SIRT2 regulates high mobility group protein B1 nucleoplasmic shuttle and degradation via deacetylation in microglia.

High mobility group protein B1 (HMGB1) acts as a pathogenic inflammatory response to mediate ranges of conditions such as epilepsy, septic shock, ischemia, traumatic brain injury, Parkinson's disease, Alzheimer's disease and mass spectrometry. HMGB1 promotes inflammation during sterile and infectious damage and plays a crucial role in disease development. Mobilization from the nucleus to the cytoplasm is the first important step in the release of HMGB1 from activated immune cells. Here, we demonstrated that Sirtuin 2 (SIRT2) physically interacts with and deacetylates HMGB1 at 43 lysine residue at nuclear localization signal locations, strengthening its interaction with HMGB1 and causing HMGB1 to be localized in the cytoplasm. These discoveries are the first to shed light on the SIRT2 nucleoplasmic shuttle, which influences HMGB1 and its degradation, hence revealing novel therapeutic targets and avenues for neuroinflammation treatment.

Programmable Photonic Time Circuits for Highly Scalable Universal Unitaries.

Programmable photonic circuits (PPCs) have garnered substantial interest for their potential in facilitating deep learning accelerations and universal quantum computations. Although photonic computation using PPCs offers ultrafast operation, energy-efficient matrix calculations, and room-temperature quantum states, its poor scalability hinders integration. This challenge arises from the temporally one-shot operation of propagating light in conventional PPCs, resulting in a light-speed increase in device footprints. Here we propose the concept of programmable photonic time circuits, utilizing time-cycle-based computations analogous to gate cycling in the von Neumann architecture and quantum computation. Our building block is a reconfigurable SU(2) time gate, consisting of two resonators with tunable resonances, and coupled via time-coded dual-channel gauge fields. We demonstrate universal U(N) operations with high fidelity using an assembly of the SU(2) time gates, substantially improving scalability from O(N^{2}) to O(N) in terms of both the footprint and the number of gates. This result paves the way for PPC implementation in very large-scale integration.

Control of localization and optical properties with deep-subwavelength engineered disorder.

The effect of deep subwavelength disorder in one-dimensional dichromic multilayer films on the optical transmission, localization length, and Goos-Hänchen shift around the critical angle is analyzed using sets of disordered multilayer films with different degrees of order metric τ. For each Gaussian-perturbed multilayer film designed by a Metropolis algorithm targeting the predetermined order metric τ, the numerically obtained localization length and transmission show excellent agreement with the recent theoretical analysis developed for disordered multilayer films, further revealing τ-dependence of the Goos-Hänchen shift across the critical angle. Emphasizing the role of deep subwavelength structures in disorder-induced transmission enhancement, our result thus paves the way toward the inverse design of a deep subwavelength disordered structural landscape for the targeted order metric τ or abnormal optical responses - including the Goos-Hänchen shift.

Topological Hyperbolic Lattices.

Non-Euclidean geometry, discovered by negating Euclid's parallel postulate, has been of considerable interest in mathematics and related fields for the description of geographical coordinates, Internet infrastructures, and the general theory of relativity. Notably, an infinite number of regular tessellations in hyperbolic geometry-hyperbolic lattices-are expected to extend Euclidean Bravais lattices and the consequent wave phenomena to non-Euclidean geometry. However, topological states of matter in hyperbolic lattices have yet to be reported. Here we investigate topological phenomena in hyperbolic geometry, exploring how the quantized curvature and edge dominance of the geometry affect topological phases. We report a recipe for the construction of a Euclidean photonic platform that inherits the topological band properties of a hyperbolic lattice under a uniform, pseudospin-dependent magnetic field, realizing a non-Euclidean analog of the quantum spin Hall effect. For hyperbolic lattices with different quantized curvatures, we examine the topological protection of helical edge states and generalize Hofstadter's butterfly, by employing two empirical parameters that measure the edge confinement and defect immunity. We demonstrate that the proposed platforms exhibit the unique spectral-magnetic sensitivity of topological immunity in highly curved hyperbolic planes. Our approach is applicable to general non-Euclidean geometry and enables the exploitation of infinite lattice degrees of freedom for band theory.

The design of 1,4-naphthoquinone derivatives and mechanisms underlying apoptosis induction through ROS-dependent MAPK/Akt/STAT3 pathways in human lung cancer cells.

The natural compound 1,4-naphthoquinone has potent anti-tumor activity. However, the clinical application of 1,4-naphthoquinone and its derivatives has been limited by their side effects. In this study, we attempted to reduce the toxicity of 1,4-naphthoquinone by synthesizing two derivatives: 2,3-dihydro-2,3-epoxy-2-propylsulfonyl-5,8-dimethoxy-1,4-naphthoquinone (EPDMNQ) and 2,3-dihydro-2,3-epoxy-2-nonylsulfonyl-5,8-dimethoxy-1,4-naphthoquinone (ENDMNQ). Then we evaluated the cytotoxicity and molecular mechanisms of these compounds in lung cancer cells. EPDMNQ and ENDMNQ significantly inhibited the viabilities of three lung cancer cell lines and induced A549 cell cycle arrest at the G1 phase. In addition, they induced the apoptosis of A549 lung cancer cells by increasing the phosphorylation of p38 and c-Jun N-terminal kinase (p-JNK), and decreasing the phosphorylation of extracellular signal-related kinase (p-ERK), protein kinase B (Akt), and signal transducer and activator of transcription 3 (STAT3). Furthermore, they increased reactive oxygen species (ROS) levels in A549 cells; however, pretreatment with the ROS inhibitor N-acetyl-l-cysteine significantly inhibited EPDMNQ- and ENDMNQ-mediated apoptosis and reversed apoptotic proteins expression. In conclusion, EPDMNQ and ENDMNQ induced G1 phase cell cycle arrest and apoptosis in A549 cells via the ROS-mediated activation of mitogen activated protein kinase (MAPK), Akt and STAT3 signaling pathways.

Mechanisms underlying isoliquiritigenin-induced apoptosis and cell cycle arrest via ROS-mediated MAPK/STAT3/NF-κB pathways in human hepatocellular carcinoma cells.

Isoliquiritigenin (ISL), a natural flavonoid isolated from plant licorice, has various pharmacological properties, including anticancer, anti-inflammatory, and antiviral effects. However, the underlying mechanisms and signaling pathways of ISL in human hepatocellular carcinoma (HCC) cells remain unknown. In this study, we evaluated the effects of ISL on the apoptosis of human HCC cells with a focus on reactive oxygen species (ROS) production. Our results showed that ISL exhibited cytotoxic effects on two human liver cancer cells in a dose-dependent manner. ISL significantly induced mitochondrial-related apoptosis and cell cycle arrest at the G2/M phase, which was accompanied by ROS accumulation in HepG2 cells. However, pretreatment with an ROS scavenger, N-acetyl-l-cysteine (NAC), inhibited ISL-induced apoptosis. In addition, ISL increased the phosphorylation levels of c-Jun N-terminal kinase (JNK), p38 kinase and inhibitor of NF-κB (IκB), and decreased the phosphorylation levels of extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription 3 (STAT3), nuclear factor-kappa B (NF-κB), these effects were blocked by NAC and mitogen-activated protein kinase (MAPK) inhibitors. Taken together, the findings of this study indicate that ISL induced HepG2 cell apoptosis via ROS-mediated MAPK, STAT3, and NF-κB signaling pathways. Therefore, ISL may be a potential treatment for human HCC, as well as other cancer types.

Design of Transverse Spinning of Light with Globally Unique Handedness.

Access to the transverse spin of light has unlocked new regimes in topological photonics. To achieve the transverse spin from nonzero longitudinal fields, various platforms that derive transversely confined waves based on focusing, interference, or evanescent waves have been suggested. Nonetheless, because of the transverse confinement inherently accompanying sign reversal of the field derivative, the resulting transverse spin handedness of each field experiences spatial inversion, which leads to a mismatch between the intensities of the field and its spin component and hinders the global observation of the transverse spin. Here, we reveal a globally pure transverse spin of the electric field in which the field intensity signifies the spin distribution. Starting from the target spin mode for the inverse design of required spatial profiles of anisotropic permittivities, we show that the elliptic-hyperbolic transition around the epsilon-near-zero permittivity allows for the global conservation of transverse spin handedness of the electric field across the topological interface between anisotropic metamaterials. Extending to the non-Hermitian regime, we develop annihilated transverse spin modes to cover the entire Poincaré sphere of the meridional plane. This result realizes the complete optical analogy of three-dimensional quantum spin states.

Bohmian Photonics for Independent Control of the Phase and Amplitude of Waves.

The de Broglie-Bohm theory is one of the nonstandard interpretations of quantum phenomena that focuses on reintroducing definite positions of particles, in contrast to the indeterminism of the Copenhagen interpretation. In spite of intense debate on its measurement and nonlocality, the de Broglie-Bohm theory based on the reformulation of the Schrödinger equation allows for the description of quantum phenomena as deterministic trajectories embodied in the modified Hamilton-Jacobi mechanics. Here, we apply the Bohmian reformulation to Maxwell's equations to achieve the independent manipulation of optical phase evolution and energy confinement. After establishing the deterministic design method based on the Bohmian approach, we investigate the condition of optical materials enabling scattering-free light with bounded or random phase evolutions. We also demonstrate a unique form of optical confinement and annihilation that preserves the phase information of incident light. Our separate tailoring of wave information extends the notion and range of artificial materials.

Quinalizarin Induces Apoptosis through Reactive Oxygen Species (ROS)-Mediated Mitogen-Activated Protein Kinase (MAPK) and Signal Transducer and Activator of Transcription 3 (STAT3) Signaling Pathways in Colorectal Cancer Cells.

BACKGROUND Quinalizarin (1,2,5,8-tetrahydroxyanthraquinone) exhibits potentially useful anticancer effects by inducing apoptosis in several types of cancer, but its underlying mechanism of action remains unknown. The present study examined the effects of quinalizarin on the induction of cell cycle arrest, apoptosis, the generation of reactive oxygen species (ROS), other underlying mechanisms, and its role in modifying colorectal cancer cell lines. MATERIAL AND METHODS The MTT assay was used to evaluate the viability of SW480 and HCT-116 cells that had been treated with quinalizarin and 5-fluorouracil (5-FU). Cell cycle arrest and apoptosis were analyzed by flow cytometry. Western blotting was used to investigate the mitochondrial pathway; Akt, MAPK, and STAT3 signaling pathways were also investigated. The relationship between ROS generation and apoptosis was analyzed by flow cytometry and western blotting. RESULTS The results indicated that quinalizarin significantly inhibits the viability of SW480 and HCT-116 cells in a dose-dependent manner. Quinalizarin induced SW480 cell cycle arrest at G2/M by regulating cyclin B1 and CDK1/2. The apoptosis-related protein expression levels of p-p53, Bad, cleaved caspase-3, cleaved PARP and p-JNK were increased in quinalizarin-treated cells, while protein expression levels Bcl-2, p-Akt, p-ERK, and p-STAT3 were decreased. Quinalizarin induced apoptosis in colorectal cancer cells by regulating MAPK and STAT3 signaling pathways via ROS generation. CONCLUSIONS Quinalizarin induces apoptosis via ROS-mediated MAPK/STAT3 signaling pathways.

The compound 2-(naphthalene-2-thio)-5,8-dimethoxy-1,4-naphthoquinone induces apoptosis via reactive oxygen species-regulated mitogen-activated protein kinase, protein kinase B, and signal transducer and activator of transcription 3 signaling in human gastric cancer cells.

Hit, Lead & Candidate Discovery It is reported that 1,4-naphthoquinones and their derivatives have potent antitumor activity in various cancers, although their clinical application is limited by observed side effects. To improve the therapeutic efficacy of naphthoquinones in the treatment of cancer and to reduce side effects, we synthesized a novel naphthoquinone derivative, 2-(naphthalene-2-thio)-5,8-dimethoxy-1,4-naphthoquinone (NTDMNQ). In this study, we explored the effects of NTDMNQ on apoptosis in gastric cancer cells with a focus on reactive oxygen species (ROS) production. Our results demonstrated that NTDMNQ exhibited the cytotoxic effects on gastric cancer cells in a dose-dependent manner. NTDMNQ significantly induced mitochondrial-related apoptosis in AGS cells and increased the accumulation of ROS. However, pre-treatment with N-acetyl-L-cysteine (NAC), an ROS scavenger, inhibited the NTDMNQ-induced apoptosis. In addition, NTDMNQ increased the phosphorylation of p38 kinase and c-Jun N-terminal kinase (JNK) and decreased the phosphorylation of extracellular signal-regulated kinase (ERK), protein kinase B (Akt), and Signal Transducer and Activator of Transcription 3 (STAT3); these effects were blocked by mitogen-activated protein kinase (MAPK) inhibitor and NAC. Taken together, the present findings indicate that NTDMNQ-induced gastric cancer cell apoptosis via ROS-mediated regulation of the MAPK, Akt, and STAT3 signaling pathways. Therefore, NTDMNQ may be a potential treatment for gastric cancer as well as other tumor types.

One-way optical modal transition based on causality in momentum space.

The concept of parity-time (PT) symmetry has been used to identify a route toward unidirectional dynamics in optical k-space: imposing asymmetry on the flow of light. Although PT-symmetric potentials have been implemented under the requirement of V(x) = V*(-x), this precondition has only been interpreted within the mathematical framework for the symmetry of Hamiltonians and has not been directly linked to unidirectionality induced by PT symmetry. In this paper, within the context of light-matter interactions, we develop an alternative route toward unidirectionality in k-space by employing the concept of causality. We demonstrate that potentials with real and causal momentum spectra produce unidirectional transitions of optical modes inside the k-continuum, which corresponds to an exceptional point on the degree of PT symmetry. Our analysis reveals a critical link between non-Hermitian problems and spectral theory and also enables multi-dimensional designer manipulation of optical modes, in contrast to the one-dimensional approach that used a Schrödinger-like equation in previous PT-symmetric optics.

Toward plasmonics with nanometer precision: nonlinear optics of helium-ion milled gold nanoantennas.

Plasmonic nanoantennas are versatile tools for coherently controlling and directing light on the nanoscale. For these antennas, current fabrication techniques such as electron beam lithography (EBL) or focused ion beam (FIB) milling with Ga(+)-ions routinely achieve feature sizes in the 10 nm range. However, they suffer increasingly from inherent limitations when a precision of single nanometers down to atomic length scales is required, where exciting quantum mechanical effects are expected to affect the nanoantenna optics. Here, we demonstrate that a combined approach of Ga(+)-FIB and milling-based He(+)-ion lithography (HIL) for the fabrication of nanoantennas offers to readily overcome some of these limitations. Gold bowtie antennas with 6 nm gap size were fabricated with single-nanometer accuracy and high reproducibility. Using third harmonic (TH) spectroscopy, we find a substantial enhancement of the nonlinear emission intensity of single HIL-antennas compared to those produced by state-of-the-art gallium-based milling. Moreover, HIL-antennas show a vastly improved polarization contrast. This superior nonlinear performance of HIL-derived plasmonic structures is an excellent testimonial to the application of He(+)-ion beam milling for ultrahigh precision nanofabrication, which in turn can be viewed as a stepping stone to mastering quantum optical investigations in the near-field.

Control of Fano asymmetry in plasmon induced transparency and its application to plasmonic waveguide modulator.

In this paper, we derive a governing equation for spectral asymmetry in electromagnetically induced transparency (EIT). From the key parameters of asymmetry factor - namely dark mode quality factor Q(d), and frequency separation between bright and dark mode Δω(bd) = (ω(b) - ω(d)) -, a logical pathway for the maximization of EIT asymmetry is identified. By taking the plasmonic metal-insulator-metal (MIM) waveguide as a platform, a plasmon-induced transparency (PIT) structure of tunable frequency separation Δω(bd) and dark mode quality factor Q(d) is suggested and analyzed. Compared to previous works on MIM-based plasmon modulators, an order of increase in the performance Fig. (12dB contrast at ~60% throughput) was achieved from the highly asymmetric, narrowband PIT spectra.

Prognostic Implications of the Admission Cardiac Troponin I Levels and Door-to-Balloon Time on Clinical Outcomes in Patients with ST-Segment Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention.

BACKGROUND: The prognostic implications of the admission cTnI level and D2B time combined on in-hospital and 1-year heart failure (HF) and mortality in STEMI patients undergoing a primary percutaneous coronary intervention (PCI) are remain uncertain. METHODS AND RESULTS: We divided the consecutive 1485 STEMI patients who underwent PCI from January 2015 to October 2019 at our hospital into three groups based on their admission cTnI levels: normal group (<0.1 ng/mL), middle group (0.1 to less than 3 ng/mL), and high group (≥3 ng/mL) and into two groups by their D2B times: >90 min (>90-D2B) and ≤90 min (≤90-D2B). During the in-hospital and 1-year follow-up periods, the incidence of composite clinical events increased significantly with the increase in the admission cTnI level (p < 0.05). In-hospital, the composite rate of death and HF events was significantly higher in the >90-D2B group compared to the ≤90-D2B group (p = 0.006), but its influence disappeared in the 1-year follow-up (p > 0.05). A multivariable logistic analysis revealed that, in the ≤90-D2B group, with the exception of the cTnI ≥3 ng/mL patients, the cTnI level had no effect on in-hospital or 1-year outcomes; in >90-D2B group, cTnI ≥3ng/mL increased outcomes in both periods. CONCLUSION: High cTnI levels (≥3 ng/mL) on admission are independent of the D2B time for predicting in-hospital and 1-year cardiac events in STEMI patients undergoing PCI.

Granulocyte colony-stimulating factor protected against brain injury in a rat cerebral hemorrhage model by modulating inflammation.

Granulocyte colony-stimulating factor (G-CSF) has been reported to exert a protective effect against secondary brain damage, but the underlying mechanisms remain unknown. We explored the ability of G-CSF to protect the brain from injury in a rat autologous blood-induced model of intracerebral hemorrhage (ICH), with a special focus on the anti-inflammation effect. An ICH was induced in 8-week-old male rats by an infusion of autologous blood, and the rats were then randomly assigned to five treatment groups: sham, ICH, and ICH+ low-dose (25 µg/kg), middle-dose (50 µg/kg), and high-dose (75 µg/kg) G-CSF. We then evaluated the levels of brain inflammation-related genes and proteins. The levels of tumor-necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) mRNA increased between days 1 and 14 post-ICH, with the highest expression on day 3. These changes were rectified by G-CSF in a dose-dependent manner. At day 3 post-injury, an elevation of the nuclear factor-kappa B (NF-κB) p65 protein level and a reduction of the inhibitor of NF-κB alpha (IκBα) protein level were observed; G-CSF treatment exerted a beneficial effect on both protein expressions. The expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins were increased; these changes were rectified by the highest dose of G-CSF. The brain-protecting effects of G-CSF are likely to be attributable, at least in part, to attenuation of the TNF-α, IL-6, iNOS, and COX-2 expressions induced by NF-κB activation in the brain tissues of this autologous blood-induced ICH rat model.

Fano-type spectral asymmetry and its control for plasmonic metal-insulator-metal stub structures.

We use coupled mode theory (CMT) to analyze a metal-insulator-metal (MIM) plasmonic stub structure, to reveal the existence of asymmetry in its transmittance spectra. Including the effect of the near field contribution for the stub structure, the observed asymmetry is interpreted as Fano-type interference between the quasi-continuum T-junction-resonator local-modes and discrete stub eigenmodes. Based on the asymmetry factor derived from the CMT analysis, methods to control transmittance asymmetry are also demonstrated.

Mode junction photonics with a symmetry-breaking arrangement of mode-orthogonal heterostructures.

Junction structures provide the foundation of digital electronics and spintronics today. An equivalent, a photonic junction to achieve systematic and drastic control of photon flow is currently missing, but is mandatory for serious all-optical signal processing. Here we propose a photonic junction built upon mode-orthogonal hetero-structures, as a fundamental structural unit for photonic integrated circuits. Controlling the optical potential of mode-orthogonal junctions, the flow of photons can be dynamically manipulated, to complete the correspondence to the electronic junction structures. Of the possible applications, we provide examples of a photonic junction diode and a multi-junction half-adder, with exceptional performance metrics. Highly directional (41dB), nearly unity throughput, ultra-low threshold-power, high quality signal regeneration at 200Gb/s, and all-optic logic operations are successfully derived with the self-induced, bi-level dynamic mode-conversion process across the junction.

Calycosin induces mitochondrial-dependent apoptosis and cell cycle arrest, and inhibits cell migration through a ROS-mediated signaling pathway in HepG2 hepatocellular carcinoma cells.

Calycosin is one of the main ingredients extracted from the Chinese medical herb, Radix astragali (RA). It has been shown to inhibit cell proliferation and induce apoptosis in several cancer cell lines, but the underlying mechanism remains unclear. The effects of calycosin on the proliferation and apoptosis of hepatocellular carcinoma (HCC) cells, as well as its mechanism, were investigated in this study. Cell Counting Kit-8 assay results suggested that calycosin had anti-proliferation effects on HCC in dose- and time-dependent manners, and had less cytotoxicity in normal cells. Hoechst/PI double staining and flow cytometry results showed cellular morphological changes and apoptosis after treatment of HepG2 cells with calycosin. The western blot assay showed calycosin decreased the expression of Bcl-2 and increased the expression of Bax, caspase-3, and PARP. Calycosin induced the activation of MAPK, STAT3, NF-κB, apoptosis-related proteins, and induced cell cycle arrest in the G0/G1 phase by regulating AKT. In addition, calycosin reduced the expression of TGF-ß1, SMAD2/3, SLUG, and vimentin. Furthermore, phosphorylation, apoptosis, and cell migration induced by calycosin were mediated by the production of reactive oxygen species. These events could be inhibited by pretreatment with N-acetyl-L-cysteine. Calycosin resisted HCC by activating ROS-mediated MAPK, STAT3, and NF-κB signaling pathways.

Out of plane mode conversion and manipulation of Surface Plasmon Polariton waves.

We propose a rigorous design method of structured gratings for out of plane mode conversion, line focusing and manipulation of Surface Plasmon Polariton (SPP) waves. Employing a blazed grating to incorporate the directionality of SPP launch, and at the same time controlling grating depth and chirp to account for the radiation loss and diffraction angle, it was possible to achieve high efficiency and flexible SPP to freespace mode conversion. Devices with advanced functionalities, such as balanced SPP power splitter, and SPP wavelength demultiplexer are demonstrated with over 75% of power efficiencies at reasonable working distances of less than several wavelengths.

Machine learning identifies scale-free properties in disordered materials.

The vast amount of design freedom in disordered systems expands the parameter space for signal processing. However, this large degree of freedom has hindered the deterministic design of disordered systems for target functionalities. Here, we employ a machine learning approach for predicting and designing wave-matter interactions in disordered structures, thereby identifying scale-free properties for waves. To abstract and map the features of wave behaviors and disordered structures, we develop disorder-to-localization and localization-to-disorder convolutional neural networks, each of which enables the instantaneous prediction of wave localization in disordered structures and the instantaneous generation of disordered structures from given localizations. We demonstrate that the structural properties of the network architectures lead to the identification of scale-free disordered structures having heavy-tailed distributions, thus achieving multiple orders of magnitude improvement in robustness to accidental defects. Our results verify the critical role of neural network structures in determining machine-learning-generated real-space structures and their defect immunity.