Natural product myricetin is a pan-KDM4 inhibitor which with poly lactic-co-glycolic acid formulation effectively targets castration-resistant prostate cancer.

BACKGROUND: Castration-resistant prostate cancer (CRPC) with sustained androgen receptor (AR) signaling remains a critical clinical challenge, despite androgen depletion therapy. The Jumonji C-containing histone lysine demethylase family 4 (KDM4) members, KDM4A‒KDM4C, serve as critical coactivators of AR to promote tumor growth in prostate cancer and are candidate therapeutic targets to overcome AR mutations/alterations-mediated resistance in CRPC. METHODS: In this study, using a structure-based approach, we identified a natural product, myricetin, able to block the demethylation of histone 3 lysine 9 trimethylation by KDM4 members and evaluated its effects on CRPC. A structure-based screening was employed to search for a natural product that inhibited KDM4B. Inhibition kinetics of myricetin was determined. The cytotoxic effect of myricetin on various prostate cancer cells was evaluated. The combined effect of myricetin with enzalutamide, a second-generation AR inhibitor toward C4-2B, a CRPC cell line, was assessed. To improve bioavailability, myricetin encapsulated by poly lactic-co-glycolic acid (PLGA), the US food and drug administration (FDA)-approved material as drug carriers, was synthesized and its antitumor activity alone or with enzalutamide was evaluated using in vivo C4-2B xenografts. RESULTS: Myricetin was identified as a potent α-ketoglutarate-type inhibitor that blocks the demethylation activity by KDM4s and significantly reduced the proliferation of both androgen-dependent (LNCaP) and androgen-independent CRPC (CWR22Rv1 and C4-2B). A synergistic cytotoxic effect toward C4-2B was detected for the combination of myricetin and enzalutamide. PLGA-myricetin, enzalutamide, and the combined treatment showed significantly greater antitumor activity than that of the control group in the C4-2B xenograft model. Tumor growth was significantly lower for the combination treatment than for enzalutamide or myricetin treatment alone. CONCLUSIONS: These results suggest that myricetin is a pan-KDM4 inhibitor and exhibited potent cell cytotoxicity toward CRPC cells. Importantly, the combination of PLGA-encapsulated myricetin with enzalutamide is potentially effective for CRPC.

Extract the Degradation Information in Squeezed States with Machine Learning.

In order to leverage the full power of quantum noise squeezing with unavoidable decoherence, a complete understanding of the degradation in the purity of squeezed light is demanded. By implementing machine-learning architecture with a convolutional neural network, we illustrate a fast, robust, and precise quantum state tomography for continuous variables, through the experimentally measured data generated from the balanced homodyne detectors. Compared with the maximum likelihood estimation method, which suffers from time-consuming and overfitting problems, a well-trained machine fed with squeezed vacuum and squeezed thermal states can complete the task of reconstruction of the density matrix in less than one second. Moreover, the resulting fidelity remains as high as 0.99 even when the antisqueezing level is higher than 20 dB. Compared with the phase noise and loss mechanisms coupled from the environment and surrounding vacuum, experimentally, the degradation information is unveiled with machine learning for low and high noisy scenarios, i.e., with the antisqueezing levels at 12 dB and 18 dB, respectively. Our neural network enhanced quantum state tomography provides the metrics to give physical descriptions of every feature observed in the quantum state with a single scan measurement just by varying the local oscillator phase from 0 to 2π and paves a way of exploring large-scale quantum systems in real time.

Influence of atmospheric helium on secondary clocks.

Glass-cell-based secondary clocks, including coherent population trapping (CPT) clocks, are the most used clocks in modern laboratories and in industry. However, the reported frequency accuracies of those secondary clocks were always much worse than expected, though all error sources have been previously discussed. In this report, a high-precision measurement on the spectral frequency-linewidth relation (FL-R) is first used for revealing a new error source in secondary clocks by which we answer the puzzle raised in Opt. Lett.38, 3186 (2013)10.1364/OL.38.003186.

Frequency-Dependent Squeezed Vacuum Source for Broadband Quantum Noise Reduction in Advanced Gravitational-Wave Detectors.

The astrophysical reach of current and future ground-based gravitational-wave detectors is mostly limited by quantum noise, induced by vacuum fluctuations entering the detector output port. The replacement of this ordinary vacuum field with a squeezed vacuum field has proven to be an effective strategy to mitigate such quantum noise and it is currently used in advanced detectors. However, current squeezing cannot improve the noise across the whole spectrum because of the Heisenberg uncertainty principle: when shot noise at high frequencies is reduced, radiation pressure at low frequencies is increased. A broadband quantum noise reduction is possible by using a more complex squeezing source, obtained by reflecting the squeezed vacuum off a Fabry-Perot cavity, known as filter cavity. Here we report the first demonstration of a frequency-dependent squeezed vacuum source able to reduce quantum noise of advanced gravitational-wave detectors in their whole observation bandwidth. The experiment uses a suspended 300-m-long filter cavity, similar to the one planned for KAGRA, Advanced Virgo, and Advanced LIGO, and capable of inducing a rotation of the squeezing ellipse below 100 Hz.

Resonance in modulation instability from non-instantaneous nonlinearities.

To explore resonance phenomena in the nonlinear region, we show by experimental measurements and theoretical analyses that resonance happens in modulation instability from non-instantaneous nonlinearities in photorefractive crystals. With a temporally periodic modulation in the external bias voltage, corresponding to a modulation in the nonlinear strength, an enhancement in the visibility of MI at resonant frequency is reported through spontaneous optical pattern formations. Theoretical curves obtained from a nonlinear non-instantaneous Schrödinger equation give good agreement to experimental data.

Chalcone derivatives inhibit human platelet aggregation and inhibit growth in human bladder cancer cells.

In an effort to develop potent cyclooxygenase-1 (COX-1) inhibitors used as anticancer agent, a series of 2',5'-dimethoxychalcones was screened to evaluate their antiplatelet effect on human washed platelets suspension. Compound 2 exhibited potent inhibition of human washed platelet aggregation induced by collagen, significantly inhibited collagen- and arachidonic acid-induced thromboxane B2 release, and revealed inhibitory effect on COX-1 activity. Molecular docking studies showed that 1, 2, and 4 were bound in the active site of COX-1. These indicated that the antiplatelet effect of these compounds were mainly mediated through the suppression of COX-1 activity and reduced the thromboxane formation. To investigate the mechanistic action of COX-1 inhibitor enhanced the cytotoxic effect against human bladder cancer cells, NTUB1, we assessed the cytotoxic effect of 2 against NTUB1. Treatment of NTUB1 cells with various concentrations of 2 led to a concentration-dependent increase of cell death and decrease of reactive oxygen species levels. The flow-cytometric analysis showed that 2 induced a G1 phase cell cycle arrest but did not accompany an appreciable sub-G1 phase in NTUB1 cells. In addition, compound 2 increased p21 and p27 expressions and did not inhibit the expression of COX-1 in NTUB1 cells. Our results suggested that 2 enhanced cell growth inhibition or antiproliferative activity in NTUB1 cells through G1 arrest by COX-1 independent mechanism.

KDM4B as a target for prostate cancer: structural analysis and selective inhibition by a novel inhibitor.

The KDM4/JMJD2 Jumonji C-containing histone lysine demethylases (KDM4A-KDM4D), which selectively remove the methyl group(s) from tri/dimethylated lysine 9/36 of H3, modulate transcriptional activation and genome stability. The overexpression of KDM4A/KDM4B in prostate cancer and their association with androgen receptor suggest that KDM4A/KDM4B are potential progression factors for prostate cancer. Here, we report the crystal structure of the KDM4B·pyridine 2,4-dicarboxylic acid·H3K9me3 ternary complex, revealing the core active-site region and a selective K9/K36 site. A selective KDM4A/KDM4B inhibitor, 4, that occupies three subsites in the binding pocket is identified by virtual screening. Pharmacological and genetic inhibition of KDM4A/KDM4B significantly blocks the viability of cultured prostate cancer cells, which is accompanied by increased H3K9me3 staining and transcriptional silencing of growth-related genes. Significantly, a substantial portion of differentially expressed genes are AR-responsive, consistent with the roles of KDM4s as critical AR activators. Our results point to KDM4 as a useful therapeutic target and identify a new inhibitor scaffold.

Absolute frequency of cesium 6S-8S 822 nm two-photon transition by a high-resolution scheme.

We present an alternative scheme for determining the frequencies of cesium (Cs) atom 6S-8S Doppler-free transitions. With the use of a single electro-optical crystal, we simultaneously narrow the laser linewidth, lock the laser frequency, and resolve a narrow spectrum point by point. The error budget for this scheme is presented, and we prove that the transition frequency obtained from the Cs cell at room temperature and with one-layer µ-metal shielding is already very near that for the condition of zero collision and zero magnetic field. We point out that a sophisticated linewidth measurement could be a good guidance for choosing a suitable Cs cell for better frequency accuracy.

CIC signal processing embedded system a modulizable platform for multi-domain signal processing.

IT (Information Technology) industry is well developed in IC (Integrated Circuit) design, SoC (System-on-a-Chip), embedded, and etc. in Taiwan. Most of the commonly-used platforms are not configurable or modulizable at the moment. The biomedical academia in Taiwan is eager for a flexible biomedical signal sensing platform. This paper presents a novel multi-domain nano-sensor signal processing embedded system. The platform can be tailored for different demands of biomedical signal sensing.

Force field measurements within the exclusion zone of water.

Water molecules play critical roles in many biological functions, such as protein dynamics, enzymatic activities, and cellular responses. Previous nuclear magnetic resonance and neutron scattering studies have shown that water molecules bind to specific sites on surfaces and form localized clusters. However, most current experimental techniques cannot measure dynamic behaviors of ordered water molecules on cell-size (10 µm) scale. Recently, the long-distance effect of structured water has been demonstrated by Pollack and his colleagues. Namely, there is a structured water layer near the hydrophilic surface that can exclude solutes (Zheng et al, Adv Colloid Interface Sci 127:19-27, 2006; Pollack 2006, Adv Colloid Interface Sci 103:173-196, 2003). The repelling forces of water clusters inside this exclusion region are investigated in this study. With a laser tweezers system, we found the existence of an unexpected force fields inside the solute-free exclusion zone near a Nafion surface. Our results suggest that the water clusters could transduce mechanical signals on the micrometer range within the exclusion zone. This unexpected inhomogeneous force field near the hydrophilic surface would provide a new insight into cellular activities, leading to a potential new physical chemistry mechanism for cell biology.

High-resolution 133Cs 6S-6D, 6S-8S two-photon spectroscopy using an intracavity scheme.

This Letter presents an intracavity scheme for diode laser based two-photon spectroscopy. To demonstrate generality, three (133)Cs hyperfine transition groups of different wavelengths are shown. For the 6S-6D transitions, we achieved a 10(2) times better signal-to-noise ratio than in previous work [J. Phys. Soc. Jpn. 74, 2487 (2005)] with 10(-3) times less laser power, revealing some previously vague and unobserved spectra. Possible mutual influences between the two-photon absorber and laser cavity were investigated for the first time to our knowledge, which leads to the application of a reliable hand-sized optical frequency reference. Our approach is applicable for most of the two-photon spectroscopy of alkali atoms.

Determining the binding mode and binding affinity constant of tyrosine kinase inhibitor PD153035 to DNA using optical tweezers.

Accurately predicting binding affinity constant (K(A)) is highly required to determine the binding energetics of the driving forces in drug-DNA interactions. Recently, PD153035, brominated anilinoquinazoline, has been reported to be not only a highly selective inhibitor of epidermal growth factor receptor but also a DNA intercalator. Here, we use a dual-trap optical tweezers to determining K(A) for PD153035, where K(A) is determined from the changes in B-form contour length (L) of PD153035-DNA complex. Here, L is fitted using a modified wormlike chain model. We found that a noticeable increment in L in 1 mM sodium cacodylate was exhibited. Furthermore, our results showed that K(A)=1.18(±0.09)×10(4) (1/M) at 23±0.5°C and the minimum distance between adjacent bound PD153035≈11 bp. We anticipate that by using this approach we can determine the complete thermodynamic profiles due to the presence of DNA intercalators.

Quantification of Interleukin-6 in cell culture medium using surface plasmon resonance biosensors.

Interleukin (IL)-6, a multifunctional cytokine, is widely used as an index for illnesses such as inflammatory and autoimmune disorders, coronary artery disease, neurological disease, and gestational problems. It is thus very important to be able to precisely quantify the level of IL-6 for disease diagnosis and any subsequent therapy. Surface plasmon resonance (SPR) biosensors are sensitive in detecting the interaction between biomolecules by sensing the changes in the refractive index on the sensor chip. This study investigated the SPR technique to determine the IL-6 secretion of human fibroblast MRC5-CVI cells induced by lipopolysaccharide (LPS). To reduce non-specific binding, a mixed self-assembled monolayer of mercaptoundecanoic acid (MUA) and mercaptohexanol (MCH) was attached to the sensor, and then used for IL-6 determination using a sandwich type immunoassay. In addition, two antibody immobilization methods were applied to the sensor surface-direct immobilization and indirect immobilization via protein G affinity. The results demonstrated that the direct immobilization method had a better antibody binding capacity on the sensor surface. The level of cellular IL-6 secretion detected by the SPR biosensor showed a consistent correlation with the commercial kit of IL-6 enzyme-linked immunosorbent assay.

A generalized, periodic nonlinearity-reduced interferometer for straightness measurements.

Periodic nonlinearity is a systematic error limiting the accuracy of displacement measurements at the nanometer level. However, an interferometer with a displacement measurement accuracy of less than 1 nm is required in nanometrology and in fundamental scientific research. To meet this requirement, a generalized, periodic nonlinearity-reduced interferometer, based on three construction principles has been developed for straightness measurements. These three construction principles have resulted in an interferometer with a highly stable design with reduced periodic nonlinearity. Verifications by a straightness interferometer have demonstrated that the periodic nonlinearity was less than 40 pm. The results also demonstrate that the interferometer design is capable of subnanometer accuracy and is useful in nanometrology.

Mediating effect of cooperative norm in predicting organizational citizenship behaviors from procedural justice climate.

Although the relationships between procedural justice climate and organizational citizenship behaviors have been examined in recent years, little research has explored the mechanism by which procedural justice climate shapes individual employee prosocial behaviors in the workplace. The purpose of this study was to examine the mediating role of a group-level cooperative norm on the relationships between the group-level procedural justice climate and individual-level organizational citizenship behaviors. The survey involved 45 work groups in four different industry fields in Taiwan, including manufacturing, technology, banking, and insurance, and each of the groups was composed of one supervisor and three subordinates. Cross-level analyses using hierarchical linear modeling (HLM) indicated that the cooperative norm fully mediated the relationship between procedural justice climate and individual helping behaviors. Procedural justice climate indirectly affects individual helping behaviors through their effects on the cooperative norm.

Cesium 6S(1/2) --> 8S(1/2) two-photon-transition-stabilized 822.5 nm diode laser.

A cesium 6S(1/2) --> 8S(1/2) two-photon-transition (TPT)-stabilized 822.5 nm diode laser is reported for the first time to our knowledge. Allan deviation of 4.4 x 10(-13) (60 s) was achieved, and the possible systematic errors were evaluated as smaller than 2 kHz. We demonstrate that the cesium TPT-stabilized diode laser could be a reliable frequency reference at 822.5 nm wavelength.

Heterodyne interferometric system with subnanometer accuracy for measurement of straightness.

A generalized laser interferometer system based on three design principles, i.e., heterodyne frequency, prevention of mixing, and perfect symmetry, is described. These design principles give rise to an interferometer in a highly stable system with no periodic nonlinearity. A novel straightness sensor, consisting of a straightness prism and a straightness reflector, is incorporated into the generalized system to form a straightness interferometer. A Hewlett-Packard commercial linear interferometer was used to validate the interferometer's parameters. Based on the present design, the interferometer has a gain of 0.348, a periodic nonlinearity of less than 40 pm, and a displacement noise of 12 pm/mean square root of Hz at a bandwidth of 7.8 kHz. This system is useful for precision straightness measurements.

Sensitivity-tunable optical sensors based on surface plasmon resonance and phase detection.

We present an improved optical sensor based on surface plasmon resonance and phase detection. The sensor incorporates a surface plasmon resonance (SPR) device and a total internal reflection (TIR) device. In addition, a quarter-wave-plate (QWP) is placed in front of and behind the sensor. This gives rise to the optimization of the response curve and then the sensitivity. Theoretical simulations have been developed and verified by experimental results. With this new design, we obtain a sensitivity-tunable optical sensor whose resolving ability of refractive index is 1 x 10-6 RI.