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Reducing lunar dust adhesion to various material surfaces is important for protecting equipment from damage during lunar exploration missions. In this study, we investigate the lunar dust-mitigation ability and dust adhesion force of aluminum (Al) substrates prepared using different etching methods. Among them, composite etching methods (combining chemical and electrochemical steps) can result in multiscale structures with micro- and nanoroughness, reducing the contact area between the substrate and thus decreasing lunar dust adhesion. After composite etching, the dust adhesion force of the Al substrate was significantly reduced by 80% from 45.53 to 8.89 nN. The dust adhesion force of Al substrates dominates their dust-mitigation performance in floating dust environments. The lunar dust coverage (2.19%) of the Al substrate modified by composite etching (placed with a tilt angle of 90°) was 4-fold lower than that of the pristine Al substrate (9.11%), indicating excellent lunar-dust repellence. In addition, other factors such as tilt angle of the substrate and dust loading significantly affect dust-mitigation performance of the modified Al substrates. The Al substrate with an excellent dust-mitigation ability highlights good potential for lunar exploration missions.

Background: The study on explosive boiling phenomenon has received increasing attention because it involves many industries, such as advanced micro-, nano-electromechanical and nano-electronic cooling systems, laser steam cleaning, and so on. Objective: In the present work, the explosive boiling of ultra-thin liquid film over two-dimensional nanomaterial surface in confined space with particular emphasis under the three different influencing factors: various heights of nanostructures, various wetting conditions of solid-liquid interface as well as various heat source temperatures. Methods: Molecular Dynamics simulations (MDs) in present work have been adopted to simulate the whole explosive boiling process. Results: For different heat source temperature case, the higher the heat temperature is, the less time the explosive boiling spends after relaxation. For nanostructure case, nanostructure surface significantly increases heat transfer rate and then leads to the increase of phase transition rate of explosive boiling. For different wetting property case, the increase of surface wettability results in an increase of phase transition to some degree. Conclusion: The addition of nanostructures, the higher heat source temperature and good wettability between thin liquid film and substrate surface dramatically improve thermal heat transfer from solid surface to liquid film, which will give rise to explosive boiling occur. In addition, the non-vaporized argon layer still exists in these three factors despite continuous thermal transmission from the substrate surface to liquid argon film adjacent to the solid surface even other vaporized argon atoms.

Based on a bistable mechanism, a novel low- ${g}$ MEMS inertial switch with dual functions of self-locking and reverse-unlocking is presented, along with its fabrication and verification. This MEMS switch is fabricated on a Silicon-On-Insulator (SOI) wafer by using deep reactive ion etching (DRIE), Bosch processing, and wafer bonding technologies. A two-level system is proposed to realize dual functions of this switch, which mainly consists of a spring-mass-damping system as the first level and a bistable structure as the second level. According to the finite element analysis (FEA), the theoretical formula of the bistable structure has been successfully verified to deduce the static mechanical properties. Under positive and negative acceleration excitations, the dynamic response characteristics of the switch has been systematically simulated further. Furthermore, this inertial switch has been tested by using a centrifugal acceleration turntable, and its self-locking threshold and reverse unlocking threshold are 8 ${g}$ and 105 ${g}$ , respectively. Finally, the contact resistance of this MEMS switch is measured about $0.75~\Omega $ by a probe station. [2020-0302]

This paper describes an optimization method for analyzing the mechanical characteristics of a bistable structure used in inertial switch. For the purpose of obtaining the optimal design of the bistable structure, a robust optimization based on radial basis function agent model is developed, to minimizing variability of the performance due to fabrication errors and changes of material properties. The two-objective optimization function that minimizes the uncertainty of the forward threshold force and the reverse threshold force in the bistable characteristic curve is determined. As a result of the robust optimization, the maximum force used to toggle the bistable beam is reduced from $21.81\ \mu \mathrm{N}$ to $13.81\ \mu \mathrm{N}$ and the contact force band at 95% confidence is narrowed from $\pm 1.68\ \mu \mathrm{N}$ to $\pm 0.82\ \mu \mathrm{N}$ , verified by a finite element simulation in ANSYS.

The retinoic acid receptor-related orphan receptor γ (RORγ) is a ligand-dependent transcription factor of the nuclear receptor super family that underpins metabolic activity, immune function, and cancer progression. Despite being a valuable drug target in health and disease, our understanding of the ligand-dependent activities of RORγ is far from complete. Like most nuclear receptors, RORγ must recruit coregulatory protein to enact the RORγ target gene program. To date, a majority of structural studies have been focused exclusively on the RORγ ligand-binding domain and the ligand-dependent recruitment of small peptide segments of coregulators. Herein, we examine the ligand-dependent assembly of full length RORγ:coregulator complexes on cognate DNA response elements using structural proteomics and small angle x-ray scattering. The results from our studies suggest that RORγ becomes elongated upon DNA recognition, preventing long range interdomain crosstalk. We also determined that the DNA binding domain adopts a sequence-specific conformation, and that coregulatory protein may be able to ‘sense’ the ligand- and DNA-bound status of RORγ. We propose a model where ligand-dependent coregulator recruitment may be influenced by the sequence of the DNA to which RORγ is bound. Overall, the efforts described herein will illuminate important aspects of full length RORγ and monomeric orphan nuclear receptor target gene regulation through DNA-dependent conformational changes.

A molecular dynamics (MD) study is carried out to reveal the phenomenon about the normal and explosive boiling of ultra-thin liquid argon film absorbed on MoS2 surface with different wetting condit...

This study presents a method of dividing the beam into two elements beam constraint model (TEBCM) to analysis the bistable characteristic between the force and displacement. Moreover, a formula D 1 for defining the second order bending mode during the deformation of the V-beam is obtained. The finite elements analysis (FEA) is conducted in this study to validate the theoretical study of bistable feature. A comparison between the theoretical solutions and FEA results shows good agreement. Results further show that to design a bistable V-beam mechanism, the tilted angle should be larger for the critical beam length, simultaneously, the beam length should be longer for the critical tilted angle.

A bi-directional hybrid energy harvester (HEH) is presented in this paper to scavenge energy from ultra-low frequency mechanical excitations. The proposed HEH consists of two piezoelectric cantilever beams, a suspended magnet, and a set of coil. Specifically, the two piezoelectric beams work as a conventional piezoelectric energy harvester (PEH), whereas the suspended magnet and the coil constitute an electromagnetic energy harvester (EMEH). The two energy-harvesting units (PEH and EMEH), which are sensitive to excitations coming from different directions, are coupled by the suspended magnet, through which the PEH and EMEH are coherently integrated. The suspended magnet not only induces the coil to generate electricity but also actuates the PEH to work, achieving the simultaneous energy extraction from one excitation through two conversion mechanisms. The dynamic model of the HEH is established. Theoretical simulations and experimental measurements under the sinusoidal excitation indicate that the nonlinear interaction between the PEH and EMEH actuates the two energy-harvesting units to oscillate either chaotically or periodically with large amplitudes, which can improve both the PEH and the EMEH power outputs at ultra-low frequencies, not only expanding the HEH working bandwidth but also making the HEH suitable for ultra-low frequency energy harvesting. Moreover, the hand-shaking test shows that the HEH has a better charging performance than an individual energy-harvesting unit for charging a capacitor. Under the hand-shaking induced excitation, the fabricated HEH prototype can also light up tens of light-emitting diodes (LEDs), demonstrating its potential application for powering some portable electronics.

Microbial fuel cells (MFCs) have been widely viewed as one of the most promising alternative sources of renewable energy. A recognition of needs of efficient development methods based on multidisciplinary research becomes crucial for the optimization of MFCs. Modeling of MFCs is an effective way for not only gaining a thorough understanding of the effects of operation conditions on the performance of power generation but also becomes of essential interest to the successful implementation of MFCs. The MFC models encompass the underlying reaction process and limiting factors of the MFC. The models come in various forms, such as the mathematical equations or the equivalent circuits. Different modeling focuses and approaches of the MFC have emerged. In this study, we present a state of the art of MFCs modeling; the past modeling methods are reviewed as well. Models and modeling methods are elaborated on based on the classification provided by Mechanism-based models and Application-based models. Mechanisms, advantages, drawbacks, and application fields of different models are illustrated as well. We exhibit a complete and comprehensive exposition of the different models for MFCs and offer further guidance to promote the performance of MFCs.

Wettability, as one of the important properties of solid surface, may influence heat and mass transfer in boiling process. Molecular dynamics method is employed to investigate the effects of wettability on normal and explosive boiling of ultra-thin liquid argon film absorbed on a heated solid aluminium surface in a confined space in present work. The initial three-phase molecular system is comprised of solid aluminium wall, liquid argon and vapour argon and is run for three different solid–liquid interfacial wettability (lyophilic, lyophobic and neutral surfaces), which achieves a balance at 90 K. After equilibrium period, two different jump temperatures degree, 150 and 350 K, are set on heat source layers separately to characterise the boiling phenomena, namely, low-temperature degree for normal boiling and high-temperature degree for explosive boiling in which temperature of solid wall is far beyond the critical temperature of liquid argon. The simulation results indicate that the wetting condition of solid–liquid interfacial surface have significant effects on both cases of boiling phenomena. Furthermore, the heat transfer rate with good wettability (lyophilic) is much higher than bad wettability (lyophobic) with same jump temperature degree.

EPAC proteins are therapeutic targets for the potential treatment of cardiac hypertrophy and cancer metastasis. Several laboratories use a tetrahydroquinoline analog, CE3F4, to dissect the role of EPAC1 in various disease states. Here, we report SAR studies with tetrahydroquinoline analogs that explore various functional groups. The most potent EPAC inhibitor 12a exists as a mixture of inseparable E (major) and Z (minor) rotamers. The rotation about the N-formyl group indeed impacts the activity against EPAC.

Microbial fuel cells (MFCs) have been widely viewed as one of the most promising alternative renewable energy source. MFCs have attracted a large amount of interest in the past decade and much scientific effort has been dedicated to making this technology more efficient. MFCs are complex bioelectrochemical system that generates electrical energy by the catalytic reaction of organic substrates. The study of MFCs requires an interdisciplinary approach. Experimental method is time-consuming and uneconomical. Modelling of MFCs is an effective way not only for thorough understanding the effects of operation conditions on the power generation performance, but also for the successful implementation of MFCs. The state of the art of MFCs modelling is present in this article. Models and modelling methods are elaborated based on the classification of mechanism-based models and application-based models. Furthermore, mechanism, advantages, drawbacks, and application fields of different models are illustrated.

As approximately 70% of human breast tumors are estrogen receptor α (ERα)-positive, estrogen and ERα play essential roles in breast cancer development. By interrupting the ERα signaling pathway, endocrine therapy has been proven to be an effective therapeutic strategy. In this study, we identified a mechanism by which Transcription Start Site (TSS)-associated histone H3K27 acetylation signals the Super Elongation Complex (SEC) to regulate transcriptional elongation of the ESR1 (ERα) gene. SEC interacts with H3K27ac on ESR1 TSS through its scaffold protein AFF4. Depletion of AFF4 by siRNA or CRISPR/Cas9 dramatically reduces expression of ESR1 and its target genes, consequently inhibiting breast cancer cell growth. More importantly, a AFF4 mutant which lacks H3K27ac interaction failed to rescue ESR1 gene expression, suggesting H3K27 acetylation at TSS region is a key mark bridging the transition from transcriptional initiation to elongation, and perturbing SEC function can be an alternative strategy for targeting ERα signaling pathway at chromatin level., Gao et al. study the relationship between AFF4 and acetylated histone H3K27 in the context of estrogen receptor alpha signaling. They use a series of pull down assays, genetic backgrounds, and global sequencing analysis and show that AFF4 binds to H2K27ac at promoters and influences the ER alpha signaling and breast cancer cell growth.

The study of nanocrystalline(NC) polycrystals is a hot topic, and the study of nanomaterial properties by molecular dynamics has become the first choice for many researchers. The purpose of this paper is to simulate the tensile tests of single and polycrystalline tantalum by molecular dynamics(MD) to obtain its mechanical properties. Firstly, the Ravelo-EAM potential was used to conduct tensile tests on tantalum in the direction. Secondly, it can be seen that the elastic modulus E 100 decreases with the temperature gradually increases from 1 K to 1500 K according to the simulation results. Finally, the Hall-Petch(H-P) effect based on grain size is verified from the tensile test of polycrystalline tantalum.

Mounting evidence is revealing a granularity within gene regulation that occurs at the level of mRNA translation. Within mammalian cells, canonical cap-dependent mRNA translation is dependent upon the interaction between the m7G cap-binding protein eukaryotic initiation factor 4E (eIF4E) and the scaffolding protein eukaryotic initiation factor 4G (eIF4G), the latter of which facilitates pre-translation initiation complex assembly, mRNA circularization, and ultimately ribosomal scanning. In breast epithelial cells, we previously demonstrated that the CELF1 RNA-binding protein promotes the translation of epithelial to mesenchymal transition (EMT) effector mRNAs containing GU-rich elements (GREs) within their 3’ untranslated regions (UTRs). Here we show that within this context, CELF1 directly binds to both the eIF4E cap-binding protein and Poly(A) binding protein (PABP), promoting translation of GRE-containing mRNAs in mesenchymal cells. Disruption of this CELF1/eIF4E interaction inhibits both EMT induction and experimental metastasis. Our findings illustrate a novel way in which non-canonical mechanisms of translation initiation underlie transitional cellular states within the context of development or human disease.

N,N-Diphenylamines were discovered as potent and selective EPAC2 inhibitors. A study was conducted to determine the structure-activity relationships in a series of inhibitors of which several compounds displayed submicromolar potencies. Selectivity over the related EPAC1 protein was also demonstrated. Computational modeling reveals an allosteric site that is distinct from the cAMP binding domain shared by both EPAC isoforms, providing a theory with regards to subtype selectivity.

Differential Scanning Fluorimetry Guided Refolding (DGR) is a simple methodology that can be used to rapidly screen for and identify conditions capable of accurately refolding protein preparations, such as those obtained from Escherichia coli inclusion bodies. It allows for the production in E. coli of functional proteins that would otherwise require far more expensive production methods. This unit describes how to set up a DGR refolding assay, perform DGR refolding trials in microplate format, use MeltTraceur Web software to interactively analyze the resulting data, scale-up protein production via refolding, and lastly, validate that the protein is properly folded. © 2018 by John Wiley & Sons, Inc.

Transient receptor potential canonical 6 (TRPC6) proteins form receptor-operated Ca2+-permeable channels, which have been thought to bring benefit to the treatment of diseases, including cancer. However, selective antagonists for TRPC channels are rare and none of them has been tested against gastric cancer. Compound 14a and analogs were synthesized by chemical elaboration of previously reported TRPC3/6/7 agonist 4o. 14a had very weak agonist activity at TRPC6 expressed in HEK293 cells but exhibited strong inhibition on both 4o-mediated and receptor-operated activation of TRPC6 with an IC50 of about 1 μM. When applied to the culture media, 14a suppressed proliferation of AGS and MKN45 cells with IC50 values of 17.1 ± 0.3 and 18.5 ± 1.0 μM, respectively, and inhibited tube formation and migration of cultured human endothelial cells. This anti-tumor effect on gastric cancer was further verified in xenograft models using nude mice. This study has found a new tool compound which shows excellent therapeutic potential against human gastric cancer most likely through targeting TRPC6 channels.

Background and PurposeTransient receptor potential canonical (TRPC) channels play important roles in a broad array of physiological functions and are involved in various diseases. However, due to a lack of potent subtype-specific inhibitors the exact roles of TRPC channels in physiological and pathophysiological conditions have not been elucidated.

Exchange proteins directly activated by cAMP (EPACs) are critical cAMP-dependent signaling pathway mediators that play important roles in cancer, diabetes, heart failure, inflammations, infections, neurological disorders and other human diseases. EPAC specific modulators are urgently needed to explore EPAC's physiological function, mechanism of action and therapeutic applications. On the basis of a previously identified EPAC specific inhibitor hit ESI-09, herein we have designed and synthesized a novel series of 2-substituted phenyl-N-phenyl-2-oxoacetohydrazonoyl cyanides as potent EPAC inhibitors. Compound 31 (ZL0524) has been discovered as the most potent EPAC inhibitor with IC50 values of 3.6 µM and 1.2 µM against EPAC1 and EPAC2, respectively. Molecular docking of 31 onto an active EPAC2 structure predicts that 31 occupies the hydrophobic pocket in cAMP binding domain (CBD) and also opens up new space leading to the solvent region. These findings provide inspirations for discovering next generation of EPAC inhibitors.

Transient receptor potential canonical 3/6/7 (TRPC3/6/7) are highly homologous receptor-operated non-selective cation channels. Despite their physiological significance, very few selective and potent agonists are available for functional examination of these channels. Using a cell-based high throughput screening approach, a lead compound with the pyrazolopyrimidine skeleton was identified as a TRPC6 agonist. Synthetic schemes for the lead and its analogues were established, and structural–activity relationship studies were carried out. A series of potent and direct agonists of TRPC3/6/ 7 channels were identified, and among them, 4m–4p have a potency order of TRPC3 > C7 > C6, with 4n being the most potent with an EC50 of

Evaporation and explosive boiling of ultra-thin liquid film are of great significant fundamental importance for both science and engineering applications. Wettability, as one of the important properties of solid surface. So it is necessary to understand the influence of wetting property between liquid film and solid surface on explosive boiling. The simulations are carried out for three systems with different solid-liquid interface wettability, from hydrophilic to hydrophobic, to investigate two different boiling phenomena. The jump temperature is set as 300 K for explosive boiling in present study. The results reveal that, with the wettability change from hydrophobic to hydrophilic, the phase transition rate of ultra-thin liquid argon film increases extremely rapidly.

Two series of novel EPAC antagonists are designed, synthesized and evaluated in an effort to develop diversified analogues based on the scaffold of the previously identified high-throughput (HTS) hit 1 (ESI-09). Further SAR studies reveal that the isoxazole ring A of 1 can tolerate chemical modifications with either introduction of flexible electron-donating substitutions or structurally restrictedly fusing with a phenyl ring, leading to identification of several more potent and diversified EPAC antagonists (e.g., 10 (NY0617), 14 (NY0460), 26 (NY0725), 32 (NY0561), and 33 (NY0562)) with low micromolar inhibitory activities. Molecular docking studies on compounds 10 and 33 indicate that these two series of compounds bind at a similar site with substantially different interactions with the EPAC proteins. The findings may serve as good starting points for the development of more potent EPAC antagonists as valuable pharmacological probes or potential drug candidates.

In the central nervous system, canonical transient receptor potential (TRPC) channels have been implicated in mediating neuronal excitation induced by stimulating metabotropic receptors, including group 1 metabotropic glutamate receptors (mGluRs). Lateral septal (LS) neurons express high levels of TRPC4 and group I mGluRs. However, to what extent native TRPC4-containing channels (TRPC4-cc) are activated as well as the impact of different levels of TRPC4-cc activation on neuronal excitability remain elusive. Here, we report that stimulating LS neurons with group I mGluR agonist, (S)-3,5-DHPG, causes either an immediate increase in firing rate or an initial burst followed by a pause of firing, which can be correlated with below-threshold-depolarization (BTD) or above-threshold-plateau-depolarization (ATPD), respectively, in whole-cell recordings. The early phase of BTD and the entire ATPD are completely absent in neurons from TRPC4−/− mice. Moreover, in the same LS neurons, BTD can be converted to ATPD at more depolarized potentials or with a brief current injection, suggesting that BTD and ATPD may represent partial and full activations of TRPC4-cc, respectively. We show that coincident mGluR stimulation and depolarization is required to evoke strong TRPC4-cc current, and Na+ and Ca2+ influx, together with dynamic changes of intracellular Ca(2+), are essential for ATPD induction. Our results suggest that TRPC4-cc integrates metabotropic receptor stimulation with intracellular Ca(2+) signals to generate two interconvertible depolarization responses to affect excitability of LS neurons in distinct fashions.

Ca2+ mobilization from intracellular stores represents an important cell signalling process that is regulated, in mammalian cells, by inositol-1,4,5-trisphosphate (InsP3), cyclic ADP ribose and nicotinic acid adenine dinucleotide phosphate (NAADP). InsP3 and cyclic ADP ribose cause the release of Ca2+ from sarcoplasmic/endoplasmic reticulum stores by the activation of InsP3 and ryanodine receptors (InsP3Rs and RyRs). In contrast, the nature of the intracellular stores targeted by NAADP and the molecular identity of the NAADP receptors remain controversial, although evidence indicates that NAADP mobilizes Ca2+ from lysosome-related acidic compartments. Here we show that two-pore channels (TPCs) comprise a family of NAADP receptors, with human TPC1 (also known as TPCN1) and chicken TPC3 (TPCN3) being expressed on endosomal membranes, and human TPC2 (TPCN2) on lysosomal membranes when expressed in HEK293 cells. Membranes enriched with TPC2 show high affinity NAADP binding, and TPC2 underpins NAADP-induced Ca2+ release from lysosome-related stores that is subsequently amplified by Ca2+-induced Ca2+ release by InsP3Rs. Responses to NAADP were abolished by disrupting the lysosomal proton gradient and by ablating TPC2 expression, but were only attenuated by depleting endoplasmic reticulum Ca2+ stores or by blocking InsP3Rs. Thus, TPCs form NAADP receptors that release Ca2+ from acidic organelles, which can trigger further Ca2+ signals via sarcoplasmic/endoplasmic reticulum. TPCs therefore provide new insights into the regulation and organization of Ca2+ signals in animal cells, and will advance our understanding of the physiological role of NAADP.

Microbial fuel cells (MFCs) are envisioned as one of the most promising alternative renewable energy sources because they can generate electric current continuously while treating waste. Terrestrial Microbial Fuel Cells (TMFCs) can be inoculated and work on the use of soil, which further extends the application areas of MFCs. Energy supply, as a primary influential factor determining the lifetime of Wireless Sensor Network (WSN) nodes, remains an open challenge in sensor networks. In theory, sensor nodes powered by MFCs have an eternal life. However, low power density and high internal resistance of MFCs are two pronounced problems in their operation. A single-hop WSN powered by a TMFC experimental setup was designed and experimented with. Power generation performance of the proposed TMFC, the relationships between the performance of the power generation and the environment temperature, the water content of the soil by weight were measured by experiments. Results show that the TMFC can achieve good power generation performance under special environmental conditions. Furthermore, the experiments with sensor data acquisition and wireless transmission of the TMFC powering WSN were carried out. We demonstrate that the obtained experimental results validate the feasibility of TMFCs powering WSNs.

cAMP signaling plays a key role in regulating pain sensitivity. Here, we uncover a previously unidentified molecular mechanism in which direct phosphorylation of the exchange protein directly activated by cAMP 1 (EPAC1) by G protein kinase 2 (GRK2) suppresses Epac1-to-Rap1 signaling, thereby inhibiting persistent inflammatory pain. Epac1−/− mice are protected against inflammatory hyperalgesia in the complete Freund’s adjuvant (CFA) model. Moreover, the Epac-specific inhibitor ESI-09 inhibits established CFA-induced mechanical hyperalgesia without affecting normal mechanical sensitivity. At the mechanistic level, CFA increased activity of the Epac target Rap1 in dorsal root ganglia of WT, but not of Epac1−/−, mice. Using sensory neuronspecific overexpression of GRK2 or its kinase-dead mutant in vivo, we demonstrate that GRK2 inhibits CFA-induced hyperalgesia in a kinase activity-dependent manner. In vitro, GRK2 inhibits Epac1-to-Rap1 signaling by phosphorylation of Epac1 at Ser-108 in the Disheveled/ Egl-10/pleckstrin domain. This phosphorylation event inhibits agonist-induced translocation of Epac1 to the plasma membrane, thereby reducing Rap1 activation. Finally, we show that GRK2 inhibits Epac1-mediated sensitization of the mechanosensor Piezo2 and that Piezo2 contributes to inflammatory mechanical hyperalgesia. Collectively, these findings identify a key role of Epac1 in chronic inflammatory pain and a molecular mechanism for controlling Epac1 activity and chronic pain through phosphorylation of Epac1 at Ser-108. Importantly, using the Epac inhibitor ESI-09, we validate Epac1 as a potential therapeutic target for chronic pain., National Institutes of Health Grants R01 NS073939, R01 NS074999, R01 GM066170, and R01GM106218 and High-End Instrumentation Program 1S10OD012304-01; Cancer Prevention Research Institute of Texas Core Facility Grant RP130397 (a University of Texas System Science and Technology Acquisition and Retention grant); Ministerio de Economía y Competitividad Grant SAF2014-55511-R; Comunidad de Madrid Grant S2010/BMD-2332 (Inter-Disciplinary Research Network); Ministerio Sanidad y Consumo-Instituto Carlos III Cardiovascular Network Grant RD12/0042/0012; a European Foundation for the Study of Diabetes– Novo Nordisk grant; and by Universidad Autónoma de Madrid–Banco de Santander

In order to solve the problem of spatial blind region existing in a two-axis photoelectric tracking system, a type of three-axis photoelectric tracking system is designed, which can track the target in the whole space. The kinematical model of the three-axis photoelectric tracking system with a redundant degree of freedom is constructed by quaternion, and a high-speed tracking strategy of the three-axis photoelectric tracking system is proposed based on the minimum norm least squares solution. Via triangular transformation of the three-axis kinematical function, the Moore–Penrose generalized inverse matrix of function is gained, and the minimum norm least squares solution of three-axis angular increments are solved. The results of simulation and experiment show that this tracking strategy does not need the complex optimization process, that the system is able to realize a three-axis linkage continuous tracking movement in whole space, and that the tracking angular increments of three axes get much smaller, so the tracking performance of this tracking strategy is more superior to the two-axis tracking strategy.

In order to model the adhesive contact across different length scales, a multiscale approach is developed and used to study the adhesive contact behaviors between a rigid cylinder and an elastic face-centered cubic (FCC) substrate. The approach combines an atomistic treatment of the interfacial region with an elastic mechanics method description of the continuum region. The two regions are connected by a coupling region where nodes of the continuum region are refined to atoms of the atomistic region. Moreover, the elastic constants of FCC crystals are obtained directly from the Lennard-Jones potential to describe the elastic response characteristics of the continuum region, which ensures the consistency of material proprieties between atomistic and continuum regions. The multiscale approach is examined by comparing it with the pure MD simulation, and the results indicate that the multiscale modeling approach agrees well with the MD method in studying the adhesive contact behaviors.

This letter presents a monostable piezoelectric energy harvester (PEH) for achieving enhanced energy extraction from low-level excitations. The proposed PEH is realized by introducing symmetric magnetic attraction to a piezoelectric cantilever beam and a pair of stoppers to confine the maximum deflection of the beam. The lumped parameter model of such a system is presented and experimentally validated. Theoretical simulations and experimental measurements demonstrate that the proposed design can bring about a wider operating bandwidth and higher output voltage than the linear PEH. Under a sinusoidal vibration with an amplitude of 3 m/s2, a 54% increase in the operating bandwidth and a 253% increase in the magnitude of output power are achieved compared to its linear counterpart. Moreover, the proposed PEH exhibits rich dynamic features, including the tunable operating bandwidth, adjustable voltage and power levels, and softening hysteresis.

Transient receptor potential A1 (TRPA1) forms nonselective cation channels implicated in acute inflammatory pain and nociception. The mechanism of ligand activation of TRPA1 may involve either covalent modification of cysteine residues or conventional reversible ligand-receptor interactions. For certain electrophilic prostaglandins, covalent modification has been considered as the main mechanism involved in their stimulatory effect on TRPA1. Because some nonsteroidal anti-inflammatory drugs (NSAIDs) are structural analogs of prostaglandins, we examined several nonelectrophilic NSAIDs on TRPA1 activation using electrophysiological techniques and intracellular Ca(2+) measurements and found that a selected group of NSAIDs can act as TRPA1 agonists. Extracellularly applied flufenamic, niflumic, and mefenamic acid, as well as flurbiprofen, ketoprofen, diclofenac, and indomethacin, rapidly activated rat TRPA1 expressed in Xenopus oocytes and human TRPA1 endogenously expressed in WI-38 fibroblasts. Similarly, the NSAID ligands activated human TRPA1 inducibly expressed in HEK293 cells, but the responses were absent in uninduced and parental HEK293 cells. The response to fenamate agonists was blocked by TRPA1 antagonists, AP-18, HC-030031, and ruthenium red. At subsaturating concentrations, the fenamate NSAIDs also potentiate the activation of TRPA1 by allyl isothiocyanate, cinnamaldehyde, and cold, demonstrating positive synergistic interactions with other well-characterized TRPA1 activators. Importantly, among several thermosensitive TRP channels, the stimulatory effect is specific to TRPA1 because flufenamic acid inhibited TRPV1, TRPV3, and TRPM8. We conclude that fenamate NSAIDs are a novel class of potent and reversible direct agonists of TRPA1. This selective group of TRPA1-stimulating NSAIDs should provide a structural basis for developing novel ligands that noncovalently interact with TRPA1 channels.

Background and purpose: Selective androgen receptor modulators are of great value in the treatment of prostate cancer. The purpose of this study was to provide a preliminary characterization of a new class of non-steroidal androgen receptor modulators discovered in a high-throughput screening campaign. Experimental approach: Competitive receptor binding, luciferase-based reporter methods, cell proliferation and in vivo assays were employed to evaluate an initial set of compounds from chemistry efforts. Key results: Forty-nine analogues from the chemistry efforts showed high affinity binding to androgen receptors, agonist and/or antagonist activities in both CV-1 and MDA-MB-453 transfection assays. A proliferation assay in LNCaP cells also exhibited this profile. A representative of these non-steroidal compounds (compound 21) was devoid of activity at other nuclear receptors (oestrogen, progesterone, glucocorticoid and mineralocorticoid receptors) in the CV-1 co-transfection assay. At the same time, in an immature castrated rat model, it behaved as an androgen receptor antagonist against the growth of prostate, seminal vesicles and levator ani induced by exogenous androgen. Separation of compound 21 into its enantiomers showed that nearly all the androgen receptor modulating activity and binding resided in the dextrorotatory compound (23) while the laevorotatory isomer (22) possessed weak or little effect depending on the cell type studied. Conclusions and implications: These non-steroidal compounds may represent a new class of androgen receptor modulators for the treatment of not only prostate cancer but other clinical conditions where androgens and androgen receptors are involved in the pathological processes. British Journal of Pharmacology (2008) 154, 440–450; doi:10.1038/bjp.2008.107; published online 14 April 2008

Exchange proteins directly activated by cAMP (EPAC) as guanine nucleotide exchange factors mediate the effects of the pivotal second messenger cAMP, thereby regulating a wide variety of intracellular physiological and pathophysiological processes. A series of novel 2-(isoxazol-3-yl)-2-oxo-N′-phenyl-acetohydrazonoyl cyanide EPAC antagonists was synthesized and evaluated in an effort to optimize properties of the previously identified high-throughput (HTS) hit 1 (ESI-09). Structure–activity relationship (SAR) analysis led to the discovery of several more active EPAC antagonists (e.g., 22 (HJC0726), 35 (NY0123), and 47 (NY0173)) with low micromolar inhibitory activity. These inhibitors may serve as valuable pharmacological probes to facilitate our efforts in elucidating the biological functions of EPAC and developing potential novel therapeutics against human diseases. Our SAR results have also revealed that further modification at the 3-, 4-, and 5-positions of the phenyl ring as well as the 5-position of the isoxazole moiety may allow for the development of more potent EPAC antagonists.

cAMP-elevating agents such as the incretin hormone glucagon-like peptide-1 potentiate glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. However, a debate has existed since the 1970s concerning whether or not cAMP signaling is essential for glucose alone to stimulate insulin secretion. Here, we report that the first-phase kinetic component of GSIS is cAMP-dependent, as revealed through the use of a novel highly membrane permeable para-acetoxybenzyl (pAB) ester prodrug that is a bioactivatable derivative of the cAMP antagonist adenosine-3′,5′-cyclic monophosphorothioate, Rp-isomer (Rp-cAMPS). In dynamic perifusion assays of human or rat islets, a step-wise increase of glucose concentration leads to biphasic insulin secretion, and under these conditions, 8-bromoadenosine-3′,5′-cyclic monophosphorothioate, Rp-isomer, 4-acetoxybenzyl ester (Rp-8-Br-cAMPS-pAB) inhibits first-phase GSIS by up to 80%. Surprisingly, second-phase GSIS is inhibited to a much smaller extent (≤20%). Using luciferase, fluorescence resonance energy transfer, and bioluminescence resonance energy transfer assays performed in living cells, we validate that Rp-8-Br-cAMPS-pAB does in fact block cAMP-dependent protein kinase activation. Novel effects of Rp-8-Br-cAMPS-pAB to block the activation of cAMP-regulated guanine nucleotide exchange factors (Epac1, Epac2) are also validated using genetically encoded Epac biosensors, and are independently confirmed in an in vitro Rap1 activation assay using Rp-cAMPS and Rp-8-Br-cAMPS. Thus, in addition to revealing the cAMP dependence of first-phase GSIS from human and rat islets, these findings establish a pAB-based chemistry for the synthesis of highly membrane permeable prodrug derivatives of Rp-cAMPS that act with micromolar or even nanomolar potency to inhibit cAMP signaling in living cells.

The cAMP signaling cascade is one of the most frequently targeted pathways for the development of pharmaceutics. A plethora of recent genetic and pharmacological studies suggest that exchange proteins directly activated by cAMP (EPACs) are implicated in multiple pathologies. Selective EPAC inhibitors have been recently developed. One specific inhibitor, ESI-09, has been shown to block EPAC activity and functions, as well as to recapitulate genetic phenotypes of EPAC knockout mice when applied in vivo. However, a recent study raised concern that ESI-09 might act as a non-specific protein denaturant. Herein, we present a detailed biochemical and pharmacological characterization, as well as a structure-activity relationship (SAR) analysis of ESI-09. Our studies show that ESI-09 dose-dependently inhibits activity of both EPAC1 and EPAC2 with apparent IC50 values well below the concentrations shown to induce “protein denaturation”. Moreover, the ESI-09's action towards EPAC proteins is highly sensitive to minor modifications of the 3-chlorophenyl moiety. Taken together, these results demonstrate that ESI-09 indeed acts as an EPAC specific antagonist and does not significantly destabilize/denature proteins at pharmacological effective concentrations. This conclusion is further supported by NMR data showing that ESI-09 induces residue-dependent chemical shift changes at low concentrations, while preserving well dispersed peaks.

The nucleotide sequence of Streptomyces lividans linear plasmid SLP2 consists of 50,410 bp (C. H. Huang, C. Y. Chen, H. H. Tsai, C. Chen, Y. S. Lin, and C. W. Chen, Mol. Microbiol. 47: 1563-1576, 2003). Here we report that the basic SLP2 locus for plasmid replication in circular mode resembles that of Streptomyces linear plasmids pSLA2 and SCP1 and comprises iterons SLP2 and the adjacent rep SLP2 gene. More efficient replication additionally required the 47-bp sequence between bp 581 and 628 upstream of the iterons. Replacement of either the iterons or the rep gene of SLP2 by the corresponding genes of pSLA2 or SCP1 still allows propagation in Streptomyces , although the transformation frequencies were 3 orders of magnitude lower than the original plasmids, suggesting that these plasmids share similar replication mechanisms. To replicate SLP2 in linear mode, additional SLP2 loci—either mtap SLP2 / tpg SLP2 or mtap SLP2 / ilrA SLP2 —were required. IlrA SLP2 protein binds specifically to the iterons SLP2 in vitro. Interactions were detected between these SLP2-borne replication proteins (Mtap SLP2 , Tpg SLP2 , and IlrA SLP2 ) and the telomeric replication proteins (TpgL, TapL, and TpgL) of the S. lividans chromosome, respectively, but the SLP2 proteins failed to interact. These results suggest that SLP2 recruits chromosomally encoded replication proteins for its telomere replication.

This study presents a shoe-mounted nonlinear piezoelectric energy harvester (PEH) with intent to capture energy from human walking. The PEH consists of a piezoelectric cantilever beam magnetically coupled to a ferromagnetic ball and a crossbeam. A sleeve is included to guide the travel of the ball. Experimental measurements and theoretical simulations demonstrate that the proposed design can collect energy from diverse excitation sources with different directions produced by the foot, including vibrations, swing motions, and the compressive force. The ball and the crossbeam sense the swing motion and the compressive force, respectively, and then actuate the piezoelectric beam to function. The piezoelectric beam senses the vibration along the tibial axis and generates electricity. The proposed PEH achieves the superposition of these excitations and generates multiple peaks in voltage output within one gait cycle. The output power generated by the fabricated prototype ranges from 0.03 mW to 0.35 mW when the...

Harvesting energy from the surrounding environment through piezoelectric conversion is a promising method for implementing self-sustained low-power devices. To date, most piezoelectric energy harvesters (PEHs) developed can only scavenge energy from the unidirectional mechanical vibration. This deficiency severely limits the adaptability of PEHs because the real-world excitations may involve different mechanical motions and the mechanical vibration may come from various directions. To tackle this issue, we proposed a multipurpose PEH, which is composed of a ferromagnetic ball, a cylindrical track and four piezoelectric cantilever beams. In this paper, theoretical and experimental studies were carried out to examine the performance of the multipurpose PEH. The experimental results indicate that, under the vibrations that are perpendicular to the ground, the maximum peak voltage is increased by 3.2 V and the bandwidth of the voltage above 4 V is expanded by more than 4 Hz by the proposed PEH as compared to its linear counterpart; the maximum power output of 0.8 mW is attained when the PEH is excited at 39.5 Hz. Under the sway motion around different directions on the horizontal plane, significant power outputs, varying from 0.05 mW to 0.18 mW, are also generated by the multipurpose PEH when the sway angle is larger than 5[Formula: see text] and the sway frequency is smaller than 2.8 Hz. In addition, the multipurpose PEH demonstrates the capacity of collecting energy from the rotation motion, and approximately 0.14 mW power output is achieved when the rotation frequency is 1 Hz.