With the demand for low‐power‐operating artificial intelligence systems, bio‐inspired memristor devices exhibit potential in terms of high‐density memory functions and the emulation of the synaptic ...dynamics of the human brain. The 2D material MXene attracts considerable interest for use in resistive‐switching memory and artificial synapse devices owing to its excellent physicochemical properties in memristor devices. However, few memristive and synaptic MXene devices that display increased switching performances are reported, with no significant results. Herein, the conductivity of MXene (Ti3C2Tx) is engineered via etching and oxidation to enhance the switching performance of the device. The exceptional properties of partially oxidized MXene memristors include large memory windows and low threshold biases, and the complex spike‐timing‐dependent plasticity synaptic rules are also emulated. The low threshold potential distribution, reliable retention time (104 s), and distinct resistance states with a high ON–OFF ratio (>104) are the main memory‐related features of this device. The experimentally determined switching potentials of the optimized device are also uniformly distributed, according to a statistical probability‐based approach. This investigation may promote the essential material properties for use in high‐density non‐volatile memory storage and artificial synapse systems in the field of innovative nanoelectronic devices.
Exquisite improvements are witnessed for MXene memristors. Conventional memory cells confront the demands of future data‐intensive computing applications. This sortation has led the research on constructing the memristors with novel 2D functional materials for advanced applications of next‐generation memory technology. MXene for high‐density computing and synapse functionality at low power (among all Ti3C2) with edge detection applicability are manifested.
Aim: We investigated the effects of metabolic syndrome (MetS) and its components, including a body shape index (ABSI), on increased arterial stiffness measured using the cardio-ankle vascular index ...(CAVI) according to sex and age strata.Methods: A total of 7127 asymptomatic Korean participants aged 21–90 years (men, 69.4%) were included. Age–sex-specific increased CAVI was defined as having the highest quartile of CAVI in each age group.Results: The CAVI increased with age and was higher in men. MetS was associated with an increased risk of high CAVI by 1.30 times in men and 1.45 times in women. The risk of high CAVI with an increasing MetS risk score was greater in women. MetS was significantly associated with increased CAVI in men only aged 51–70 years and in women aged ≥ 51 years, and the size of association increased with age (odds ratio (OR) of 1.41 in 51–70 years vs. OR of 2.96 in ≥ 71 years of women). Among MetS components, triglyceride (men, all ages), hypertension (men, 51–70 years; women, ≤ 70 years), glucose intolerance (men, 51–70 years; women, ≥ 51 years), and HDL-cholesterol (women, ≥ 71 years) were associated with increased CAVI.Unlike increased waist circumference (WC), increased ABSI revealed an association with high CAVI. MetS diagnosed with ABSI instead of WC was more significantly associated with increased CAVI in all age–sex groups. Conclusion: The association of MetS and its components with increased CAVI differed with age and sex, which might provide a new insight for the management of MetS risk factors to promote vascular health.
Indonesia declared an ambitious plan to restore its degraded and fire‐prone peatlands, which have been a source of significant greenhouse gas and haze. However, the progress has been slow and the ...plan cannot succeed without sustained social supports and political will. Although many previous studies argued for the need to see ecological restoration in socio‐economic contexts, empirical assessments have been lacking for how restoration is operationalized on the ground. We interviewed 47 key informants involved in four different projects in Central Kalimantan, Indonesia, and assessed their definitions, goals, and practices of peatland restoration. Most of the actors we interviewed defined peatland restoration primarily in an ecological context following the global concept of ecological restoration. However, all four restoration projects were designed without determining reference and trajectory conditions. Their intermediate goals and practices were more focused on engaging local communities and developing sustainable livelihood options than improving the ecological conditions of peatlands. To be internally consistent, peatland restoration needs to recognize a social dimension in its process, as well as in its goal. Setting clear trajectory conditions is also important to clarify achievable goals and measurable intermediate outcomes. We propose the following definition of peatland restoration: a process of assisting the recovery of degraded peatland ecosystems to achieve the appropriate trajectories defined through multi‐stakeholder collaboration within social‐ecological contexts. We hope to generate healthy debates to further refine the definition that encompasses both social and ecological dimensions to generate broader support for sustaining and expanding peatland restoration projects in Indonesia.
Background
Atopic dermatitis (AD) is a complex condition characterized by impaired epithelial barriers and dysregulated immune cells. In this study, we demonstrated Forsythia velutina Nakai extract ...(FVE) simultaneously inhibits basophils, macrophages, keratinocytes, and T cells that are closely interrelated in AD development.
Methods
We analyzed the effect of FVE on nitric oxide and reactive oxygen species (ROS) production in macrophages, basophil degranulation, T cell activation, and tight junctions in damaged keratinocytes. Expression of cell‐type‐specific inflammatory mediators was analyzed, and the underlying signaling pathways for anti‐inflammatory effects of FVE were investigated. The anti‐inflammatory effects of FVE were validated using a DNCB‐induced mouse model of AD. Anti‐inflammatory activity of compounds isolated from FVE was validated in each immune cell type.
Results
FVE downregulated the expression of inflammatory mediators and ROS production in macrophages through TLR4 and NRF2 pathways modulation. It significantly reduced basophil degranulation and expression of type 2 (T2) and pro‐inflammatory cytokines by perturbing FcεRI signaling. Forsythia velutina Nakai extract also robustly inhibited the expression of T2 cytokines in activated T cells. Furthermore, FVE upregulated the expression of tight junction molecules in damaged keratinocytes and downregulated leukocyte attractants, as well as IL‐33, an inducer of T2 inflammation. In the AD mouse model, FVE showed superior improvement in inflammatory cell infiltration and skin structure integrity compared to dexamethasone. Dimatairesinol, a lignan dimer, was identified as the most potent anti‐inflammatory FVE compound.
Conclusion
Forsythia velutina Nakai extract and its constituent compounds demonstrate promising efficacy as a therapeutic option for prolonged AD treatment by independently inhibiting various cell types associated with AD and disrupting the deleterious link between them.
Forsythia velutina Nakai extract (FVE) was investigated for atopic dermatitis (AD) treatment. FVE Nakai extract inhibits TLR4‐mediated inflammatory MAPK and NF‐κB signaling in macrophages, activates the NRF2‐mediated ROS scavenging pathway, downregulates T2 cytokine expression in activated basophils and T cells, and restores skin barrier function in keratinocytes. The potent anti‐AD effects of FVE were validated in a mouse model. The active constituents of FVE were identified as lignan compounds and their rarely reported dimers.Abbreviations: AD, atopic dermatitis; FcεRI, high affinity IgE receptor; FVE, Forsythia velutina Nakai extract; LPS, lipopolysaccharide; MAPK, mitogen‐activated protein kinase; NF‐κB, nuclear factor kappa B; NRF2, NF‐erythroid 2‐related factor 2; ROS, reactive oxygen species; TLR4, Toll‐like receptor 4; T2, type 2.
Objective
Genetic variants of the cytoplasmic FMR1‐interacting protein 2 (CYFIP2) encoding an actin‐regulatory protein are associated with brain disorders, including intellectual disability and ...epilepsy. However, specific in vivo neuronal defects and potential treatments for CYFIP2‐associated brain disorders remain largely unknown. Here, we characterized Cyfip2 heterozygous (Cyfip2+/−) mice to understand their neurobehavioral phenotypes and the underlying pathological mechanisms. Furthermore, we examined a potential treatment for such phenotypes of the Cyfip2+/− mice and specified a neuronal function mediating its efficacy.
Methods
We performed behavioral analyses of Cyfip2+/− mice. We combined molecular, ultrastructural, and in vitro and in vivo electrophysiological analyses of Cyfip2+/− prefrontal neurons. We also selectively reduced CYFIP2 in the prefrontal cortex (PFC) of mice with virus injections.
Results
Adult Cyfip2+/− mice exhibited lithium‐responsive abnormal behaviors. We found increased filamentous actin, enlarged dendritic spines, and enhanced excitatory synaptic transmission and excitability in the adult Cyfip2+/− PFC that was restricted to layer 5 (L5) neurons. Consistently, adult Cyfip2+/− mice showed increased seizure susceptibility and auditory steady‐state responses from the cortical electroencephalographic recordings. Among the identified prefrontal defects, lithium selectively normalized the hyperexcitability of Cyfip2+/− L5 neurons. RNA sequencing revealed reduced expression of potassium channel genes in the adult Cyfip2+/− PFC. Virus‐mediated reduction of CYFIP2 in the PFC was sufficient to induce L5 hyperexcitability and lithium‐responsive abnormal behavior.
Interpretation
These results suggest that L5‐specific prefrontal dysfunction, especially hyperexcitability, underlies both the pathophysiology and the lithium‐mediated amelioration of neurobehavioral phenotypes in adult Cyfip2+/− mice, which can be implicated in CYFIP2‐associated brain disorders. ANN NEUROL 2020;88:526–543
Hepatocellular carcinoma (HCC), one of the most common malignant cancers worldwide, is associated with substantial mortality. Because HCCs have strong resistance to conventional chemotherapeutic ...agents, novel therapeutic strategies are needed to improve survival in patients with HCC. The multicellular tumor spheroid (MCTS) model is a powerful method for anticancer research because of its ability to mimic the complexity and heterogeneity of tumor tissue, the three-dimensional cellular context of tumor tissue, and the pathophysiological gradients of in vivo tumors. However, it is difficult to obtain meaningful results from the MCTS model without considering the conditions of clinical tumors. We, therefore, provided a proof of concept to determine whether spheroid models simulate in vivo tumor microenvironments. Through a high-throughput screening for HCC therapy using the MCTS model, we selected inhibitors of Na
/K
-ATPase (ouabain and digoxin) that could suppress cell growth and migration via inhibition of the epithelial-mesenchymal transition of HCC in vivo and in vitro. The results showed that this model provides a new paradigm for high-throughput drug screening and will significantly improve the efficiency of identifying new drugs for HCC treatment. Through utilization of MCTS models, here we found that inhibitors of Na
/K
-ATPase may be feasible as a novel target to sensitize HCC cells.
Hepatocellular carcinoma (HCC) is among the most common malignant cancers worldwide, with an increasing incidence associated with an increase in deaths due to liver cancer. HCC is typically detected ...at an advanced stage in patients with underlying liver dysfunction, resulting in high mortality. The identification of HCC-specific targets represents a desired but unmet need for liver cancer treatment.
To identify potentially novel HCC therapeutic targets, we performed a secretome analysis using HCC spheroids. Sorbitol dehydrogenase (SORD) was identified as uniquely enriched in the secretomes and lysates derived from HCC spheroids, and high SORD expression in HCC tissues was associated with favorable effects on overall survival among patients with liver cancer. We found that the introduction of excess SORD in HCC cells inhibited tumor growth and stemness by enhancing necroptosis signal and bypassing energy-yielding pathways through regulation of lactate dehydrogenase A (LDHA) expression and mitochondrial dynamics. Treatment with human recombinant SORD (hrSORD) controlled HCC cell growth and regulated macrophage polarization in the tumor microenvironment.
These results demonstrate that SORD plays critical functional roles in HCC suppression through polyol pathway–independent mechanisms, suggesting that targeting SORD expression might represent a promising therapeutic strategy for liver cancer therapy.
•SORD expression in tumor tissues is associated with favorable prognosis in HCC patients.•Excess SORD in HCC promotes inhibition of tumor growth by enhancing necroptosis signal and bypassing aerobic glycolysis.•SORD attenuates tumor growth through ZNF530 regulation in HCC cells.•SORD regulates macrophage polarization in the tumor microenvironment.
The endoplasmic reticulum (ER) is the principal organelle in the cell for protein folding and trafficking, lipid synthesis, and cellular calcium homeostasis. Perturbation of ER function results in ...activation of the unfolded protein response (UPR) and is implicated in abnormal lipid biosynthesis and development of insulin resistance. In this study, we investigated whether transcription of sphingosine kinase (Sphk)2 is regulated by ER stress‐mediated UPR pathways. Sphk2, a major isotype of sphingosine kinase in the liver, was transcriptionally up‐regulated by tunicamycin and lipopolysaccharides. Transcriptional regulation of Sphk2 was mediated by activation of activating transcription factor (ATF)4 as demonstrated by promoter assays, immunoblotting, and small interfering RNA analyses. In primary hepatocytes, adenoviral Sphk2 expression elevated cellular sphingosine 1 phosphate (S1P) and activated protein kinase B phosphorylation, with no alteration of insulin receptor substrate phosphorylation. Hepatic overexpression of Sphk2 in mice fed a high‐fat diet (HFD) led to elevated S1P and reduced ceramide, sphingomyelin, and glucosylceramide in plasma and liver. Hepatic accumulation of lipid droplets by HFD feeding was reduced by Sphk2‐mediated up‐regulation of fatty acid (FA) oxidizing genes and increased FA oxidation in liver. In addition, glucose intolerance and insulin resistance were ameliorated by improved hepatic insulin signaling through Sphk2 up‐regulation. Conclusion: Sphk2 is transcriptionally up‐regulated by acute ER stress through activation of ATF4 and improves perturbed hepatic glucose and FA metabolism. (Hepatology 2015;62:135‐146)
The authors investigated the utility of noninvasive hemodynamic assessment in the identification of high-risk plaques that caused subsequent acute coronary syndrome (ACS).
ACS is a critical event ...that impacts the prognosis of patients with coronary artery disease. However, the role of hemodynamic factors in the development of ACS is not well-known.
Seventy-two patients with clearly documented ACS and available coronary computed tomographic angiography (CTA) acquired between 1 month and 2 years before the development of ACS were included. In 66 culprit and 150 nonculprit lesions as a case-control design, the presence of adverse plaque characteristics (APC) was assessed and hemodynamic parameters (fractional flow reserve derived by coronary computed tomographic angiography FFRCT, change in FFRCT across the lesion △FFRCT, wall shear stress WSS, and axial plaque stress) were analyzed using computational fluid dynamics. The best cut-off values for FFRCT, △FFRCT, WSS, and axial plaque stress were used to define the presence of adverse hemodynamic characteristics (AHC). The incremental discriminant and reclassification abilities for ACS prediction were compared among 3 models (model 1: percent diameter stenosis %DS and lesion length, model 2: model 1 + APC, and model 3: model 2 + AHC).
The culprit lesions showed higher %DS (55.5 ± 15.4% vs. 43.1 ± 15.0%; p < 0.001) and higher prevalence of APC (80.3% vs. 42.0%; p < 0.001) than nonculprit lesions. Regarding hemodynamic parameters, culprit lesions showed lower FFRCT and higher △FFRCT, WSS, and axial plaque stress than nonculprit lesions (all p values <0.01). Among the 3 models, model 3, which included hemodynamic parameters, showed the highest c-index, and better discrimination (concordance statistic c-index 0.789 vs. 0.747; p = 0.014) and reclassification abilities (category-free net reclassification index 0.287; p = 0.047; relative integrated discrimination improvement 0.368; p < 0.001) than model 2. Lesions with both APC and AHC showed significantly higher risk of the culprit for subsequent ACS than those with no APC/AHC (hazard ratio: 11.75; 95% confidence interval: 2.85 to 48.51; p = 0.001) and with either APC or AHC (hazard ratio: 3.22; 95% confidence interval: 1.86 to 5.55; p < 0.001).
Noninvasive hemodynamic assessment enhanced the identification of high-risk plaques that subsequently caused ACS. The integration of noninvasive hemodynamic assessments may improve the identification of culprit lesions for future ACS. (Exploring the Mechanism of Plaque Rupture in Acute Coronary Syndrome Using Coronary CT Angiography and Computational Fluid Dynamic EMERALD; NCT02374775)
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Recently, the fabrication of 3D circuits has attracted significant attention in the context of the realization of a new‐generation of printed electronics. In particular, form‐factor free Cu ...conductors have been recognized as the key to a constituent layer that can interconnect on demand a variety of active/passive components on arbitrarily designable platforms. However, even with their characteristic advantages of cost‐effectiveness and high electrical conductivity, 3D printed Cu circuits have been not suggested, owing to the difficulty of suppressing undesirable oxidation reactions and the absence of appropriate strategies for transforming the 3D particulate layers into device‐quality conductive ones. In this study, multidimensional particles are proposed that allow for deep penetration of incident photons in the surface‐conformal laser writing process, mechanisms of which are fully clarified based on an optical simulation‐based physical interpretation. The critical factors determining the electrical properties are elucidated through a spectroscopy‐based investigation for 3D structured Cu conductors. It is demonstrated that 16.5 µm thick Cu features (with values of resistivity and resistance of 15 µΩ cm and 0.91 Ω cm−1, respectively) can be created simply by successive 3D printing and laser writing processes, facilitating a user‐friendly design of low‐cost, high performance, form‐factor free electrical circuits.
A 3D printable fluid comprising multi‐dimensional Cu particles for the formation of highly conductive Cu layers on 3D structures is suggested. It is demonstrated that the Cu features can be created on demand via successive 3D printing and 3D laser writing processes, with resistivity and resistance values of 15 μΩ cm and 0.91 Ω cm‐1 respectively.
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