bioimaging analysis. Cx3cr1-GFP mice are widely used in studying the liver macrophages such as the NAFLD model. Here, we have developed a tool for two-photon microscopic observation to study the interactions between LDs labeled with LD2 and liver capsule macrophages labeled with GFP in vivo. LD2, a small-molecule two-photon excitation fluorescent probe for LDs, exhibits deep-red (700 nm) fluorescence upon excitation at 880 nm, high cell staining ability and photostability, and low cytotoxicity. This probe can clearly observe LDs through two-photon microscopy (TPM) and enables the simultaneous imaging of GFP+ liver capsule macrophages (LCMs) in vivo in the liver capsule of Cx3cr1-GFP mice. In the NAFLD mouse model, Cx3cr1 + LCMs and LDs increased with the progress of fatty liver disease, and spatiotemporal changes in LCMs were observed through intravital 3D TPM images. LD2 will aid in studying the interactions and immunological roles of hepatic macrophages and LDs to better understand NAFLD.
Chronic obstructive pulmonary disease (COPD), an inflammatory lung disease, causes approximately 3 million deaths each year; however, its pathological mechanisms are not fully understood. In this ...study, we examined whether HX110B, a mixture of Taraxacum officinale, Dioscorea batatas, and Schizonepeta tenuifolia extracts, could suppress porcine pancreatic elastase (PPE)-induced emphysema in mice and its mechanism of action. The therapeutic efficacy of HX110B was tested using a PPE-induced emphysema mouse model and human bronchial epithelial cell line BEAS-2B. In vivo data showed that the alveolar wall and air space expansion damaged by PPE were improved by HX110B administration. HX110B also effectively suppresses the expression levels of pro-inflammatory mediators including IL-6, IL-1beta, MIP-2, and iNOS, while stimulating the expression of lung protective factors such as IL-10, CC16, SP-D, and sRAGE. Moreover, HX110B improved the impaired OXPHOS subunit gene expression. In vitro analysis revealed that HX110B exerted its effects by activating the PPAR-RXR signaling pathways. Overall, our data demonstrated that HX110B could be a promising therapeutic option for COPD treatment.
Although the development of several inflammatory diseases can be initiated in response to CD44 receptor signaling dysregulation, anti‐CD44 antibody therapy has been discontinued in clinical trials ...owing to its severe adverse effects. Moreover, biocompatible materials that block CD44 are unknown. Here, self‐assembled levan nanoparticles (LevNPs) through simple nanoprecipitation without chemical conjugation of biocompatible levan are developed. LevNPs are prepared through a simple nanoprecipitation without chemical conjugation; this results in particles with a consistently dispersed hydrodynamic diameter of approximately 230 nm. The physicochemical properties of LevNP are well‐maintained even after long‐term storage in a physiological buffer, suggesting that LevNPs are stable and useful for various biomedical applications. A protein array and an in silico LevNP‐CD44 interaction assay reveal that LevNPs specifically bind to CD44. Importantly, CD44 is highly expressed in the cartilage of patients with osteoarthritis (OA). LevNPs showed no cytotoxicity and reduced catabolic factor expression in an OA mimic in vitro. Furthermore, intra‐articular injection of LevNPs exhibited long‐term retention ability in the knee joint and protection against posttraumatic OA cartilage destruction in mice with medial meniscus destabilization–induced OA. These results show that LevNPs are biocompatible and exhibit potential as a nanotherapeutic for protecting against OA pathogenesis by directly blocking CD44.
Fructose‐derived levan nanoparticles are developed as anti‐inflammatory nanotherapeutic agents, which are biocompatible materials. They are found to be effective as anti‐inflammatory agents by blocking CD44 activation through an interaction with the N‐terminal CD44 sequence and LevNP. These particles can be used to alleviate inflammatory osteoarthritis and may be applicable for treating various inflammatory diseases.
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