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The lithium deposited via the complex electrochemical heterogeneous lithium deposition reaction (LDR) process on a lithium foil-based anode (LFA) forms a high-aspect-ratio shape whenever the reaction kinetics reach its limit, threatening battery safety. Thereby, a research strategy that boosts the LDR kinetics is needed to construct a high-power and safe lithium metal anode. In this study, the kinetic limitations of the LDR process on LFA are elucidated through operando and ex situ observations using in-depth electrochemical analyses. In addition, ultra-thin (≈0.5 µm) and high modulus (≥19 GPa) double-walled carbon nanotube (DWNT) membranes with different surface properties are designed to catalyze high-safety LDRs. The oxygen-functionalized DWNT membranes introduced on the LFA top surface simultaneously induce multitudinous lithium nuclei, leading to film-like lithium deposition even at a high current density of 20 mA cm-2. More importantly, the layer-by-layer assembly of the oxygen-functionalized and pristine DWNT membranes results in different surface energies between the top and bottom surfaces, enabling selective surface LDRs underneath the high-modulus bilayer membranes. The protective LDR on the bilayer-covered LFA guarantees an invulnerable cycling process in large-area pouch cells at high current densities for more than 1000 cycles, demonstrating the practicability of LFA in a conventional liquid electrolyte system.
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A growing global health concern is metabolic syndrome, which is defined by low HDL, diabetes, hypertension, and abdominal obesity. Nuclear receptors are attractive targets for treatment of diseases associated with metabolic syndrome. Liver X receptors (LXRs) have become one of the most significant pharmacological targets among nuclear receptors. Multiple research studies emphasize the essential function of the liver X receptor (LXR) in the pathophysiology of metabolic syndrome. Puniceloid D, among natural products, demonstrated promising effects on LXRα. However, attempts at the total synthesis of natural products were faced with challenges, including long synthetic steps and low yields, requiring a more efficient approach. In this study, for the first time, we successfully synthesized puniceloid D through a seven-step process and conducted docking studies to gain a comprehensive understanding of the interactions involved in the binding of puniceloid D to LXR within different heterodimeric contexts. Our understanding of the pathophysiology of metabolic syndrome could be improved by these findings, which might assist with the development of novel treatment strategies.
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Produtos Biológicos , Síndrome Metabólica , Humanos , Receptores X do Fígado , Micro-Ondas , Produtos Biológicos/farmacologia , CabeçaRESUMO
Layered oxides widely used as lithium-ion battery electrodes are designed to be cycled under conditions that avoid phase transitions. Although the desired single-phase composition ranges are well established near equilibrium, operando diffraction studies on many-particle porous electrodes have suggested phase separation during delithiation. Notably, the separation is not always observed, and never during lithiation. These anomalies have been attributed to irreversible processes during the first delithiation or reversible concentration-dependent diffusion. However, these explanations are not consistent with all experimental observations such as rate and path dependencies and particle-by-particle lithium concentration changes. Here, we show that the apparent phase separation is a dynamical artefact occurring in a many-particle system driven by autocatalytic electrochemical reactions, that is, an interfacial exchange current that increases with the extent of delithiation. We experimentally validate this population-dynamics model using the single-phase material Lix(Ni1/3Mn1/3Co1/3)O2 (0.5 < x < 1) and demonstrate generality with other transition-metal compositions. Operando diffraction and nanoscale oxidation-state mapping unambiguously prove that this fictitious phase separation is a repeatable non-equilibrium effect. We quantitatively confirm the theory with multiple-datastream-driven model extraction. More generally, our study experimentally demonstrates the control of ensemble stability by electro-autocatalysis, highlighting the importance of population dynamics in battery electrodes (even non-phase-separating ones).
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In this study, we proposed an online learning method using spike-timing dependent plasticity (STDP) whose operation is analogous to gradient descent, the most successful learning algorithm for nonspiking artificial neural networks (ANNs). With a model of a 4-terminal synaptic transistor we previously reported, a single-layer neural network implemented on the cross-point array was simulated by MATLAB to train binary MNIST samples with gradient descent algorithm. In addition, a proposed pulse scheme based on STDP was used to train the same network by applying teaching pulses having positive and negative timing differences with respect to input pulses to the back gate of the synaptic transistors. By comparing the extracted synaptic weight maps from both methods, therefore, the network trained by gradient descent was almost equally reproduced by the proposed method which was performed fully on hardware without computer calculation.
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Educação a Distância , Plasticidade Neuronal , Algoritmos , Redes Neurais de Computação , NeurôniosRESUMO
Various kinds of nanostructured materials have been extensively investigated as lithium ion battery electrode materials derived from their numerous advantageous features including enhanced energy and power density and cyclability. However, little is known about the microscopic origin of how nanostructures can enhance lithium storage performance. Herein, we identify the microscopic origin of enhanced lithium storage in anatase TiO2 nanostructure and report a reversible and stable route to achieve enhanced lithium storage capacity in anatase TiO2. We designed hollow anatase TiO2 nanostructures composed of interconnected â¼5 nm sized nanocrystals, which can individually reach the theoretical lithium storage limit and maintain a stable capacity during prolonged cycling (i.e., 330 mAh g-1 for the initial cycle and 228 mAh g-1 for the 100th cycle, at 0.1 A g-1). In situ characterization by X-ray diffraction and X-ray absorption spectroscopy shows that enhanced lithium storage into the anatase TiO2 nanocrystal results from the insertion reaction, which expands the crystal lattice during the sequential phase transition (anatase TiO2 â Li0.55TiO2 â LiTiO2). In addition to the pseudocapacitive charge storage of nanostructures, our approach extends the utilization of nanostructured TiO2 for significantly stabilizing excess lithium storage in crystal structures for long-term cycling, which can be readily applied to other lithium storage materials.
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Mitsugumin 53 (MG53) is an E3 ligase that interacts with and ubiquitinates insulin receptor substrate-1 (IRS-1) in skeletal muscle; thus, an MG53-IRS-1 interaction disruptor (MID), which potentially sensitizes insulin signaling with an elevated level of IRS-1 in skeletal muscle, is an excellent candidate for treating insulin resistance. To screen for an MID, we developed a bimolecular luminescence complementation system using an N-terminal luciferase fragment fused with IRS-1 and a C-terminal luciferase fragment fused with an MG53 C14A mutant that binds to IRS-1 but does not have E3 ligase activity. An MID, which was discovered using the bimolecular luminescence complementation system, disrupted the molecular association of MG53 with IRS-1, thus abolishing MG53-mediated IRS-1 ubiquitination and degradation. Thus, the MID sensitized insulin signaling and increased insulin-elicited glucose uptake with an elevated level of IRS-1 in C2C12 myotubes. These data indicate that this MID holds promise as a drug candidate for treating insulin resistance.
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Proteínas de Transporte/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Insulina/metabolismo , Proteínas dos Microtúbulos/metabolismo , Músculo Esquelético/metabolismo , Proteínas Nucleares/metabolismo , Mapas de Interação de Proteínas/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Transcrição/metabolismo , Células Cultivadas , Humanos , Resistência à Insulina , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteólise , Transdução de Sinais/efeitos dos fármacos , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases/metabolismo , UbiquitinaçãoRESUMO
Brain-inspired neuromorphic systems have attracted much attention as new computing paradigms for power-efficient computation. Here, we report a silicon synaptic transistor with two electrically independent gates to realize a hardware-based neural network system without any switching components. The spike-timing dependent plasticity characteristics of the synaptic devices are measured and analyzed. With the help of the device model based on the measured data, the pattern recognition capability of the hardware-based spiking neural network systems is demonstrated using the modified national institute of standards and technology handwritten dataset. By comparing systems with and without inhibitory synapse part, it is confirmed that the inhibitory synapse part is an essential element in obtaining effective and high pattern classification capability.
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Aberrant sialylation has long been correlated with human cancer. Increased ST6 Gal I (ß-galactoside α 2, 6 sialyltransferase) and consequently higher levels of cell-surface α 2, 6 sialylation has been associated with human colorectal cancer (CRC) metastasis. We have extensive circumstantial data that sialylation is connected to cancer metastasis, but we do not understand in detail how sialylation can switch on/off multiple steps in cancer metastasis. To investigate the molecular mechanism underlying the ST6Gal I-mediated metastasis of CRC, we silenced the ST6Gal I gene in a metastatic SW620 CRC cell line (SW620-shST6Gal I) and examined the metastatic behavior of the cells. We found that various hallmarks of metastatic ability were considerably enhanced in ST6Gal 1-depleted SW620 clones, as assessed both in vitro and in vivo . In particular, the metastasis suppressor, KAI1, was down-regulated in ST6Gal I-deficient SW620 clones. This reflected the increased exosome-mediated exportation of KAI1, and was associated with a decrease in the KAI1-mediated inhibition of integrin. These findings indicate that gene silencing of ST6Gal I could enhance metastasis of CRC by down-regulating KAI1 activity and rescuing its negative effects on integrin signaling.
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Cancer therapies attempt to destroy the entire tumor, but this tends to require toxic compounds and high doses of radiation. Recently, considerable attention has focused on therapy-induced senescence (TIS), which can be induced in cancer cells by low doses of therapeutic drugs or radiation and provides a barrier to tumor development. However, the molecular mechanisms governing TIS remain elusive. Special attention has been paid to the potential chemopreventive effect of aspirin against human colorectal cancer. In this study, we investigated the effects of aspirin on TIS of human colorectal carcinoma (CRC) cells and show that it occurs via sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK), two key regulators of cellular metabolism. Aspirin increased the senescence of CRC cells, increased the protein levels of SIRT1, phospho-AMPK (T172), and phospho-acetyl CoA carboxylase (S79), and reduced the cellular level of ATP. Small-interfering RNA-mediated downregulation or pharmacological inhibition of SIRT1 or AMPK significantly attenuated the aspirin-induced cellular senescence in CRC cells. In contrast, treatment with a SIRT1 agonist or an AMP analog induced cellular senescence. Remarkably, SIRT1 knockdown abrogated the aspirin-induced activation of AMPK, and vice versa. During the progression of aspirin-induced cellular senescence in CRC cells, SIRT1 showed increased deacetylase activity at a relatively early time point but was characterized by decreased activity with increased cytoplasmic localization at a later time point. Collectively, these novel findings suggest that aspirin could provide anticancer effects by inducing senescence in human CRC cells through the reciprocal regulation of SIRT1-AMPK pathways.
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Proteínas Quinases Ativadas por AMP/metabolismo , Aspirina/metabolismo , Senescência Celular/fisiologia , Neoplasias Colorretais/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Sirtuína 1/metabolismo , Aspirina/administração & dosagem , Senescência Celular/efeitos dos fármacos , Células HCT116 , HumanosRESUMO
To address whether mitochondrial biogenesis is essential for skeletal myogenesis, C2C12 myogenesis was investigated after knockdown of NADH dehydrogenase (ubiquintone) flavoprotein 1 (NDUFV1), which is an oxidative phosphorylation complex I subunit that is the first subunit to accept electrons from NADH. The NDUFVI knockdown enhanced C2C12 myogenesis by decreasing the NAD(+)/NADH ratio and subsequently inactivating SIRT1 and SIRT1 activators (pyruvate, SRT1720, and resveratrol) abolished the NDUFV1 knockdown-induced myogenesis enhancement. However, the insulin-elicited activation of insulin receptor ß (IRß) and insulin receptor substrate-1 (IRS-1) was reduced with elevated levels of protein-tyrosine phosphatase 1B after NDUFV1 knockdown in C2C12 myotubes. The NDUFV1 knockdown-induced blockage of insulin signaling was released by protein-tyrosine phosphatase 1B knockdown in C2C12 myotubes, and we found that NDUFV1 or SIRT1 knockdown did not affect mitochondria biogenesis during C2C12 myogenesis. Based on these data, we can conclude that complex I dysfunction-induced SIRT1 inactivation leads to myogenesis enhancement but blocks insulin signaling without affecting mitochondria biogenesis.
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Complexo I de Transporte de Elétrons/deficiência , Complexo I de Transporte de Elétrons/metabolismo , Insulina/metabolismo , Doenças Mitocondriais/metabolismo , Desenvolvimento Muscular/fisiologia , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/metabolismo , Sirtuína 1/antagonistas & inibidores , Animais , Linhagem Celular , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Complexo I de Transporte de Elétrons/genética , Técnicas de Silenciamento de Genes , Resistência à Insulina/fisiologia , Camundongos , Modelos Biológicos , Desenvolvimento Muscular/genética , Fibras Musculares Esqueléticas/metabolismo , NAD/metabolismo , Fosforilação Oxidativa , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , RNA Interferente Pequeno/genética , Transdução de Sinais , Sirtuína 1/genética , Sirtuína 1/metabolismoRESUMO
Objective: Lingual fixed retainers, made from 0.0175-inch 3-strand twisted stainless steel wire (TW) and 0.016 × 0.022-inch straight rectangular wire (RW), are generally used in clinical practice. This study aimed to calculate their accuracy by comparing the discrepancy between computer-aided customized retainers made from these two types of wires. Methods: Eleven orthodontic patients were selected, resulting in 22 maxillary and mandibular three-dimensional printing dental models. Two types of lingual fixed retainers were bonded from canine to canine. To determine the accuracy, five points were chosen for each model, resulting in 110 selected points. The absolute values of the distances on the x-, y-, and z-axes were measured to compare the accuracy of the two types of computer-aided retainers. Results: The accuracy of the two types of retainers did not differ significantly in the x- and z-axes, but only in the y-axis (P < 0.01), where RW-fixed retainers exhibited a slightly but significantly increased distance compared to the TW. Conclusions: Both types of retainers showed high accuracy; however, RW had a slight but statistically significant difference along the y-axis compared with TW. This type of computer-aided design/computer-aided manufacturing bending machine is limited to two dimensions, and the dental arch is curved. Therefore, RW may require slight manual adjustment by the practitioner after manufacturing.
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Cellular senescence, a hallmark of aging, is pathogenically linked to the development of aging-related diseases. This study demonstrates that FRMD6, an upstream component of the Hippo/YAP signaling cascade, is a key regulator of senescence. Proteomic analysis revealed that FRMD6 is upregulated in senescent IMR90 fibroblasts under various senescence-inducing conditions. Silencing FRMD6 mitigated the senescence of IMR90 cells, suggesting its requirement in senescence. Conversely, the overexpression of FRMD6 alone induced senescence in cells and in lung tissue, establishing a causal link. The elevated FRMD6 levels correlated well with increased levels of the inhibitory phosphorylated YAP/TAZ. We identified cellular communication network factor 3 (CCN3), a key component of the senescence-associated secretory phenotype regulated by YAP, whose administration attenuated FRMD6-induced senescence in a dose-dependent manner. Mechanistically, FRMD6 interacted with and activated MST kinase, which led to YAP/TAZ inactivation. The expression of FRMD6 was regulated by the p53 and SMAD transcription factors in senescent cells. Accordingly, the expression of FRMD6 was upregulated by TGF-ß treatment that activates those transcription factors. In TGF-ß-treated IMR90 cells, FRMD6 mainly segregated with p21, a senescence marker, but rarely segregated with α-SMA, a myofibroblast marker, which suggests that FRMD6 has a role in directing cells towards senescence. Similarly, in TGF-ß-enriched environments, such as fibroblastic foci (FF) from patients with idiopathic pulmonary fibrosis, FRMD6 co-localized with p16 in FF lining cells, while it was rarely detected in α-SMA-positive myofibroblasts that are abundant in FF. In sum, this study identifies FRMD6 as a novel regulator of senescence and elucidates the contribution of the FRMD6-Hippo/YAP-CCN3 axis to senescence.
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Energy-absorbing materials have extensive applications in aerospace and automotive applications. Research has shown buckling initiators, or triggers, in energy-absorbing tubular structures increase the energy absorbed by encouraging the side panels to fold when loaded out of plane in compression conditions. Additively manufactured TPE honeycombs were designed in this study to include these buckling initiators, which introduced a slight decrease in initial weight, as well as initial stress concentrations, while improving crashworthiness characteristics. The samples with buckling initiators (1BI) showed an increase in crush efficiency when directly compared to their no buckling initiator (0BI) counterparts. The 1BI samples maintained an increased crush efficiency regardless of the strain rate used. The samples with 1BI were able to better equilibrate the peak stress with the plateau stress. These honeycomb samples were found to maintain their crush efficiency, even after multiple rounds of compression testing. The quasi-static 0BI samples experienced a 23.4% decrease in the peak stress after multiple rounds of compression testing, while the 1BI samples saw approximately a 23.0% decrease. The 1BI samples averaged a decrease in crush efficiency of 0.5%, while the 0BI samples saw a decrease in crush efficiency of 5%. As the strain rate increased, the crush efficiency for the 1BI samples showed an increase in performance, with a smaller degradation in crush efficiency over multiple uses. Visco-elastic honeycomb with buckling initiators has a higher energy absorption than samples with no buckling initiators when exposed to multiple impact cycles.
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Senescence, a hallmark of aging, is a factor in age-related diseases (ARDs). Therefore, targeting senescence is widely regarded as a practicable method for modulating the effects of aging and ARDs. Here, we report the identification of regorafenib, an inhibitor of multiple receptor tyrosine kinases, as a senescence-attenuating drug. We identified regorafenib by screening an FDA-approved drug library. Treatment with regorafenib at a sublethal dose resulted in effective attenuation of the phenotypes of ßPIX knockdown- and doxorubicin-induced senescence and replicative senescence in IMR-90 cells; cell cycle arrest, and increased SA-ß-Gal staining and senescence-associated secretory phenotypes, particularly increasing the secretion of interleukin 6 (IL-6) and IL-8. Consistent with this result, slower progression of ßPIX depletion-induced senescence was observed in the lungs of mice after treatment with regorafenib. Mechanistically, the results of proteomics analysis in diverse types of senescence indicated that growth differentiation factor 15 and plasminogen activator inhibitor-1 are shared targets of regorafenib. Analysis of arrays for phospho-receptors and kinases identified several receptor tyrosine kinases, including platelet-derived growth factor receptor α and discoidin domain receptor 2, as additional targets of regorafenib and revealed AKT/mTOR, ERK/RSK, and JAK/STAT3 signaling as the major effector pathways. Finally, treatment with regorafenib resulted in attenuation of senescence and amelioration of porcine pancreatic elastase-induced emphysema in mice. Based on these results, regorafenib can be defined as a novel senomorphic drug, suggesting its therapeutic potential in pulmonary emphysema.
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Enfisema , Enfisema Pulmonar , Síndrome do Desconforto Respiratório , Camundongos , Animais , Suínos , Senoterapia , Tirosina , Senescência Celular/genéticaRESUMO
Colon cancer is associated with a poor prognosis, motivating strategies to prevent its development. An encouraging preventative strategy is the use of nutraceuticals; however, scientific verification of therapeutic functions and mechanisms of biological activity are necessary for the acceptance of dietary supplements in cancer treatment. Berberine is a benzylisoquinoline alkaloid extracted from many kinds of medicinal plants that has been extensively used as a Chinese traditional medicine. Recently, berberine has been reported to possess antitumoral activities. Among the various cellular targets of berberine is AMP-activated protein kinase (AMPK), which regulates tumor progression and metastasis. However, the specific role of berberine-induced AMPK activation and its effects on the metastatic potential of colon cancer remain largely unknown. The present study investigated berberine-induced activation of AMPK and its effects on colon cancer cell migration. Berberine decreased the migration of SW480 and HCT116 cells. We found that berberine activated AMPK in human colon cancer cell lines. Notably, berberine-induced activation of AMPK reduced the integrin ß1 protein levels and decreased the phosphorylation of integrin ß1 signaling targets. Knockdown of AMPKα1 subunits using small interfering RNA significantly attenuated berberine-induced downregulation of integrin ß1 and inhibition of tumor cell migration. Collectively, our results suggest that berberine-induced AMPK activation inhibits the metastatic potential of colon cancer cells by decreasing integrin ß1 protein levels and downstream signaling.
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Proteínas Quinases Ativadas por AMP/biossíntese , Antineoplásicos/farmacologia , Berberina/farmacologia , Movimento Celular/efeitos dos fármacos , Neoplasias do Colo/enzimologia , Integrina beta1/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Neoplasias do Colo/patologia , Regulação para Baixo , Ativação Enzimática/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: KAI1 was initially identified as a metastasis-suppressor gene in prostate cancer. It is a member of the tetraspan transmembrane superfamily (TM4SF) of membrane glycoproteins. As part of a tetraspanin-enriched microdomain (TEM), KAI1 inhibits tumor metastasis by negative regulation of Src. However, the underlying regulatory mechanism has not yet been fully elucidated. CUB-domain-containing protein 1 (CDCP1), which was previously known as tetraspanin-interacting protein in TEM, promoted metastasis via enhancement of Src activity. To better understand how KAI1 is involved in the negative regulation of Src, we here examined the function of KAI1 in CDCP1-mediated Src kinase activation and the consequences of this process, focusing on HIF-1 α and VEGF expression. METHODS: We used the human prostate cancer cell line PC3 which was devoid of KAI1 expression. Vector-transfected cells (PC3-GFP clone #8) and KAI1-expressing PC3 clones (PC3-KAI1 clone #5 and #6) were picked after stable transfection with KAI1 cDNA and selection in 800 µg/ml G418. Protein levels were assessed by immunoblotting and VEGF reporter gene activity was measured by assaying luciferase activitiy. We followed tumor growth in vivo and immunohistochemistry was performed for detection of HIF-1, CDCP1, and VHL protein level. RESULTS: We demonstrated that Hypoxia-inducible factor 1α (HIF-1α) and VEGF expression were significantly inhibited by restoration of KAI1 in PC3 cells. In response to KAI1 expression, CDCP1-enhanced Src activation was down-regulated and the level of von Hippel-Lindau (VHL) protein was significantly increased. In an in vivo xenograft model, KAI1 inhibited the expression of CDCP1 and HIF-1α. CONCLUSIONS: These novel observations may indicate that KAI1 exerts profound metastasis-suppressor activity in the tumor malignancy process via inhibition of CDCP1-mediated Src activation, followed by VHL-induced HIF-1α degradation and, ultimately, decreased VEGF expression.
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Antígenos CD/fisiologia , Moléculas de Adesão Celular/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteína Kangai-1/fisiologia , Proteínas de Neoplasias/fisiologia , Neoplasias da Próstata/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Quinases da Família src/metabolismo , Antígenos de Neoplasias , Linhagem Celular Tumoral , Movimento Celular , Humanos , Immunoblotting , Imuno-Histoquímica , Proteína Kangai-1/metabolismo , Luciferases/metabolismo , Masculino , Invasividade Neoplásica , Neoplasias da Próstata/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismoRESUMO
The research in this paper entails the design of material systems with tunable energy-absorbing properties. Hollow glass microspheres of different densities are layered using dry powder printing and subsequently sintered to form a cellular structure. The tunability of the bilayer foams is investigated using various combinations of hollow microspheres with different densities and different thickness ratios of the layers. The mechanical responses to quasi-static uniaxial compression of the bilayer foams are also investigated. These bilayer samples show different mechanical responses from uniform samples with a distinctive two-step stress-strain profile that includes a first and second plateau stress. The strain where the second plateau starts can be tuned by adjusting the thickness ratio of the two layers. The resulting tunable stress-strain profile demonstrates tunable energy absorption. The tunability is found to be more significant if the density values of each layer differ largely. For comparison, bilayer samples are fabricated using epoxy at the interface instead of a sintering process and a different mechanical response is shown from a sintered sample with the different stress-strain profile. Designing the layered foams allows tuning of the stress-strain profile, enabling desired energy-absorbing properties which are critical in diverse impact conditions.
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Slug is a transcription factor belonging to the slug/snail superfamily. The protein is involved in embryonic development and epithelial-mesenchymal transition of tumors. Slug is also under temporal regulation during cell cycle. Here, we examined relationship between pSlugS158 (site-specific phosphorylation) and the cell cycle, and checked whether its phosphorylation level reflects mitotic activity in tissue specimens. Cell cycle analysis was performed after cell synchronization. To evaluate pSlugS158 identifying mitotic figures, we performed immunohistochemistry (IHC) for pSlugS158 in various formalin-fixed paraffin-embedded tissues; in addition, mitotic counts were compared with those in sections stained with hematoxylin and eosin (HE) and IHC for PHH3, a mitotic marker. We found that the level of pSlugS158 protein increased specifically at M phase and decreased at the G1/S phases in vitro. In almost all tested tissues, nuclear stain of pSlugS158 was identified in the cell with mitotic figures. There was no significant difference in mitotic counts between HE- and pSlugS158-stained sections. In conclusion, pSlugS158 may be a novel and practical immunohistochemical marker for detecting mitotic figures in human tissues.
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Biomarcadores Tumorais , Mitose , Fatores de Transcrição da Família Snail , Biomarcadores Tumorais/análise , Amarelo de Eosina-(YS) , Hematoxilina , Humanos , Imuno-Histoquímica , Índice Mitótico , Fosforilação , Projetos PilotoRESUMO
Aggregation of misfolded alpha-synuclein (α-synuclein) is a central player in the pathogenesis of neurodegenerative diseases. Therefore, the regulatory mechanism underlying α-synuclein aggregation has been intensively studied in Parkinson's disease (PD) but remains poorly understood. Here, we report p21-activated kinase 4 (PAK4) as a key regulator of α-synuclein aggregation. Immunohistochemical analysis of human PD brain tissues revealed an inverse correlation between PAK4 activity and α-synuclein aggregation. To investigate their causal relationship, we performed loss-of-function and gain-of-function studies using conditional PAK4 depletion in nigral dopaminergic neurons and the introduction of lentivirus expressing a constitutively active form of PAK4 (caPAK4; PAK4S445N/S474E), respectively. For therapeutic relevance in the latter setup, we injected lentivirus into the striatum following the development of motor impairment and analyzed the effects 6 weeks later. In the loss-of-function study, Cre-driven PAK4 depletion in dopaminergic neurons enhanced α-synuclein aggregation, intracytoplasmic Lewy body-like inclusions and Lewy-like neurites, and reduced dopamine levels in PAK4DAT-CreER mice compared to controls. Conversely, caPAK4 reduced α-synuclein aggregation, as assessed by a marked decrease in both proteinase K-resistant and Triton X100-insoluble forms of α-synuclein in the AAV-α-synuclein-induced PD model. Mechanistically, PAK4 specifically interacted with the NEDD4-1 E3 ligase, whose pharmacological inhibition and knockdown suppressed the PAK4-mediated downregulation of α-synuclein. Collectively, these results provide new insights into the pathogenesis of PD and suggest PAK4-based gene therapy as a potential disease-modifying therapy in PD.
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Ubiquitina-Proteína Ligases Nedd4 , Doença de Parkinson , alfa-Sinucleína , Animais , Camundongos , Ubiquitina-Proteína Ligases Nedd4/genética , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Substância Negra/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismoRESUMO
We introduce a simple and easy way to functionalize the surface of various carbonaceous materials through the ultraviolet light/ozone (UV/O3) plasma where we utilize the zero-, one-, and two-dimensional carbon frameworks. In a general manner, the lamps of a UV/O3 generator create two different wavelengths (λ = 185 and 254 nm); the shorter wavelength (λ = 185 nm) dissociates the oxygen (O2) in air and the longer wavelength (λ = 254 nm) dissociates the O3 and creates the reactive and monoatomic oxygen radical, which tends to incorporate onto the defects of the carbons. By tailoring the association and dissociation of the oxygen with various forms, carbon black, carbon nanofibers, and graphite flakes, chosen as representative models for the zero-, one-, and two-dimensional carbon frameworks, their structure can be oxidized, respectively, which is known as photochemical oxidation. Various carbons have their own distinctive morphology and electron transport properties, which are applicable for the lithium-sulfur (Li-S) cell. We, here, report on the improvement of electrochemical performance of the lithium/sulfur cell through such an efficient functionalization approach.