FRMD6 determines the cell fate towards senescence: involvement of the Hippo-YAP-CCN3 axis.

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.

High-Power and Large-Area Anodes for Safe Lithium-Metal Batteries.

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.

Microwave-Promoted Total Synthesis of Puniceloid D for Modulating the Liver X Receptor.

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.

Visco-Elastic Honeycomb Structures with Increased Energy Absorption and Shape Recovery Performance Using Buckling Initiators.

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.

Defining regorafenib as a senomorphic drug: therapeutic potential in the age-related lung disease emphysema.

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.

Tunable Energy Absorbing Property of Bilayer Amorphous Glass Foam via Dry Powder Printing.

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.

p21-activated kinase 4 controls the aggregation of α-synuclein by reducing the monomeric and aggregated forms of α-synuclein: involvement of the E3 ubiquitin ligase NEDD4-1.

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.

pSlugS158 immunohistochemistry is a novel promising mitotic marker for FFPE samples: a pilot study.

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.

Effects of Photochemical Oxidation of the Carbonaceous Additives on Li-S Cell Performance.

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.

Fictitious phase separation in Li layered oxides driven by electro-autocatalysis.

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).

Design considerations for lithium-sulfur batteries: mass transport of lithium polysulfides.

Irreversible loss of soluble lithium polysulfides (LiPSs) is a major obstacle deteriorating the performance of lithium-sulfur batteries. Multiple innovative approaches have recently been developed to resolve these LiPS issues. Melt-diffusion of sulfur into porous carbon is a representative solution for preventing the diffusion out of LiPSs, which aims to coordinate the sulfur on the electrochemically active site, accordingly. However, it has been overlooked that the mass transport motion of LiPSs has a crucial role in achieving high-performance. In this paper, we highlight the importance of the mass transport of soluble sulfur in the cathode structure by introducing various starting materials, i.e., solid sulfur using melt-diffusion and a catholyte, using 3-dimensional ordered macroporous carbon. The capacity of the sulfur cathode using melt-diffusion is well conserved in carbon with small pores because LiPSs are slowly diffused away, however, the catholyte derived sulfur cathode shows superior performance in carbon with large pores due to their rapid mass transport. The comparison with the four different combinations that control the pore size and mass transport reveals that proper selection of the initial state of starting materials using porous carbons demonstrates the optimal cell performance.

Integrin-mediated adhesions in regulation of cellular senescence.

Bioinformatic and functional data link integrin-mediated cell adhesion to cellular senescence; however, the significance of and molecular mechanisms behind these connections are unknown. We now report that the focal adhesion-localized ßPAK-interacting exchange factor (ßPIX)-G protein-coupled receptor kinase interacting protein (GIT) complex controls cellular senescence in vitro and in vivo. ßPIX and GIT levels decline with age. ßPIX knockdown induces cellular senescence, which was prevented by reexpression. Loss of ßPIX induced calpain cleavage of the endocytic adapter amphiphysin 1 to suppress clathrin-mediated endocytosis (CME); direct competition of GIT1/2 for the calpain-binding site on paxillin mediates this effect. Decreased CME and thus integrin endocytosis induced abnormal integrin signaling, with elevated reactive oxygen species production. Blocking integrin signaling inhibited senescence in human fibroblasts and mouse lungs in vivo. These results reveal a central role for integrin signaling in cellular senescence, potentially identifying a new therapeutic direction.

An Online Learning Method Using Spike-Timing Dependent Plasticity for Neuromorphic Systems.

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.

PAK4 signaling in health and disease: defining the PAK4-CREB axis.

p21-Activated kinase 4 (PAK4), a member of the PAK family, regulates a wide range of cellular functions, including cell adhesion, migration, proliferation, and survival. Dysregulation of its expression and activity thus contributes to the development of diverse pathological conditions. PAK4 plays a pivotal role in cancer progression by accelerating the epithelial-mesenchymal transition, invasion, and metastasis. Therefore, PAK4 is regarded as an attractive therapeutic target in diverse types of cancers, prompting the development of PAK4-specific inhibitors as anticancer drugs; however, these drugs have not yet been successful. PAK4 is essential for embryonic brain development and has a neuroprotective function. A long list of PAK4 effectors has been reported. Recently, the transcription factor CREB has emerged as a novel effector of PAK4. This finding has broad implications for the role of PAK4 in health and disease because CREB-mediated transcriptional reprogramming involves a wide range of genes. In this article, we review the PAK4 signaling pathways involved in prostate cancer, Parkinson's disease, and melanogenesis, focusing in particular on the PAK4-CREB axis.

Engineering Titanium Dioxide Nanostructures for Enhanced Lithium-Ion Storage.

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 ∼5 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 → Li0.55TiO2 → 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.

The p21-activated kinase 4-Slug transcription factor axis promotes epithelial-mesenchymal transition and worsens prognosis in prostate cancer.

Epithelial-mesenchymal transition (EMT) facilitates cancer invasion and metastasis and thus accelerates cancer progression. p21-activated kinase 4 (PAK4) is a critical regulator of prostate cancer (PC) progression. Here, we report that PAK4 activation promotes PC progression through the EMT regulator Slug. We find that phosphorylated PAK4S474 (pPAK4) levels, an index of PAK4 activation, were tightly associated with Gleason score (p < 0.001), a clinical indicator of PC progression, but not with prostate serum antigen levels or tumor stage. Stable silencing of PAK4 in PC cells reduced their potential for EMT, cellular invasion, and metastasis in vivo. PAK4 bound and directly phosphorylated Slug at two previously unknown sites, S158 and S254, which resulted in its stabilization. The non-phosphorylatable form SlugS158A/S254A upregulated transcription of CDH1, which encodes E-cadherin, and thus suppressed EMT and invasion, to a greater extent than did wild-type Slug. The strong EMT inducer TGF-ß elevated pPAK4 and pSlugS158 levels; PAK4 knockdown or introduction of a dominant-negative form of PAK4 inhibited both TGF-ß-stimulated EMT and an increase in pSlugS158 levels. Finally, immunohistochemistry revealed a positive correlation between pPAK4 and pSlugS158 but an inverse correlation between pSlugS158 and E-cadherin. The results suggest that the PAK4-Slug axis represents a novel pathway that promotes PC progression.

Silicon synaptic transistor for hardware-based spiking neural network and neuromorphic system.

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.

MG53-IRS-1 (Mitsugumin 53-Insulin Receptor Substrate-1) Interaction Disruptor Sensitizes Insulin Signaling in Skeletal Muscle.

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.

Silencing of ST6Gal I enhances colorectal cancer metastasis by down-regulating KAI1 via exosome-mediated exportation and thereby rescues integrin signaling.

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.

Neuromorphic System Based on CMOS Inverters and Si-Based Synaptic Device.

We developed an analog neuron circuit that can work with Si-based synaptic devices. N-channel and p-channel synaptic devices connected to current mirrors constitute the synaptic connection and integration parts to implement the excitation and inhibition mechanisms of biological neurons. The normal inverter controlling delay time and the modified inverter making negative pulse constitute the action-potential generation part to generate output action-potential. Connecting output potential to the synaptic device, we implement the spike-timing-dependent-plasticity (STDP) mechanism, adjusting the conductance of synapse. As we have constituted the analog neuron circuit using 4-terminal synaptic device without additional switch and logic operation, we can emulate the operation of the neuron with minimum number of devices and power dissipation.