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Clinical management of castration-resistant prostate cancer (CRPC) resulting from androgen deprivation therapy (ADT) remains challenging. Many studies indicate that androgen receptor splice variants (ARVs) play a critical role in the development of CRPC, including resistance to the new generation of inhibitors of androgen receptor (AR) action. ARVs are constitutively active and lack the ligand-binding domain (LBD), thereby allowing prostate cancer (PC) to maintain AR activity despite therapies that target the AR (full-length AR; AR-FL). Previously, we have reported that long-term ADT increases the neuroendocrine (NE) hormone – Gastrin Releasing Peptide (GRP) and its receptor (GRP-R) expression in PC cells. Further, we demonstrated that activation of GRP/GRP-R signaling increases ARVs expression by activating NF-κB signaling, thereby promoting cancer progression to CRPC. Most importantly, as a cell surface protein, GRP-R is easily targeted by drugs to block GRP/GRP-R signaling. In this study, we tested if blocking GRP/GRP-R signaling by targeting GRP-R using GRP-R antagonist is sufficient to control CRPC progression. Our studies show that blocking GRP/GRP-R signaling by targeting GRP-R using RC-3095, a selective GRP-R antagonist, efficiently inhibits NF-κB activity and ARVs (AR-V7) expression in CRPC and therapy-induced NEPC (tNEPC) cells. In addition, blocking of GRP/GRP-R signaling by targeting GRP-R can sensitize CRPC cells to anti-androgen treatment (such as MDV3100). Further, preclinical animal studies indicate combination of GRP-R antagonist (targeting ARVs) with anti-androgen (targeting AR-FL) is sufficient to inhibit CRPC and tNEPC tumor growth.

The present studies were conducted to evaluate key serum proteins and other components that mediate anchorage-independent growth (3-D growth) of LNCaP prostate cancer cells as spheroids. The cells were cultured on ultra-low attachment plates in the absence and presence of fetuin-A and with or without extracellular vesicles. The data show that fetuin-A (alpha 2HS glycoprotein) is the serum protein that mediates 3-D growth in these cells. It does so by sequestering extracellular vesicles of various sizes on the surfaces of rounded cells that grow as spheroids. These vesicles in turn transmit growth signals such as the activation of AKT and MAP kinases in a pattern that differs from the activation of these key growth signaling pathways in adherent and spread cells growing in 2-D. In the process of orchestrating the movement and disposition of extracellular vesicles on these cells, fetuin-A is readily internalized in adhered and spread cells but remains on the surfaces of non-adherent cells. Taken together, our studies suggest the presence of distinct signaling domains or scaffolding platforms on the surfaces of prostate tumor cells growing in 3-D compared to 2-D.

Membrane-type acoustic metamaterials (MAMs) have recently received widespread attention due to their good low-frequency sound-transmission-loss (STL) performance. A fast prediction method for the STL of rectangular membranes loaded with masses of arbitrary shapes and surface density values is proposed as a semi-analytical model for calculating the STL of membrane-type acoustic metamaterials. Through conformal mapping theory, the mass blocks of arbitrary shapes were transformed into regular shapes, which simplified the calculation model of acoustic propagation loss prediction, and the prediction results were verified by finite element simulations. The results show that the change in mass surface density was closely related to the size and frequency distribution of STL. The influence of the mass center on the STL and characteristic frequency of the film metamaterial is discussed.

The existing sandwich structure of the aircraft cabin demonstrates a good sound insulation effect in medium and high frequency bands, but poor in the low frequency band. Therefore, we propose an infinite new lightweight broadband noise control structure and study its sound transmission loss (STL). The structure is an orthogonally rib-stiffened honeycomb double sandwich structure with periodic arrays of shunted piezoelectric patches, and demonstrates lighter mass and better strength than the existing sandwich structure. The structure is equivalent according to Hoff’s equal stiffness theory and the effective medium (EM) method. Using the virtual work principle for a periodic element, two infinite sets of coupled equations are obtained. They are solved by truncating them in a finite range until the solution converges. The correctness and validity of the model are verified by using simulation results and theoretical predictions. Eventually, a further study is performed on the factors influencing the STL. All the results demonstrate that the STL in low-frequency can be improved by the structure, and the sound insulation bandwidth is significantly broadened by adding shunted piezoelectric patches. The structure can provide a new idea for the design of broadband sound insulation.

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Upon complexation with protonated amino acids, one-handed helical polynorbornenes appended with monoaza-18-crown-6 (7a) are obtained. The cooperativity is observed as revealed by the sergeant−soldier effect and the majority rule. When sterically hindered amino acids such as phenylalanine, isovaline or proline, esters of amino acids, and aminoalcohols are used, the Δε values in CD spectra are significantly reduced. The protonated ammonium ion may form complex with a crown ether moiety whereas the carboxylic acid may form hydrogen bonding with the adjacent crown ether pendant resulting in unidirectional orientation of the pendants leading to a helical scaffold. The corresponding dimer 10with the same isotactic stereochemistry as that of polynorbornene 7abehaves similarly to exhibit bisignate CD curve upon treatment with protonated alanine. On the other hand, polynorbornene with monoaza-15-crown-5 (7b) does not exhibit any CD response under the same conditions. [ABSTRACT FROM AUTHOR]

novel combined process of machining silicon carbide (SiC) ceramics with electrical discharge milling and mechanical grinding is presented. The process is able to effectively machine a large surface area on SiC ceramics with a good surface quality. The effect of tool polarity on the process performance has been investigated. The effects of peak current, peak voltage, pulse on-time and pulse off-time on the material removal rate (MRR), electrode wear ratio (EWR), and surface roughness (SR) have been investigated with Taguchi experimental design. The mathematical models for the MRR, EWR, and SR have been established with the stepwise regression method. The experiment results show that the MRR, EWR, and SR can reach 46.2543 mm/min, 20.7176%, and 0.0340 µm, respectively, with each optimal combination level of machining parameters. [ABSTRACT FROM AUTHOR]

Machining fluid is a primary factor that affects the material removal rate, surface quality, and electrode wear of electrical discharge machining (EDM). Kerosene is the most commonly used working fluid in die sinking EDM, but it shows low ignition temperature and high volatility; if the improper operations are undertaken, it can cause conflagration. Using distilled water or pure water as the machining fluid in EDM, no fire hazard occurs, and the working environment is well; however, using distilled water or pure water as the machining fluid in EDM, the material removal rate of machining large surface is low, and the machine tool is easily eroded. Emulsion-1 and emulsion-2 used as working fluid in die sinking EDM are developed. The compositions of emulsion-1 and emulsion-2 are introduced. In comparison with kerosene, emulsion-1 and emulsion-2 used in EDM show high material removal rate, low surface roughness, high discharge gap, and good working environment. The electrode wear ratio in emulsion-1 is lower than that in kerosene. The electrode wear ratio in emulsion-2 is higher than that in kerosene. The effects of composition and concentration of emulsifier on the emulsion property and EDM performance have been investigated. The comparative tests of EDM performance with kerosene, emulsion-1, and emulsion-2 have been done. [ABSTRACT FROM AUTHOR]

A new method which employs a group pulse power supply for electric discharge milling of the silicon carbide ceramic with the resistivity of 500 Ω.cm is presented. Due to the good machining stability and high pulse utilization, the material removal rate (MRR) can reach 72.9 mm³/min. The effects of high-frequency pulse duration, high-frequency pulse interval, peak voltage, peak current, polarity, rotate speed and group frequency on the process performance have been investigated. Also the EDMed surface microstructure is examined with a scanning electron microscope (SEM), an X-ray diffraction (XRD), an energy dispersive spectrometer (EDS) and a micro hardness tester. The results show that the conditions of smaller high-frequency pulse duration and pulse interval, higher peak voltage and peak current, and positive tool polarity are suitable for machining the SiC ceramic. The optimal rotate speed is 1090 r/min and the preferable group frequency is 730 Hz. In addition, there is a small quantity of iron on machined surface when machining with steel electrode. The average grain size of the EDMed surface is smaller than that of the unprocessed, and the micro hardness of machined surface is superior to that of the unprocessed. [ABSTRACT FROM AUTHOR]

In this paper, a trench-assisted low-bending-loss large-mode-field-area multi-core fiber with air hole is proposed, which can achieve dual-mode transmission. The influence of structural parameters on fiber performance is analyzed systematically, and the structure of the trench, with a lower refractive index than the cladding, is also analyzed and optimized. By adjusting the structural parameters, the effective mode field area of the fundamental mode can reach 2003.24 um2 at 1550 nm, and when the bending radius is 1 cm, the bending loss is 2.57 × 10−3 dB/m. The practical implementation of the proposed fiber is feasible using existing fabrication technology and is applicable to the transmission of large-capacity optical communication systems and high-power lasers.

Although the bubble contacting a uniformly superaerophilic surface has caused concern due to its application potential in various engineering equipment, such as mineral flotation, very little is known about the mechanism of how the bubble spreads on a surface with anisotropic superaerophilicity. To unveil this mystery, we experimentally studied the anisotropic behavior of a bubble (2 mm in diameter) spreading on the superaerophilic straight trajectories (SALTs) of different widths (0.5 mm−5 mm) in water using a high-speed shadowgraphy system. The 1−3 bounces mostly happened as the bubble approached the SALTs before its spreading. It is first observed that the bubble would be split into two highly symmetrical sub-bubbles with similar migration velocity in opposite directions during the anisotropic spreading. Two essential mechanisms are found to be responsible for the anisotropic spreading on the narrow SALTs (W ≤ 2 mm with two subregimes) and the wide SALTs (W ≥ 3 mm with four subregimes). Considering the combined effect of the surface tension effect of SALT and Laplace pressure, a novel model has been developed to predict the contact size r(t) as a function of time. The nice agreement between this model and our experiments reconfirms that the surface tension effect and Laplace pressure prevail over the hydrostatic pressure.

Modifying the genomes of many organisms is becoming as easy as manipulating DNA in test tubes, which is made possible by two recently developed techniques based on either the customizable DNA binding protein, TALEN, or the CRISPR/Cas9 system. Here, we describe a series of efficient applications derived from these two technologies, in combination with various homologous donor DNA plasmids, to manipulate the Drosophila genome: (1) to precisely generate genomic deletions; (2) to make genomic replacement of a DNA fragment at single nucleotide resolution; and (3) to generate precise insertions to tag target proteins for tracing their endogenous expressions. For more convenient genomic manipulations, we established an easy-to-screen platform by knocking in a white marker through homologous recombination. Further, we provided a strategy to remove the unwanted duplications generated during the “ends-in” recombination process. Our results also indicate that TALEN and CRISPR/Cas9 had comparable efficiency in mediating genomic modifications through HDR (homology-directed repair); either TALEN or the CRISPR/Cas9 system could efficiently mediate in vivo replacement of DNA fragments of up to 5 kb in Drosophila, providing an ideal genetic tool for functional annotations of the Drosophila genome.

Patients with advanced prostate cancer almost invariably develop osseous metastasis. Although many studies indicate that the activation of NF-κB signaling appears to be correlated with advanced cancer and promotes tumor metastasis by influencing tumor cell migration and angiogenesis, the influence of altered NF-κB signaling in prostate cancer cells within boney metastatic lesions is not clearly understood. While C4-2B and PC3 prostate cancer cells grow well in the bone, LNCaP cells are difficult to grow in murine bone following intraskeletal injection. Our studies show that when compared to LNCaP, NF-κB activity is significantly higher in C4-2B and PC3, and that the activation of NF-κB signaling in prostate cancer cells resulted in the increased expression of the osteoclast inducing genes PTHrP and RANKL. Further, conditioned medium derived from NF-κB activated LNCaP cells induce osteoclast differentiation. In addition, inactivation of NF-κB signaling in prostate cancer cells inhibited tumor formation in the bone, both in the osteolytic PC3 and osteoblastic/osteoclastic mixed C4-2B cells; while the activation of NF-κB signaling in LNCaP cells promoted tumor establishment and proliferation in the bone. The activation of NF-κB in LNCaP cells resulted in the formation of an osteoblastic/osteoclastic mixed tumor with increased osteoclasts surrounding the new formed bone, similar to metastases commonly seen in patients with prostate cancer. These results indicate that osteoclastic reaction is required even in the osteoblastic cancer cells and the activation of NF-κB signaling in prostate cancer cells increases osteoclastogenesis by up-regulating osteoclastogenic genes, thereby contributing to bone metastatic formation.

BACKGROUND:Notch signaling is a highly conserved pathway in multi-cellular organisms ranging from flies to humans. It controls a variety of developmental processes by stimulating the expression of its target genes in a highly specific manner both spatially and temporally. The diversity, specificity and sensitivity of the Notch signaling output are regulated at distinct levels, particularly at the level of ligand-receptor interactions. METHODOLOGY/PRINCIPAL FINDINGS:Here, we report that the Drosophila gene uninflatable (uif), which encodes a large transmembrane protein with eighteen EGF-like repeats in its extracellular domain, can antagonize the canonical Notch signaling pathway. Overexpression of Uif or ectopic expression of a neomorphic form of Uif, Uif*, causes Notch signaling defects in both the wing and the sensory organ precursors. Further experiments suggest that ectopic expression of Uif* inhibits Notch signaling in cis and acts at a step that is dependent on the extracellular domain of Notch. Our results suggest that Uif can alter the accessibility of the Notch extracellular domain to its ligands during Notch activation. CONCLUSIONS/SIGNIFICANCE:Our study shows that Uif can modulate Notch activity, illustrating the importance of a delicate regulation of this signaling pathway for normal patterning.

BACKGROUND: The family of RecQ DNA helicases plays an important role in the maintenance of genomic integrity. Mutations in three of the five known RecQ family members in humans, BLM, WRN and RecQ4, lead to disorders that are characterized by predisposition to cancer and premature aging. METHODOLOGY/PRINCIPAL FINDINGS: To address the in vivo functions of Drosophila RecQ4 (dRecQ4), we generated mutant alleles of dRecQ4 using the targeted gene knock-out technique. Our data show that dRecQ4 mutants are homozygous lethal with defects in DNA replication, cell cycle progression and cell proliferation. Two sets of experiments suggest that dRecQ4 also plays a role in DNA double strand break repair. First, mutant animals exhibit sensitivity to gamma irradiation. Second, the efficiency of DsRed reconstitution via single strand annealing repair is significantly reduced in the dRecQ4 mutant animals. Rescue experiments further show that both the N-terminal domain and the helicase domain are essential to dRecQ4 function in vivo. The N-terminal domain is sufficient for the DNA repair function of dRecQ4. CONCLUSIONS/SIGNIFICANCE: Together, our results show that dRecQ4 is an essential gene that plays an important role in not only DNA replication but also DNA repair and cell cycle progression in vivo.