Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway.

Amino acids are required for activation of the mammalian target of rapamycin (mTOR) kinase, which regulates protein translation, cell size, and autophagy. However, the amino acid sensor that directly couples intracellular amino acid-mediated signaling to mTORC1 is unknown. Here we show that leucyl-tRNA synthetase (LRS) plays a critical role in amino acid-induced mTORC1 activation by sensing intracellular leucine concentration and initiating molecular events leading to mTORC1 activation. Mutation of LRS amino acid residues important for leucine binding renders the mTORC1 pathway insensitive to intracellular levels of amino acids. We show that LRS directly binds to Rag GTPase, the mediator of amino acid signaling to mTORC1, in an amino acid-dependent manner and functions as a GTPase-activating protein (GAP) for Rag GTPase to activate mTORC1. This work demonstrates that LRS is a key mediator for amino acid signaling to mTORC1.

Monolithic 3D integration of 2D materials-based electronics towards ultimate edge computing solutions.

Three-dimensional (3D) hetero-integration technology is poised to revolutionize the field of electronics by stacking functional layers vertically, thereby creating novel 3D circuity architectures with high integration density and unparalleled multifunctionality. However, the conventional 3D integration technique involves complex wafer processing and intricate interlayer wiring. Here we demonstrate monolithic 3D integration of two-dimensional, material-based artificial intelligence (AI)-processing hardware with ultimate integrability and multifunctionality. A total of six layers of transistor and memristor arrays were vertically integrated into a 3D nanosystem to perform AI tasks, by peeling and stacking of AI processing layers made from bottom-up synthesized two-dimensional materials. This fully monolithic-3D-integrated AI system substantially reduces processing time, voltage drops, latency and footprint due to its densely packed AI processing layers with dense interlayer connectivity. The successful demonstration of this monolithic-3D-integrated AI system will not only provide a material-level solution for hetero-integration of electronics, but also pave the way for unprecedented multifunctional computing hardware with ultimate parallelism.

Three-dimensional imaging performance of photoelectrochemical cells.

A photoelectrochemical (PEC) cell produces hydrogen energy using solar energy and an electrochemical reaction. In the hydrogen production process with water decomposition, electrons move from the anode to the cathode, and by measuring the current value at this time, the PEC cell can generate hydrogen and function as an image sensor at the same time. Due to the characteristics of the PEC cell that can perform both functions simultaneously, it can be applied as a device that can detect and respond to the surrounding environment without the need for an observation system such as a camera. We present the imaging performance of PEC cells. The effectiveness of the experiment was confirmed by applying the PEC cells to integral imaging, one of the three-dimensional (3D) imaging techniques.

Investigation of the factors responsible for the low oral bioavailability of alizarin using a sensitive LC-MS/MS method: In vitro, in situ, and in vivo evaluations.

Alizarin (1,2-dihydroxyanthraquinone) is an anthraquinone reddish dye widely used for painting and textile dyeing. As the biological activity of alizarin has recently attracted increasing attention from researchers, its therapeutic potential as complementary and alternative medicine is of interest. However, no systematic research has been conducted on the biopharmaceutical and pharmacokinetic aspects of alizarin. Therefore, this study aimed to comprehensively investigate the oral absorption and intestinal/hepatic metabolism of alizarin using a simple and sensitive tandem mass spectrometry method developed and validated in-house. The present method for the bioanalysis of alizarin has merits, including a simple pretreatment procedure, small sample volume, and adequate sensitivity. Alizarin exhibited pH-dependent moderate lipophilicity and low solubility with limited intestinal luminal stability. Based on the in vivo pharmacokinetic data, the hepatic extraction ratio of alizarin was estimated to be 0.165-0.264, classified as a low level of hepatic extraction. In an in situ loop study, considerable fractions (28.2%-56.4%) of the alizarin dose were significantly absorbed in gut segments from the duodenum to ileum, suggesting that alizarin may be classified as the Biopharmaceutical Classification System class II. An in vitro metabolism study using rat and human hepatic S9 fractions revealed that glucuronidation and sulfation, but not NADPH-mediated phase I reactions and methylation, are significantly involved in the hepatic metabolism of alizarin. Taken together, it can be estimated that the fractions of oral alizarin dose unabsorbed from the gut lumen and eliminated by the gut and liver before reaching the systemic circulation are 43.6%-76.7%, 0.474%-36.3%, and 3.77%-5.31% of the dose, respectively, resulting in a low oral bioavailability of 16.8%. Therefore, the oral bioavailability of alizarin depends primarily on its chemical degradation in the gut lumen and secondarily on first-pass metabolism.

Integral imaging using a MoS2 Schottky diode.

We report the performance of a MoS2 Schottky diode on three-dimensional (3D) integral imaging. The MoS2 Schottky diode has asymmetric Pt electrodes for the Schottky contact and Ti/Au electrodes for the ohmic contact. Such a Schottky diode exhibits an excellent rectification ratio of 103, a broad spectral photoresponse in the 450-700 nm range, an almost ideal linearity of 1, and a wide linear dynamic range of 106 dB. We successfully conduct object pickup experiments using integral imaging and validate the feasibility of a single-pixel imager as a 3D image sensor.

High-performance coaxial piezoelectric energy generator (C-PEG) yarn of Cu/PVDF-TrFE/PDMS/Nylon/Ag.

Coaxial type piezoelectric energy generator (C-PEG) nanofiber was fabricated by a self-designed continuous electrospinning deposition system. Piezoelectric PVDF-TrFE nanofiber as an electroactive material was electrospun at a discharge voltage of 9-12 kV onto a simultaneously rotating and transverse moving Cu metal wire at an angular velocity of ω g = 60-120 RPM. The piezoelectric coefficient d33 of the PVDF-TrFE nanofiber was approximately -20 pm V-1. The generated output voltage (V G) increased according to the relationship exp(-α P) (α = 0.41- 0.57) as the pressure (P) increased from 30 to 500 kpa. The V G values for ten and twenty pieces of C-PEG were V G = 3.9 V and 9.5 V at P = 100 kpa, respectively, relatively high output voltages compared to previously reported values. The high V G for the C-PEG stems from the fact that it can generate a fairly high V G due to the increased number of voltage collection points compared to a conventional two-dimensional (2-dim) capacitor type of piezoelectric film or fiber device. C-PEG yarn was also fabricated via the dip-coating of a PDMS polymer solution, followed by winding with Ag-coated nylon fiber as an outer electrode. The current and power density of ten pieces of C-PEG yarn were correspondingly 22 nA cm-2 and 8.6 µW cm-3 at V G = 1.97 V, higher than previously reported values of 5.54 and 6 µW cm-3. The C-PEG yarn, which can generate high voltage compared to the conventional film/nanofiber mat type, is expected to be very useful as a wearable energy generator system.

Analysis of the Relationship between the Expression Levels of Neutrophil Gelatinase-Associated Lipocalin and Cytokine Genes in Bone Marrow.

Background: Recently, various associations of NGAL with several hematological cancers have been reported. However, given that the regulation of NGAL gene expression by cytokines is tissue-specific, NGAL expression in relation to those of cytokine genes has not been analyzed in bone marrow (BM) tissue. The purpose of this study was to analyze the association between NGAL and 48 cytokine gene expression levels in mononuclear cells (MNCs) of BM at the time of diagnosis of hematological malignancy and to explore the expression pattern of NGAL and related cytokine genes in patients with hematological malignancies and controls. Methods: BM MNCs were isolated from 48 patients, who were classified as patients presenting myeloproliferative neoplasm, acute myeloid leukemia, myelodysplastic syndrome, and as controls. NGAL and cytokine genes were analyzed using NanoString. Data on hematological parameters were collected from medical records. Single and multiple regression analyses were performed to analyze relationships. Results: Normalized counts of 26 cytokine genes were related to NGAL normalized counts, while STAT3 and TLR4 normalized counts had the highest explanatory power. The following multiple regression model was developed: NGAL normalized counts=4316.825 + 9.056 × STAT3 normalized counts + 844.226 × IL5 normalized counts + 17.540 × TLR1 normalized counts - 28.206 × TLR2 normalized counts - 42.524 × IRAK4 normalized counts. In the multiple regression analysis, STAT3 and TLR4 normalized counts showed multicollinearity. NGAL, STAT3, IL5, and TLR4 normalized counts showed similar intergroup patterns. Conclusions: NGAL normalized counts was predicted by a multiple regression model, while they showed similar intergroup patterns to STAT3, IL5, and TLR4 normalized counts.

All 2D WSe2/MoS2 heterojunction photodiode and its image sensor application.

Two-dimensional (2D) layered van der Waals atomic crystals exhibit many fascinating properties. In particular, their dangling-bond-free nature enables different 2D materials to be stacked on the top of each other without restraint, thereby forming a heterostructure. In this study, a high-performance all 2D WSe2/MoS2 heterojunction photodiode with a graphene contact as an electrode is demonstrated. It exhibits an excellent electrical performance (ideality factor of 1.2 and rectification ratio of 104), a broad spectral photoresponse (from 450 to 980 nm), and a remarkable linearity with a linear dynamic range of 113 dB. Finally, a self-powered single pixel imager is demonstrated as a feasible optoelectronic application.

Residual modulation reduction in optical sectioning using a suitable spatial light modulator waveform.

We propose a method to improve the axial response of structured illumination microscopy via selection of an illumination pattern with a sinusoidal or square wave within the cutoff frequency of the imaging system. Residual modulation within a sectioned image is mitigated by accurate phase-shifting via the electrical spatial light modulator control signal, which is based on an illumination pattern having a suitable waveform. Reduction in residual modulation is observed in the sinusoidal pattern with a spatial frequency sufficiently below the cutoff frequency of the imaging system. This reduction is larger for the square wave as the spatial frequency approaches one-third of the cutoff frequency.

Functional Fragments of AIMP1-Derived Peptide (AdP) and Optimized Hydrosol for Their Topical Deposition by Box-Behnken Design.

Aminoacyl-tRNA synthetase complex-interacting multifunctional protein 1 (AIMP1)-derived peptide (AdP) has been developed as a cosmeceutical ingredient for skin anti-aging given its fibroblast-activating (FA) and melanocyte-inhibiting (MI) functions. However, a suitable strategy for the topical delivery of AdP was required due to its low-permeable properties. In this study, FA and MI domains of AdP (FA-AdP and MI-AdP, respectively) were determined by functional domain mapping, where the activities of several fragments of AdP on fibroblast and melanocyte were tested, and a hydrosol-based topical delivery system for these AdP fragments was prepared. The excipient composition of the hydrosol was optimized to maximize the viscosity and drying rate by using Box-Behnken design. The artificial skin deposition of FA-AdP-loaded hydrosol was evaluated using Keshary-Chien diffusion cells equipped with Strat-M membrane (STM). The quantification of the fluorescent dye-tagged FA-AdP in STM was carried out by near-infrared fluorescence imaging. The optimized hydrosol showed 127-fold higher peptide deposition in STM than free FA-AdP (p < 0.05). This work suggests that FA- and MI-AdP are active-domains for anti-wrinkle and whitening activities, respectively, and the hydrosol could be used as a promising cosmetic formulation for the delivery of AdPs to the skin.

AIMP1 negatively regulates adipogenesis by inhibiting PPARγ.

Adipogenesis is known to be controlled by the concerted actions of transcription factors and co-regulators. However, little is known about the mechanism of regulation of the transcription factors that control adipogenesis. In addition, the adipogenic roles of translational factors remain unclear. Here, we show that aminoacyl tRNA synthetase-interacting multifunctional protein 1 (AIMP1, also known as p43), an auxiliary factor that is associated with a macromolecular tRNA synthetase complex, negatively regulates adipogenesis through a direct interaction with the DNA-binding domain of peroxisome proliferator-activated receptor γ (PPARγ). We found that AIMP1 expression increases during adipocyte differentiation. Adipogenesis is augmented in AIMP1-deficient cells, as compared with control cells. AIMP1 exhibits high affinity for active PPARγ and interacts with the DNA-binding domain of PPARγ, thereby inhibiting its transcriptional activity. Thus, AIMP1 appears to function as a novel inhibitor of PPARγ that regulates adipocyte differentiation by preventing the transcriptional activation of PPARγ.

Identification of a New Morpholine Scaffold as a P2Y12 Receptor Antagonist.

The P2Y12 receptor is critical for platelet activation and is an attractive drug target for the prevention of atherothrombotic events. Despite the proven antithrombotic efficacy of P2Y12 inhibitors, these thienopyridine scaffolds are prodrugs that lack important features of the ideal antithrombotic agent. For this reason, ticagrelor-a new chemical class of P2Y12 receptor antagonist-was developed, but it can cause shortness of breath and various types of bleeding. Moreover, ticagrelor is a cytochrome P450 3A4 substrate/inhibitor and, therefore, caution should be exercised when it is used concomitantly with strong CYP3A4 inducers/inhibitors. There is a need for novel P2Y12 receptor antagonist scaffolds that are reversible and have high efficacy without associated side effects. Here, we describe a novel antagonist containing a morpholine moiety that was identified by screening libraries of commercially available compounds. The molecule, Compound E, acted on P2Y12, but not P2Y1 and P2Y13, and exhibited pharmacological characteristics that were distinct from those of ticagrelor, acting instead on P2Y12 via an allosteric mechanism. These results provide a basis for the development/optimization of a new class of P2Y12 antagonists.

Tpl2 induces castration resistant prostate cancer progression and metastasis.

Progression to metastatic castration resistant prostate cancer (CRPC) is the major lethal pathway of prostate cancer (PC). Herein, we demonstrated that tumor progression locus 2 (Tpl2) kinase is the fundamental molecule provoking progression and metastasis of CRPC. Tpl2 upregulates CXCR4 and focal adhesion kinase (FAK) to activate CXCL12/CXCR4 and FAK/Akt signalling pathway. Consequently, epithelial-mesenchymal transition (EMT) and stemness of androgen depletion independent (ADI) PC cells are induced, which is dependent on the kinase activity of Tpl2. In vitro, proliferation, clonogenicity, migration, invasion and chemoresistance of ADI PC cells were enhanced by Tpl2. In vivo, Tpl2 overexpression and downregulation showed significant stimulatory and inhibitory effects on tumorigenic and metastatic potential of ADI PC cells, respectively. Moreover, the prognostic effects of Tpl2 and expressional correlation between Tpl2 and EMT-related molecules/CXCR4 were validated in clinical PC databases. Since Tpl2 exerts metastatic progression promoting activities in CRPC, Tpl2 could serve as a novel therapeutic target for metastatic CRPC.

Converting optical scanning holograms of real objects to binary Fourier holograms using an iterative direct binary search algorithm.

In this paper, we present a three-dimensional holographic imaging system. The proposed approach records a complex hologram of a real object using optical scanning holography, converts the complex form to binary data, and then reconstructs the recorded hologram using a spatial light modulator (SLM). The conversion from the recorded hologram to a binary hologram is achieved using a direct binary search algorithm. We present experimental results that verify the efficacy of our approach. To the best of our knowledge, this is the first time that a hologram of a real object has been reconstructed using a binary SLM.

Secreted human glycyl-tRNA synthetase implicated in defense against ERK-activated tumorigenesis.

Although adaptive systems of immunity against tumor initiation and destruction are well investigated, less understood is the role, if any, of endogenous factors that have conventional functions. Here we show that glycyl-tRNA synthetase (GRS), an essential component of the translation apparatus, circulates in serum and can be secreted from macrophages in response to Fas ligand that is released from tumor cells. Through cadherin (CDH)6 (K-cadherin), GRS bound to different ERK-activated tumor cells, and released phosphatase 2A (PP2A) from CDH6. The activated PP2A then suppressed ERK signaling through dephosphorylation of ERK and induced apoptosis. These activities were inhibited by blocking GRS with a soluble fragment of CDH6. With in vivo administration of GRS, growth of tumors with a high level of CDH6 and ERK activation were strongly suppressed. Our results implicate a conventional cytoplasmic enzyme in translation as an intrinsic component of the defense against ERK-activated tumor formation.

Identification of CD23 as a functional receptor for the proinflammatory cytokine AIMP1/p43.

Aminoacyl-tRNA-synthetase-interacting multifunctional protein 1 (AIMP1/p43) can be secreted to trigger proinflammatory molecules while it is predominantly bound to a cytoplasmic macromolecular protein complex that contains several different aminoacyl-tRNA synthetases. Although its activities as a secreted signaling factor have been well characterized, the functional receptor for its proinflammatory activity has not yet identified. In this study, we have identified the receptor molecule for AIMP1 that mediates the secretion of TNF-α from THP-1 monocytic cells and primary human peripheral blood mononuclear cells (PBMCs). In a screen of 499 soluble receptors we identified CD23, a known low-affinity receptor for IgE, as a high affinity binding partner of AIMP1. We found that downregulation of CD23 attenuated AIMP1-induced TNF-α secretion and AIMP1 binding to THP-1 and PBMCs. We also observed that in THP-1 and PBMCs, AIMP1-induced TNF-α secretion, mediated by CD23, involved activation of ERK1/2. Interestingly, endothelial monocyte activating polypeptide II (EMAP II), the C-terminal fragment of AIMP1 that is also known to work as a proinflammatory cytokine, was incapable of binding to CD23 and of activating ERK1/2. Therefore, identification of CD23 not only explains the inflammatory function of AIMP1 but also provides the first evidence by which the mode of action of AIMP1 can be distinguished from that of its C-terminal domain, EMAP II.

Extracellular activities of aminoacyl-tRNA synthetases: new mediators for cell-cell communication.

Over the last decade, many reports have discussed aminoacyl-tRNA synthetases (ARSs) in extracellular space. Now that so many of them are known to be secreted with distinct activities in the broad range of target cells including endothelial, various immune cells, and fibroblasts, they need to be classified as a new family of extracellular signal mediators. In this chapter the identity of the secreted ARSs, receptors, and their physiological and pathological implications will be described.

Anti-Microbial Activities of Mussel-Derived Recombinant Proteins against Gram-Negative Bacteria.

Many anti-microbial peptides (AMPs) and pro-apoptotic peptides are considered as novel anti-microbial agents, distinguished by their different characteristics. Nevertheless, AMPs exhibit certain limitations, including poor stability and potential toxicity, which hinder their suitability for applications in pharmaceutics and medical devices. In this study, we used recombinant mussel adhesive protein (MAP) as a robust scaffold to overcome these limitations associated with AMPs. Mussel adhesive protein fused with functional peptides (MAP-FPs) was used to evaluate anti-microbial activities, minimal inhibitory concentration (MIC), and time-kill kinetics (TKK) assays against six of bacteria strains. MAP and MAP-FPs were proved to have an anti-microbial effect with MIC of 4 or 8 µM against only Gram-negative bacteria strains. All tested MAP-FPs killed four different Gram-negative bacteria strains within 180 min. Especially, MAP-FP-2 and -5 killed three Gram-negative bacteria strain, including E. coli, S. typhimurium, and K. pneumoniae, within 10 min. A cytotoxicity study using Vero and HEK293T cells indicated the safety of MAP and MAP-FP-2 and -3. Thermal stability of MAP-FP-2 was also validated by HPLC analysis at an accelerated condition for 4 weeks. This study identified that MAP-FPs have novel anti-microbial activity, inhibiting the growth and rapidly killing Gram-negative bacteria strains with high thermal stability and safety.

Self-Powering Sensory Device with Multi-Spectrum Image Realization for Smart Indoor Environments.

The development of organic-based optoelectronic technologies for the indoor Internet of Things market, which relies on ambient energy sources, has increased, with organic photovoltaics (OPVs) and photodetectors (OPDs) considered promising candidates for sustainable indoor electronic devices. However, the manufacturing processes of standalone OPVs and OPDs can be complex and costly, resulting in high production costs and limited scalability, thus limiting their use in a wide range of indoor applications. This study uses a multi-component photoactive structure to develop a self-powering dual-functional sensory device with effective energy harvesting and sensing capabilities. The optimized device demonstrates improved free-charge generation yield by quantifying charge carrier dynamics, with a high output power density of over 81 and 76 µW cm-2 for rigid and flexible OPVs under indoor conditions (LED 1000 lx (5200 K)). Furthermore, a single-pixel image sensor is demonstrated as a feasible prototype for practical indoor operating in commercial settings by leveraging the excellent OPD performance with a linear dynamic range of over 130 dB in photovoltaic mode (no external bias). This apparatus with high-performance OPV-OPD characteristics provides a roadmap for further exploration of the potential, which can lead to synergistic effects for practical multifunctional applications in the real world by their mutual relevance.

Depth resolution in three-dimensional images.

The depth of field of a camera defines the depth range to be covered by the camera. In 3D images, the resolvable depth range is also determined by the depth of field (DOF). Hence the depth resolution and resolvable number of depth layers obtainable with a given 3D display will be defined within the DOF when the display has the same resolution as the total camera resolution of the array in the horizontal direction. The depth resolution and resolvable number of depth layers are mathematically derived in terms of the circle of confusion. The resolvable number of depth layers is approximately linearly proportional to the camera distance and inversely proportional to the aperture diameter of the camera objective. The accuracies of the derivations are examined experimentally. The results show that the DOF extends slightly and the depth resolution improves up to 20% more than that predicted by theory for the given experimental condition. This means that the depth resolution derived has more than 80% accuracy.