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The "dual carbon" goal has made it a mainstream trend for new energy stations (NESs) and energy storage stations (ESSs) to jointly participate in market regulation. This paper proposes a multiple time scale distributed optimization method for NESs and ESSs based on the alternate direction multiplier method (ADMM). By first considering the uncertainty of new energy output and the volatility of electricity market prices, a multi time scale revenue model is constructed for day-ahead, intraday, and real-time markets. Then, the objective function is built by maximizing the comprehensive market revenues and is simplified using the synergistic effect of NESs and ESSs. Next, the simplified objective function is solved by the ADMM, and the revenues are maximized while each energy meets the relevant constraints. Lastly, the 33-node network topology is used to illustrate the feasibility of the proposed method. The simulation results show that after optimization, the output of NESs and ESSs can coordinate work in day-ahead, intraday, and real-time markets, while the abandonment power of wind and light is significantly improved. [ABSTRACT FROM AUTHOR]

Melanoma is the most severe type of skin cancer and among the most malignant neoplasms in humans. With the growing incidence of melanoma, increased numbers of therapeutic options, and the potential to target specific proteins, understanding the basic mechanisms underlying the disease's progression and resistance to treatment has never been more important. LOXL3, SNAI1, and NES are key factors in melanoma genesis, regulating tumor growth, metastasis, and cellular differentiation. In our study, we explored the potential role of LOXL3, SNAI1, and NES in melanoma progression and metastasis among patients with dysplastic nevi, melanoma in situ, and BRAF+ and BRAF− metastatic melanoma, using immunofluorescence and qPCR analysis. Our results reveal a significant increase in LOXL3 expression and the highest NES expression in BRAF+ melanoma compared to BRAF−, dysplastic nevi, and melanoma in situ. As for SNAI1, the highest expression was observed in the metastatic melanoma group, without significant differences among groups. We found co-expression of LOXL3 and SNAI1 in the perinuclear area of all investigated subgroups and NES and SNAI1 co-expression in melanoma cells. These findings suggest a codependence or collaboration between these markers in melanoma EMT, suggesting new potential therapeutic interventions to block the EMT cascade that could significantly affect survival in many melanoma patients. [ABSTRACT FROM AUTHOR]

The purpose of this study is to investigate the suppression effect of a nonlinear energy sink (NES) on the wind-vortex-induced pipe vibration and explore the influence of damping, stiffness, and NES installation position on the suppression effect. In this work, the wind-vortex-induced vibration of an elastic pipe of a deepwater jacket was studied, and vibrations were suppressed by using an NES. A van der Pol wake oscillator was used to simulate vortex-induced force, and the dynamic equation of the pipe considering the NES was established. The Galerkin method was applied to discretize the motion equation, and the vortex-induced vibration (VIV) of the pipe at reduced wind speeds was numerically analyzed. The novelty of this research is that particle swarm optimization was used to optimize the parameters of the NES to improve vibration suppression. The influence of the installation position, nonlinear stiffness, and damping parameters of the NES on vibration suppression was analyzed. Results showed that the optimized parameter combinations of the NES can effectively reduce wind-vortex-induced pipe vibration. The installation position of the NES had a significant effect on vibration suppression, and the midpoint of the pipe was the optimal NES installation position. An increase in stiffness or a 10% decrease in damping may cause vibration suppression failure. The results of this study provide some guidance for VIV suppression in deepwater jacket pipes. [ABSTRACT FROM AUTHOR]

The “dual carbon” goal has made it a mainstream trend for new energy stations (NESs) and energy storage stations (ESSs) to jointly participate in market regulation. This paper proposes a multiple time scale distributed optimization method for NESs and ESSs based on the alternate direction multiplier method (ADMM). By first considering the uncertainty of new energy output and the volatility of electricity market prices, a multi time scale revenue model is constructed for day-ahead, intraday, and real-time markets. Then, the objective function is built by maximizing the comprehensive market revenues and is simplified using the synergistic effect of NESs and ESSs. Next, the simplified objective function is solved by the ADMM, and the revenues are maximized while each energy meets the relevant constraints. Lastly, the 33-node network topology is used to illustrate the feasibility of the proposed method. The simulation results show that after optimization, the output of NESs and ESSs can coordinate work in day-ahead, intraday, and real-time markets, while the abandonment power of wind and light is significantly improved.

Melanoma is the most severe type of skin cancer and among the most malignant neoplasms in humans. With the growing incidence of melanoma, increased numbers of therapeutic options, and the potential to target specific proteins, understanding the basic mechanisms underlying the disease’s progression and resistance to treatment has never been more important. LOXL3, SNAI1, and NES are key factors in melanoma genesis, regulating tumor growth, metastasis, and cellular differentiation. In our study, we explored the potential role of LOXL3, SNAI1, and NES in melanoma progression and metastasis among patients with dysplastic nevi, melanoma in situ, and BRAF+ and BRAF− metastatic melanoma, using immunofluorescence and qPCR analysis. Our results reveal a significant increase in LOXL3 expression and the highest NES expression in BRAF+ melanoma compared to BRAF−, dysplastic nevi, and melanoma in situ. As for SNAI1, the highest expression was observed in the metastatic melanoma group, without significant differences among groups. We found co-expression of LOXL3 and SNAI1 in the perinuclear area of all investigated subgroups and NES and SNAI1 co-expression in melanoma cells. These findings suggest a codependence or collaboration between these markers in melanoma EMT, suggesting new potential therapeutic interventions to block the EMT cascade that could significantly affect survival in many melanoma patients.

Non-equilibrium processes in the atmosphere and water were described in this paper. Spectral analysis by NES and DNES methods was applied to research water structure. The energy spectrum of water is obtained due to the non-equilibrium process of evaporation of water drops. The term Non-equilibrium energy spectrum (NES) is used in this method. The distribution function according to hydrogen bond energies f(E) is measured in reciprocal electron volts (eV-1). The differential energy spectrum DNES represents the difference between the investigated sample's NES and the control sample's NES. It is assumed that the combined influence of all factors other than those under study is identical for the control and sample. The effects of gas-solid heat exchange and calcium carbonate (CaCO3) decomposition were described. Our research aims to show peaks at 713 and in the 873 - 879 cm-1 due to shared environmental influences on calcium carbonate. The purpose of the article is to demonstrate that by studying the spectral parameters at 713 and in the range of 873 ÷ 879 cm-1, an assessment can be made for the application of the impact of water with different physicochemical parameters, air humidity, thermal effects on the quality of lime mortar solutions and chemical processes with carbon dioxide (CO2). [ABSTRACT FROM AUTHOR]

The system of linear oscillators coupled to multi-degree-of-freedom (MDOF) nonlinear attachment with combined periodic and stochastic seismic excitation is studied in this paper. The MDOF nonlinear attachment passively absorbs broadband energy from the linear system in a unidirectional and irreversible way numerically, which acts as a nonlinear energy sink (NES) in essence. The typical cubic nonlinear terms and sinusoidal nonlinear terms are considered, respectively. The periodic generalized harmonic wavelet (PGHW) and wavelet-Galerkin methods are used for motion equations, then a set of nonlinear algebraic equations can be obtained to get the wavelet coefficient of response. The quasi-Newton method is selected to solve these equations, which is more effective than the Newton method. In the numerical example, the algorithms of Single rank inverse Broyden (Rank-1 iB), Rank-2 Broyden–Fletcher–Shanno (Rank-2 BFS), Davidon–Fletcher–Powell (DFP), and Broyden–Fletcher–Goldfarb–Shanno (BFGS) are used to estimate the Jacobian matrix. The number of iterations, calculation time, and relative error are listed and compared, and it is concluded that the algorithm of Rank-1 iB is a better one for solving this problem in both cases. Finally, the displacement and estimated power spectral density (EPSD) of the response are obtained and shown. [ABSTRACT FROM AUTHOR]

This study examines the impact of entrepreneurship ecosystem factors on the recovery of entrepreneurship from the COVID-19 pandemic and offers valuable insights to drive growth. By analyzing the Serbian dataset from the Global Entrepreneurship Monitor National Expert Survey in 2022, the study employs linear regression analysis to investigate the relationship between Entrepreneurial Framework Conditions and post-pandemic recovery. Data were collected through interviews with 40 experts representing the government, academia, and industry. The National Entrepreneurship Context Index score for Serbia's entrepreneurial environment quality in 2022 is 4.6 which positions Serbia in the middle of the continuum of included country scores. The results of the analysis have shown that Market openness (β = .474; p < .01) and Achieving the UN Sustainable Economic Development Goals (β = .460; p < .01) have a direct positive impact on the recovery of entrepreneurs from the consequences of COVID-19. The limitations of the study are related to the demographics of the sample, self-reported data, geographic scope, focusing only on the Republic of Serbia, cross-sectional design that does not capture the dynamic and evolving nature of the recovery process. Given these limitations, future work could incorporate a more diverse sample to enhance the generalizability of the findings.This research provides important insights and policy recommendations to leverage entrepreneurial practices for economic recovery following the impact of the COVID-19 pandemic.

Abstract We present two methods for enhancing the efficiency of mitochondrial DNA (mtDNA) editing in mice with DddA-derived cytosine base editors (DdCBEs). First, we fused DdCBEs to a nuclear export signal (DdCBE-NES) to avoid off-target C-to-T conversions in the nuclear genome and improve editing efficiency in mtDNA. Second, mtDNA-targeted TALENs (mitoTALENs) are co-injected into mouse embryos to cleave unedited mtDNA. We generated a mouse model with the m.G12918A mutation in the MT-ND5 gene, associated with mitochondrial genetic disorders in humans. The mutant mice show hunched appearances, damaged mitochondria in kidney and brown adipose tissues, and hippocampal atrophy, resulting in premature death.

Background: With the fast development of aerospace technology, in order to improve the carrying efficiency of spacecraft, its design is gradually moving towards lighter weight and large size, such as solar wings, satellite antennas, and space manipulators. However, the application of flexible appendage can easily arouse obvious vibration during mission, which affects the operation accuracy and even threaten the safety of spacecraft structure. Purpose: To improve the working accuracy of spacecraft, the passive control strategy is adopted to suppress the serious vibration of the flexible appendage under different loads. Methods: Based on the absolute nodal coordinate formulation (ANCF), the dynamic model of spacecraft flexible appendage is established. Firstly, the single-degree-offreedom (1-DOF) and two-degree-of-freedom (2-DOF) NES are applied to the flexible beam structure. On this basis, the vibration characteristics and dynamic evolution of the coupled system are investigated under different load conditions. Results: When the initial amplitude of the NES is larger, the vibration reduction efficiency of the system becomes higher. At the same time, increasing the additional mass of the NES could also improve the effect of the structural vibration suppression. Conclusion: Vibration suppression effects on the dynamic characteristics of flexible appendage are closely related to the installation position of nonlinear energy sink. Compared with the 1-DOF NES, the 2-DOF NES has a better energy suppression effect, and the vibration energy transfer rate from the main system to the subsystem is more obvious when the additional total mass is the same. [ABSTRACT FROM AUTHOR]

Flaviviruses have a cytoplasmic replicative cycle, and crucial events, such as genome translation and replication, occur in the endoplasmic reticulum. However, some viral proteins, such as C, NS1, and NS5 from Zika virus (ZIKV) containing nuclear localization signals (NLSs) and nuclear export signals (NESs), are also located in the nucleus of Vero cells. The NS2A, NS3, and NS4A proteins from dengue virus (DENV) have also been reported to be in the nucleus of A549 cells, and our group recently reported that the NS3 protein is also located in the nucleus of Huh7 and C636 cells during DENV infection. However, the NS3 protease-helicase from ZIKV locates in the perinuclear region of infected cells and alters the morphology of the nuclear lamina, a component of the nuclear envelope. Furthermore, ZIKV NS3 has been reported to accumulate on the concave face of altered kidney-shaped nuclei and may be responsible for modifying other elements of the nuclear envelope. However, nuclear localization of NS3 from ZIKV has not been substantially investigated in human host cells. Our group has recently reported that DENV and ZIKV NS3 alter the nuclear pore complex (NPC) by cleaving some nucleoporins. Here, we demonstrate the presence of ZIKV NS3 in the nucleus of Huh7 cells early in infection and in the cytoplasm at later times postinfection. In addition, we found that ZIKV NS3 contains an NLS and a putative NES and uses the classic import (importin-a/b) and export pathway via CRM-1 to be transported between the cytoplasm and the nucleus. IMPORTANCE Flaviviruses have a cytoplasmic replication cycle, but recent evidence indicates that nuclear elements play a role in their viral replication. Viral proteins, such as NS5 and C, are imported into the nucleus, and blocking their import prevents replication. Because of the importance of the nucleus in viral replication and the role of NS3 in the modification of nuclear components, we investigated whether NS3 can be localized in the nucleus during ZIKV infection. We found that NS3 is imported into the nucleus via the importin pathway and exported to the cytoplasm via CRM-1. The significance of viral protein nuclear import and export and its relationship with infection establishment is highlighted, emphasizing the development of new host-directed antiviral therapeutic strategies. [ABSTRACT FROM AUTHOR]

SETDB1 is a histone H3-lysine 9-specific methyltransferase that fulfills epigenetic functions inside the nucleus; however, when overexpressed, SETDB1 majorily localizes in the cytoplasm. SETDB1 has a single nuclear-localization-signal (NLS) motif and two successive nuclear-export-signal (NES1 and NES2) motifs in the N-terminus, suggesting that SETDB1 localization is the consequence of a balance between the two antithetic motifs. Here, we performed a series of motif deletions to characterize their effects on the cellular movement of SETDB1. Given the cytoplasmic localization of GFP-SETDB1 in the whole form, without the NES motifs, GFP-SETDB1 was not nuclear, and 3xNLS addition plus NES removal held the majority of GFP-SETDB1 within the nucleus. The results indicated that the cytoplasmic localization of GFP-SETDB1 is the combined result of weak NLS and robust NESs. In ATF7IP-overexpressing cells, GFP-SETDB1 entered the nucleus only in the presence of the NES1 motif; neither the NES2 nor NLS motif was necessary. Since subcellular fractionation results showed that ATF7IP was nuclear-only, an intermediary protein may interact specifically with the NES1 motif after stimulation by ATF7IP. When GFP-SETDB1 had either NES1 or NES2, it was precipitated (in immunoprecipitation) and colocalized (in immunofluorescence) with ATF7IP, indicating that GFP-SETDB1 interacts with ATF7IP through the NES motifs in the nucleus. The regulated nuclear entry of SETDB1 is assumed to set a tight restriction on its abundance within the nucleus, thereby ensuring balanced nuclear SETDB1 levels.

Appropriate nucleo-cytoplasmic partitioning of proteins is a vital regulatory mechanism in phytohormone signaling and plant development. However, how this is achieved remains incompletely understood. The Karyopherin (KAP) superfamily is critical for separating the biological processes in the nucleus from those in the cytoplasm. The KAP superfamily is divided into Importin α (IMPα) and Importin β (IMPβ) families and includes the core components in mediating nucleocytoplasmic transport. Recent reports suggest the KAPs play crucial regulatory roles in Arabidopsis development and stress response by regulating the nucleo-cytoplasmic transport of members in hormone signaling. However, the KAP members and their associated molecular mechanisms are still poorly understood in maize. Therefore, we first identified seven IMPα and twenty-seven IMPβ genes in the maize genome and described their evolution traits and the recognition rules for substrates with nuclear localization signals (NLSs) or nuclear export signals (NESs) in plants. Next, we searched for the protein interaction partners of the ZmKAPs and selected the ones with Arabidopsis orthologs functioning in auxin biosynthesis, transport, and signaling to predict their potential function. Finally, we found that several ZmKAPs share similar expression patterns with their interacting proteins, implying their function in root development. Overall, this article focuses on the Karyopherin superfamily in maize and starts with this entry point by systematically comprehending the KAP-mediated nucleo-cytoplasmic transport process in plants, and then predicts the function of the ZmKAPs during maize development, with a perspective on a closely associated regulatory mechanism between the nucleo-cytoplasmic transport and the phytohormone network. [ABSTRACT FROM AUTHOR]

The generation of astrocytes from human induced pluripotent stem cells has been hampered by either prolonged differentiation—spanning over two months—or by shorter protocols that generate immature astrocytes, devoid of salient mature astrocytic traits pivotal for central nervous system (CNS) modeling. We directed stable hiPSC-derived neuroepithelial stem cells to human iPSC-derived Astrocytes (hiAstrocytes) with a high percentage of star-shaped cells by orchestrating an astrocytic-tuned culturing environment in 28 days. We employed RT-qPCR and ICC to validate the astrocytic commitment of the neuroepithelial stem cells. To evaluate the inflammatory phenotype, we challenged the hiAstrocytes with the pro-inflammatory cytokine IL-1β (interleukin 1 beta) and quantitatively assessed the secretion profile of astrocyte-associated cytokines and the expression of intercellular adhesion molecule 1 (ICAM-1). Finally, we quantitatively assessed the capacity of hiAstrocytes to synthesize and export the antioxidant glutathione. In under 28 days, the generated cells express canonical and mature astrocytic markers, denoted by the expression of GFAP, AQP4 and ALDH1L1. In addition, the notion of a mature phenotype is reinforced by the expression of both astrocytic glutamate transporters EAAT1 and EAAT2. Thus, hiAstrocytes have a mature phenotype that encompasses traits critical in CNS modeling, including glutathione synthesis and secretion, upregulation of ICAM-1 and a cytokine secretion profile on a par with human fetal astrocytes. This protocol generates a multifaceted astrocytic model suitable for in vitro CNS disease modeling and personalized medicine. [ABSTRACT FROM AUTHOR]

Gesneriaceae plant family is comprised of resurrection species, namely Boea hygrometrica and Paraboea rufescens, that are native to the Southeast Asia and Haberlea rhodopensis, Ramonda myconi, and Ramonda serbica, which are mainly found in the Balkan Peninsula. Haberlea rhodopensis is known to be able to survive extreme and prolonged dehydration. Study was carried out after the dried plant Haberlea rhodopensis Friv. had been hydrated and had reached its fresh state. Two juice samples were collected from the plant blossom: The first sample was prepared with 1% filtered water through a patented EVOdrop device. Then the sample was saturated with hydrogen with EVOdrop booster to a concentration of 1.2 ppm, pH = 7.3, ORP = −390 mV. This first sample was prepared with filtered tap water from Sofia, Bulgaria. The second sample, which was a control one, was developed with tap water from Sofia, Bulgaria, consisting of 1% solutions of Haberlea rhodopensis. A study revealed that during the drying process in H. rhodopensis the number of free water molecules decreases, and water dimers are formed. The aim of our study was to determine the number of water molecules in clusters in 1% solutions of hydrated H. rhodopensis plants. Results were analyzed according to the two types of water used in the experiment. Th EVOdrop device is equipped with an ultranano membrane and rotating jet nozzle to create a vortex water and saturation thanks to a second device EVObooster to obtain hydrogen-rich water. In the current study Hydrogen-rich water is referred to as Hydrogen EVOdrop Water (HEW). Research was conducted using the following methods—spectral methods non-equilibrium energy spectrum (NES) and differential non-equilibrium energy spectrum (DNES), mathematical models, and study of the distribution of water molecules in water clusters. In a licensed Eurotest Laboratory, the research of tap water before and after flowing through the EVOdrop device was proven. Studies have been carried out on the structuring of water molecule clusters after change of hydrogen bond energies. The restructuring comes with rearrangement of water molecules by the energy levels of hydrogen bonds. Local extrema can be observed in the spectrum with largest amount of water molecules. The structural changes were tested using the NES and DNES spectral methods. The conducted research proved that the application of EVOdrop device and EVObooster changes the parameters of water to benefit hydration and health. [ABSTRACT FROM AUTHOR]

The NES (nonlinear energy sink) is a new type of nonlinear tuned mass damper that is connected to the shock-absorbing main structure through strong nonlinear stiffness and viscous damping. The vibrational energy in the main structure is transferred to the NES oscillator by means of target energy transfer. A shaking table test of a 1:4 scaled RC (Reinforced Concrete) frame structure model with a new type of NES shock absorber was conducted to study the damping effect of the NES shock absorber, especially for the influence of joint strength and deformation. The NES used in this experiment has a relatively large nonlinear stiffness and a wide vibration absorption frequency band. The variation of reinforcement strains, node failure mode, and structural natural frequency of 1 story and two-layer joints of the model frame structure with NES were studied. The test results showed that NES could effectively reduce the strains of longitudinal reinforcement and stirrup in beams and columns and delay the plastic hinge development at the bottom and the top of the column. The frame model with NES installed has failures at the beam ends and shear failures at the nodes, realizing the seismic mechanism of solid columns and weak beams. Compared with ordinary seismic structures, the NES can effectively reduce the shear stress of concrete at the joints and alleviate the shear failure of joints. The final failure of the NES shock absorbing structure was the yielding of the steel bars at the bottom of the column and the crushing of the concrete at the foot of the column, and the connection between the column foot and the backplane became loose simultaneously. The decreasing rate of the vibration frequency declined due to the NES with varied broadband absorbing capability. It can be seen that the NES shock absorber not only has a good effect on reducing the seismic response of the structure, but more importantly, the damage of the structural nodes is greatly reduced, and therefore, the seismic capacity of the structure improved. [ABSTRACT FROM AUTHOR]

The aim of this paper is to investigate the vibration suppression effect of a nonlinear energy sink (NES) on the wind-vortex-induced vibration of deep-water jacket pipes. Based on nonlinear dynamical theories, the coupled dynamic equation of a deep-water jacket pipe with NES was established, and the nonlinear response characteristics and motion stability of the system were studied by using the multi-scale mixed harmonic balance method and Routh–Hurwitz criterion. The paper also analyzed the influence of the nonlinear stiffness and damping parameters of an NES on the dynamic response of the pipe. It is concluded that when the nonlinear stiffness of an NES increases to a certain extent, the motion response of the pipe appeared as a saddle-node and Hopf bifurcation, and the vibration amplitude of the pipe is greatly suppressed. For a system with nonlinear motion, NES damping mainly affects the range of the unstable region. For the system without nonlinear motion, the increases in NES damping will reduce the amplitude near the resonance region. Selecting proper parameters of an NES nonlinear stiffness and damping can effectively suppress the vortex-induced vibration of pipes. [ABSTRACT FROM AUTHOR]

Gesneriaceae plant family is comprised of resurrection species, namely Boea hygrometrica and Paraboea rufescens, that are native to the Southeast Asia and Haberlea rhodopensis, Ramonda myconi, and Ramonda serbica, which are mainly found in the Balkan Peninsula. Haberlea rhodopensis is known to be able to survive extreme and prolonged dehydration. Study was carried out after the dried plant Haberlea rhodopensis Friv. had been hydrated and had reached its fresh state. Two juice samples were collected from the plant blossom: The first sample was prepared with 1% filtered water through a patented EVOdrop device. Then the sample was saturated with hydrogen with EVOdrop booster to a concentration of 1.2 ppm, pH = 7.3, ORP = −390 mV. This first sample was prepared with filtered tap water from Sofia, Bulgaria. The second sample, which was a control one, was developed with tap water from Sofia, Bulgaria, consisting of 1% solutions of Haberlea rhodopensis. A study revealed that during the drying process in H. rhodopensis the number of free water molecules decreases, and water dimers are formed. The aim of our study was to determine the number of water molecules in clusters in 1% solutions of hydrated H. rhodopensis plants. Results were analyzed according to the two types of water used in the experiment. Th EVOdrop device is equipped with an ultranano membrane and rotating jet nozzle to create a vortex water and saturation thanks to a second device EVObooster to obtain hydrogen-rich water. In the current study Hydrogen-rich water is referred to as Hydrogen EVOdrop Water (HEW). Research was conducted using the following methods—spectral methods non-equilibrium energy spectrum (NES) and differential non-equilibrium energy spectrum (DNES), mathematical models, and study of the distribution of water molecules in water clusters. In a licensed Eurotest Laboratory, the research of tap water before and after flowing through the EVOdrop device was proven. Studies have been carried out on the structuring of water molecule clusters after change of hydrogen bond energies. The restructuring comes with rearrangement of water molecules by the energy levels of hydrogen bonds. Local extrema can be observed in the spectrum with largest amount of water molecules. The structural changes were tested using the NES and DNES spectral methods. The conducted research proved that the application of EVOdrop device and EVObooster changes the parameters of water to benefit hydration and health.

Epstein–Barr virus (EBV), the pathogen of several human malignancies, encodes many proteins required to be transported into the nucleus for viral DNA reproduction and nucleocapsids assembly in the lytic replication cycle. Here, fluorescence microscope, mutation analysis, interspecies heterokaryon assays, co-immunoprecipitation assay, RNA interference, and Western blot were performed to explore the nuclear import mechanism of EBV encoded BLLF2 protein. BLLF2 was shown to be a nucleocytoplasmic shuttling protein neither by a chromosomal region maintenance 1 (CRM1)- nor by a transporter associated with antigen processing (TAP)-dependent pathway. Yet, BLLF2’s two functional nuclear localization signals (NLSs), NLS1 (16KRQALETVPHPQNRGR31) and NLS2 (44RRPRPPVAKRRRFPR58), were identified, whereas the predicted NES was nonfunctional. Finally, BLLF2 was proven to transport into the nucleus via a Ran-dependent and importin β1-dependent pathway. This mechanism may contribute to a more extensive insight into the assembly and synthesis of EBV virions in the nucleus, thus affording a new direction for the treatment of viruses.

Epstein–Barr virus (EBV), the pathogen of several human malignancies, encodes many proteins required to be transported into the nucleus for viral DNA reproduction and nucleocapsids assembly in the lytic replication cycle. Here, fluorescence microscope, mutation analysis, interspecies heterokaryon assays, co-immunoprecipitation assay, RNA interference, and Western blot were performed to explore the nuclear import mechanism of EBV encoded BLLF2 protein. BLLF2 was shown to be a nucleocytoplasmic shuttling protein neither by a chromosomal region maintenance 1 (CRM1)- nor by a transporter associated with antigen processing (TAP)-dependent pathway. Yet, BLLF2's two functional nuclear localization signals (NLSs), NLS1 (16KRQALETVPHPQNRGR31) and NLS2 (44RRPRPPVAKRRRFPR58), were identified, whereas the predicted NES was nonfunctional. Finally, BLLF2 was proven to transport into the nucleus via a Ran-dependent and importin β1-dependent pathway. This mechanism may contribute to a more extensive insight into the assembly and synthesis of EBV virions in the nucleus, thus affording a new direction for the treatment of viruses. [ABSTRACT FROM AUTHOR]

• A new high-speed digital pulse signal acquisition and processing (SAQP) system based on micro telecommunications computing architecture (MTCA) is developed, and realizes the first application of MTCA on EAST. • The new SAQP system is capable to process and transfer data in real time. • Analyzed the characteristics of two trigger detection methods and applied them to baseline restoration, pulse processing and pile-up detection. • The real-time algorithm possesses the capability for real-time baseline restoration, n- γ discrimination, pulse amplitude analysis, pile-up event detection and dynamic pulse recording window for recording entire pulse waveform. Neutron emission spectroscopy (NES) diagnosis is an important technique in high-power thermonuclear fusion experiments for studying fast ions. In the fusion NES measurement on the Experimental Advanced Superconducting Tokamak (EAST), the liquid scintillator detector was employed. This selection was based on the detector's high sensitivity, fast time-response and superior n- γ discrimination properties. In order to meet the demands of high-parameter experiments and fully leverage the diagnostic capabilities, a new signal acquisition and processing (SAQP) system based on Micro-telecommunications computing architecture (MTCA) was developed equipped with real-time processing capabilities. The new SAQP system aims to perform real-time acquisition, processing and storage of neutron and gamma flux data from the NES system, allowing the possibility of maximum count rates of 2 Mcps during the EAST experiment. This paper presents the real-time algorithm implemented on field programmable gate array (FPGA). It possesses the capability for real-time baseline restoration, n- γ discrimination, pulse amplitude analysis, pile-up event detection and dynamic pulse recording window for recording entire pulse waveforms. The new SAQP system, including the integrated real-time algorithm, underwent detailed testing with both a signal generator and a neutron generator. The experimental results indicate that the real-time algorithm successfully achieve all expected functions, enhancing performance in n- γ discrimination and dynamically recording entire pulse waveforms at high count rates without data loss. [ABSTRACT FROM AUTHOR]

The aim of this paper is to investigate the vibration suppression effect of a nonlinear energy sink (NES) on the wind-vortex-induced vibration of deep-water jacket pipes. Based on nonlinear dynamical theories, the coupled dynamic equation of a deep-water jacket pipe with NES was established, and the nonlinear response characteristics and motion stability of the system were studied by using the multi-scale mixed harmonic balance method and Routh–Hurwitz criterion. The paper also analyzed the influence of the nonlinear stiffness and damping parameters of an NES on the dynamic response of the pipe. It is concluded that when the nonlinear stiffness of an NES increases to a certain extent, the motion response of the pipe appeared as a saddle-node and Hopf bifurcation, and the vibration amplitude of the pipe is greatly suppressed. For a system with nonlinear motion, NES damping mainly affects the range of the unstable region. For the system without nonlinear motion, the increases in NES damping will reduce the amplitude near the resonance region. Selecting proper parameters of an NES nonlinear stiffness and damping can effectively suppress the vortex-induced vibration of pipes.

3D printing (also known as additive manufacturing) has been developed for more than 30 years. The applications of 3D printing have been increasingly extended to a variety of engineering fields in recent years. The sandwich material with a high strength and overall low density is a kind of artificial material that has been extensively used in various industrial and daily life applications. This paper presents a comprehensive vibration analysis and passive control technique for a cantilevered sandwich beam with an hourglass lattice truss core fabricated with 3D printing technology. The governing equation of the beam is established by using a homogenized model and the Hamilton's principle, from which the natural frequencies are determined. The theoretical model is verified by the results from the existing literature and the finite element analysis. The frequency response of the sandwich beam measured experimentally further validates the proposed model. Subsequently, a non-linear energy sink (NES) is proposed for being employed to passively suppress the vibration of the sandwich beam. A parametric study based on the theoretical model confirms the viability of using NES to effectively control the vibration of the sandwich beam. This work presents a good demonstration of using 3D printing technology for fabricating sandwich beams with a complicated lattice core. More importantly, some guidelines regarding the dynamic analysis of sandwich beams are provided. In addition, the analytical method presented in this work provides a potential means to theoretically explore the advantages of using sandwich beams for energy harvesting in the future.

We previously demonstrated that W proteins from different Newcastle disease virus (NDV) strains localize in either the cytoplasm (e.g., NDV strain SG10) or the nucleus (e.g., NDV strain La Sota). To clarify the mechanism behind these cell localization differences, we overexpressed W protein derived from four different NDV strains or W protein associated with different cellular regions in Vero cells. This revealed that the key region for determining W protein localization is from 180 to 227 amino acids (aa). Further experiments found there is a nuclear export signal (NES) motif in the W protein at 211 to 224 aa. W protein could be transported into the nucleus via interaction with KPNA1, KPNA2, and KPNA6 in a nuclear localization signal-dependent manner, and W protein containing an NES was transported back to the cytoplasm in a chromosomal maintenance 1 (CRM1)-independent manner. Interestingly, we observed that the cytoplasm-localized W protein colocalizes with mitochondria. We rescued the NES-deletion W protein NDV strain rSG10-DWC/WDNES using an NDV reverse genetics system and found that the replication ability, virulence, and pathogenicity of an NDV strain were all higher when the W protein cellular localization was in the nucleus rather than the mitochondria. Further experiments revealed that W protein nuclear localization reduced the expression of IFN- b otherwise stimulated by NDV. Our research reveals the mechanism by which NDV W protein becomes localized to different parts of the cell and demonstrates the outcomes of nuclear or cytoplasmic localization both in vitro and in vivo, laying a foundation for subsequent functional studies of the W protein in NDV and other paramyxoviruses. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) remains the leading cause of cancer-related deaths with the lowest five-year survival rates among all of the human cancers. Multiple factors contribute to its poor outcome, including intratumor heterogeneity, along with migratory and invasive capacities of tumour cells. Over the last several years Doublecortin (DCX) has been one of the debatable factors influencing GBM cells’ migration. To resolve DCX’s ambiguous role in GBM cells’ migration, we set to analyse the expression patterns of DCX along with Nestin (NES) and Oligodendrocyte lineage transcription factor 2 (OLIG2) in 17 cases of GBM, using immunohistochemistry, followed by an analysis of single-cell RNA-seq data. Our results showed that only a small subset of DCX positive (DCX+) cells was present in the tumour. Moreover, no particular pattern emerged when analysing DCX+ cells relative position to the tumour margin. By looking into single-cell RNA-seq data, the majority of DCX+ cells were classified as non-cancerous, with a small subset of cells that could be regarded as glioma stem cells. In conclusion, our findings support the notion that glioma cells express DCX; however, there is no clear evidence to prove that DCX participates in GBM cell migration.

Chromosome region maintenance 1 (CRM1) exports nuclear export signal (NES) containing cargos from nucleus to cytoplasm and plays critical roles in cancer and viral infections. Biochemical and biophysical studies on this protein were often obstructed by its low purification yield and stability. With the help of PROSS server and NES protection strategy, we successfully designed three small fragments of CRM1, each made of four HEAT repeats and capable of binding to NESs in the absence of RanGTP. One of the fragments, C7, showed dramatically improved purification yield, thermostability, mechanostability, and resistance to protease digestion. We showed by isothermal titration that the protein kinase inhibitor NES binds to C7 at 1.18 μM affinity. Direct binding to C7 by several reported CRM1 inhibitors derived from plants were verified using pull‐down assays. These fragments might be useful for the development of CRM1 inhibitors towards treatment of related diseases. The strategy applied here might help to tackle similar problems encountered in different fields. [ABSTRACT FROM AUTHOR]

Replication protein A (RPA), a heterotrimeric complex, is the major single‐stranded DNA binding protein in eukaryotes. Recently, we characterized RPA from Trypanosoma cruzi, showing that it is involved in DNA replication and DNA damage response in this organism. Better efficiency in differentiation from epimastigote to metacyclic trypomastigote forms was observed in TcRPA‐2 subunit heterozygous knockout cells, suggesting that RPA is involved in this process. Here, we show that RPA cellular localization changes during the T. cruzi life cycle, with RPA being detected only in the cytoplasm of the metacyclic and bloodstream trypomastigotes. We also identify a nuclear export signal (NES) in the trypanosomatid RPA‐2 subunit. Mutations in the negatively charged residues of RPA‐2 NES impair the differentiation process, suggesting that RPA exportation affects parasite differentiation into infective forms. [ABSTRACT FROM AUTHOR]

Current study was aimed to evaluate the relationship between emotional eating and night eating syndrome (NES) with sleep quality among adolescents in Tabriz-Iran. The current study was conducted among eighty adolescent boys aged 12–16 years old from Tabriz-Iran. Night eating syndrome and Emotional eating were measured by validated specific questionnaires. Pittsburgh Sleep Quality Index questionnaire (PSQI) was used for assessment of sleep quality. Emotional and very emotional eaters had significantly higher protein and fat intake. Among components of PSQI, subjective sleep quality, sleep disturbances and daytime dysfunction scores among emotional and very emotional eaters were significantly higher. Moreover, adolescents with NES, had higher PSQI score and lower carbohydrate intake; whereas, intake of fat among NES group was significantly higher (P < 0.05). Our results indicated poor sleep quality and higher dietary fat intake among adolescents with emotional eating disorder and NES. Therefore, it is necessary to consider healthy nutritional pattern including low fat intake in prevention of developing emotional eating and NES among adolescents. [ABSTRACT FROM AUTHOR]

Automatic generation of artificial players is an important subject for the videogames industry. Different strategies have been proposed to implement realistic and intelligent agents for gameplaying and verification. This article presents a parallel evolutionary approach for the automation of computer player generation for video games. A learning pipeline model is defined to study the generation problem for Nintendo Entertainment System games composed of three stages: objective inference, objective refinement and artificial intelligence generation. Two case studies based on the defined pipeline are presented: an evolutionary algorithm to learn how to play the game Pinball, offloading the evaluation of the fitness function to a Xeon Phi coprocessor, and a full pipeline implementation that uses neuroevolution to generate RNNs that can play different games successfully. Results show that the proposed pipeline can be applied for the automatic generation of artificial players for the studied games. • Parallel evolutionary approaches for the automation of computer player generation for video games are introduced. • A learning pipeline model is defined to study the generation problem for Nintendo Entertainment System games. • A parallel evolutionary algorithm using Xeon Phi to learn how to play the game Pinball is presented. • A full pipeline implementation that uses neuroevolution to generate RNNs for playing different games is introduced. [ABSTRACT FROM AUTHOR]

In order to solve the vibration and energy supply problems in aerospace engineering, an nonlinear vibration absorber integrated into an energy harvester with inerters was designed. The nonlinear vibration absorber was built based on the nonlinear energy sink (NES) in which the traditional inertial components were replaced with inerters, and the energy harvester based on the giant magnetostrictive material (GMM) was integrated into this device. This NES-I-GMM device achieves vibration absorption and energy collection simultaneously. Under the background of the whole satellite vibration reduction, the modeling, simulation and analysis were carried out, and the effects of vibration reduction and energy collection were investigated through numerical computation. The numerical results show that, the NES-I-GMM device works well in vibration reduction and vibration energy collection under reasonable parameters. [ABSTRACT FROM AUTHOR]

Introduction: Night Eating Syndrome (NES) refers to an abnormal eating behavior which presents as evening hyperphagia consuming >25% calorie intake and/or nocturnal awaking with food ingestion which occurs ≥2 times per week. Although the syndrome has been described more than seven decades ago, the literature has been growing slowly on its etiology, diagnosis, and treatment. Areas covered: The proposed treatment options for NES are all at a case-study level. Moreover, our understanding of its etiology, comorbidities, and diagnosis is still premature. We performed a literature review in Medline/PubMed to identify all the studies proposing a management plan for NES and summarized all the existing data on its diagnosis and treatment. Expert opinion: To date, none of the proposed treatment options for NES have been promising and long-term data on its efficacy is lacking. The slow growth of evidence on this debilitating but underreported condition may be due to unawareness among clinicians, under-reporting by patients, and unrecognized diagnostic criteria. Objective screening of symptoms during office visits especially for patients at a high-risk for NES will identify more patients suffering from the syndrome. [ABSTRACT FROM AUTHOR]

Fennel (Foeniculum vulgare Mill.) is a member of family Apiaceae. Trans-anethole, the major component of Fennel essential oil (FEO), possesses antioxidant and hepatoprotective effects. Transdermal nanoemulsions (NEs) are advanced colloidal systems for systemic and controlled drug delivery through the stratum corneum barrier. FEO NEs were prepared using the oil Lauroglycol™ 90, as it provides a larger NE existence zone than Captex® 300, in the constructed phase diagrams. Six systems were prepared using Tween20/propylene glycol (S/CoS) in the ratios 2:1 and 3:1 with oil to S/CoS mass ratios 1:9, 2:8 and 3:7. Physicochemical characterization revealed optimum properties regarding thermodynamic stability, droplet size and pH with a Newtonian flow pattern. In vitro permeation study in rat skin revealed the highest cumulative amount permeated (µg/cm2), flux and permeability coefficient values for F4 made up of 2% FEO, 4.67% Lauroglycol™ 90, 60% S/CoS in the ratio 3:1. Results of the in vivo hepatic dysfunction study in rats indicate promising significant amelioration of liver function reflected in ALT, AST, ALP, bilirubin, albumin, malondialdehyde and ammonia plasma levels. The results signify the promising approach of FEO NEs in achieving remedy of liver toxicity. The most promising effect is inherent to F4 which imparts a more positive effect than FEO. [ABSTRACT FROM AUTHOR]

Highlights • A generalized transmissibility is proposed for the vibration absorption system. • The root mean square is employed for redefined the transmissibility. • The quasi-periodic motion is an indication of the optimal transmissibility. • Two evaluation approaches based on the energetics and transmissibility are compared. • A base for the design and parameter optimization of the NES absorbers is provided. Abstract A generalized transmissibility is proposed to evaluate nonlinear vibration absorbers. Due to possible existence of higher order harmonics and aperiodic motion, the root mean square is employed to define the transmissibility. The transmissibility beyond harmonic motion is applied to measure vibration reduction of a structure coupled with a nonlinear energy sink. Periodic steady-state responses of the coupled system are analytically predicted by the method of harmonic balance, and the stabilities of the responses are determined. The effects of parameters of the nonlinear energy sink on the transmissibility are explored based on harmonic balance solutions and numerical simulations. Phase portraits, Poincaré map and frequency spectrum reveal that quasi-periodic motions occur when periodic responses are unstable. Finally, two evaluation approaches based on the energetics and the transmissibility are compared. The investigation demonstrates the quasi-periodic motion is an indication of the optimal transmissibility. The performance of nonlinear energy sink absorbers may be extremely sensitive to parameter variations. [ABSTRACT FROM AUTHOR]

Abstract A nonlinear magnetic vibration absorber is presented and used to control vibration of a three–storey structure. A distinctive feature of the absorber concerns its versatility for tuning the linear and nonlinear stiffness coefficients, depending on simple geometric design parameters such as the distance between fixed magnets and the moving one. In particular, the absorber can be set either as a nonlinear tuned vibration absorber, a nonlinear energy sink, or a bistable tuned vibration absorber, according to whether the linear stiffness term is positive, vanishing, or negative. The response of the primary structure and the vibration mitigation are investigated in the cases of impulsive shock, free vibration with imposed initial displacement, and single frequency excitation. Significant reductions of the primary structure vibrations are obtained for the three cases investigated, showing the ability of using a vibration absorber only relying on magnetic forces for passive control. The detailed comparisons of the absorbers performance show that, in this case study, no general guidelines can be easily deduced for selecting one of the three tunings for a nonlinear absorber. Depending on the excitation, the vibratory levels, and the frequency content of the excitation, the three configurations show advantages and drawbacks that are discussed. [ABSTRACT FROM AUTHOR]

Highlights • RGNEF, an ALS-related RNA binding protein, localizes in the cytoplasm and the nucleus. • The PH domain of RGNEF contain a functional bipartite NLS. • The PH domain of RGNEF has a leptomycin-B sensitive NES. • This is first description of an overlapping NLS/NES pair embedded within a PH domain. Abstract Rho Guanine Nucleotide Exchange Factor (RGNEF) is a 190 kDa protein implicated in both amyotrophic lateral sclerosis (ALS) and cancer. Under normal physiological conditions, RGNEF is predominantly cytoplasmic with moderate levels of nuclear localization. We have identified a 23-amino acid region containing a bipartite nuclear localization signal (NLS) within the Pleckstrin Homology (PH) domain of RGNEF, which when deleted or mutated abolishes the nuclear localization of this protein. Fusion proteins containing only the PH domain demonstrated that this region by itself is able to translocate a 160 kDa protein to the nucleus. Interestingly, we also detected a nuclear export signal (NES) within the linker region of this bipartite NLS which is able to export from the nucleus a fusion protein containing two NLSs. Experiments using Leptomycin-B -an inhibitor of nuclear export- confirmed that this region promotes nuclear export in an exportin-1 dependent manner. This study is the first report demonstrating either of these signals embedded within a PH domain. Notably, this is also the first description of a functional overlapped NLS/NES signal. [ABSTRACT FROM AUTHOR]

Maeda H Mohammad,1 Ahmed M Al-Shammari,1 Ahmad Adnan Al-Juboory,2 Nahi Y Yaseen1 1Experimental Therapy Department, Iraqi Center of Cancer and Medical Genetic Research, Al-Mustansiriyah University, 2Department of Surgery, Neuroscience Hospital, Baghdad, Iraq Abstract: The in vitro isolation, identification, differentiation, and neurogenesis characterization of the sources of mesenchymal stem cells (MSCs) were investigated to produce two types of cells in culture: neural cells and neural stem cells (NSCs). These types of stem cells were used as successful sources for the further treatment of central nervous system defects and injuries. The mouse bone marrow MSCs were used as the source of the stem cells in this study. β-Mercaptoethanol (BME) was used as the main inducer of the neurogenesis pathway to induce neural cells and to identify NSCs. Three types of neural markers were used: nestin as the immaturation stage marker, neurofilament light chain as the early neural marker, and microtubule-associated protein 2 as the maturation marker through different time intervals in the neurogenesis process starting from the MSCs, (as undifferentiated cells), NSCs, production stages, and toward neuron cells (as differentiated cells). The results of different exposure times to BME of the neural markers analysis done by immunocytochemistry and real time-polymerase chain reaction helped us to identify the exact timing for the neural stemness state. The results showed that the best exposure time that may be used for the production of NSCs was 6 hours. The best maintenance media for NSCs were also identified. Furthermore, we optimized exposure to BME with different times and concentrations, which could be an interesting way to modulate specific neuronal differentiation and obtain autologous neuronal phenotypes. This study was able to characterize NSCs in culture under differentiation for neurogenesis in the pathway of the neural differentiation process by studying the expressed neural genes and the ability to maintain these NSCs in culture for further differentiation in thousands of functional neurons for the treatment of brain and spinal cord injuries and defects. Keywords: mesenchymal stem cells, neural stem cells, NES, NF-L, MAP-2

The nuclear export receptor CRM1 (XPO1) recognizes and binds specific sequence motifs termed nuclear export signals (NESs) in cargo proteins. About 200 NES motifs have been identified, but over a thousand human proteins are potential CRM1 cargos, and most of their NESs remain to be identified. On the other hand, the interaction of NES peptides with the “NES-binding groove” of CRM1 was studied in detail using structural and biochemical analyses, but a better understanding of CRM1 function requires further investigation of how the results from these in vitro studies translate into actual NES export in a cellular context. Here we show that a simple cellular assay, based on a recently described reporter (SRVB/A), can be applied to identify novel potential NESs motifs, and to obtain relevant information on different aspects of CRM1-mediated NES export. Using cellular assays, we first map 19 new sequence motifs with nuclear export activity in 14 cancer-related proteins that are potential CRM1 cargos. Next, we investigate the effect of mutations in individual NES-binding groove residues, providing further insight into CRM1-mediated NES export. Finally, we extend the search for CRM1-dependent NESs to a recently uncovered, but potentially vast, set of small proteins called micropeptides. By doing so, we report the first NES-harboring human micropeptides.

The performance of non-linear absorbers for suppression of the structure vibrations depends on the setting of the absorbers' parameters to a certain extent. A slowly varying dynamical system under investigation in the existing work is comprised of a linear oscillator coupled with an attached non-linear absorber called non-linear energy sink (NES). Slowly varying equations of the coupled system are achieved first by using the complex averaging method, and trajectory features of the slowly varying system are analysed. On that basis, the non-linear cubic stiffness design method is proposed. Considering that different damping coefficients of the NES impose a large impact on both system energy transfer and energy dissipation between the main structure and the NES, necessary damping conditions for the targeted energy transfer (TET) are obtained by using the phase trajectory analysis. With the proposed method, structure parameters of the NES are designed to get maximum absorbing effects. Finally, all these conclusions about parameters design for the NES are verified by simulation analysis. The simulation results demonstrate that the optimal vibration reduction effectiveness can be achieved with reasonably designed stiffness and damping.

Purpose: Differentiating between epileptic seizures, convulsive syncope or non-epileptic seizures is a common diagnostic challenge in the acute setting. Plasma-lactate levels have previously been proposed as a tool to aid in differentiating between epileptic and non-epileptic seizures, with lower levels of lactate suggesting a non-epileptic origin. The aim of this study was to investigate levels of lactate in non-epileptic seizures.Methods: Healthy subjects were asked to perform a simulated seizure lasting no more than 5 min. Venous blood samples were taken before and immediately after the simulated seizure and analyzed using an ABL90 FLEX yielding information about lactate, pH, pO2,pCO2, electrolytes and plasma glucose.Results: 8 people participated in the study: 6 men and 2 women aged 27-45. The average pre-simulation lactate was 1.1 mmol/L while the average pH was 7.39. The average post-simulation lactate was 10.2 mmol/L while the average pH was 7.25. This means an average increase in plasma-lactate of 9.1 mmol/L and an average drop of 0.15 in pH.Conclusion: Our data indicate that high rises in lactate levels are not specific for an epileptic origin. Further study of lactate as a marker for epileptic seizures is warrented. [ABSTRACT FROM AUTHOR]

Recent studies have demonstrated the interference of nucleocytoplasmic trafficking with the establishment and maintenance of various cancers. Nucleocytoplasmic transport is highly regulated and coordinated, involving different nuclear transport factors or receptors, importins and exportins, that mediate cargo transport from the cytoplasm into the nucleus or the other way round, respectively. The exportin CRM1 (Chromosome region maintenance 1) exports a plethora of different protein cargoes and ribonucleoprotein complexes. Structural and biochemical analyses have enabled the deduction of individual steps of the CRM1 transport cycle. In addition, CRM1 turned out to be a valid target for anticancer drugs as it exports numerous proto-oncoproteins and tumor suppressors. Clearly, detailed understanding of the flexibility, regulatory features and cooperative binding properties of CRM1 for Ran and cargo is a prerequisite for the design of highly effective drugs. The first compound found to inhibit CRM1-dependent nuclear export was the natural drug Leptomycin B (LMB), which blocks export by competitively interacting with a highly conserved cleft on CRM1 required for nuclear export signal recognition. Clinical studies revealed serious side effects of LMB, leading to a search for alternative natural and synthetic drugs and hence a multitude of novel therapeutics. The present review examines recent progress in understanding the binding mode of natural and synthetic compounds and their inhibitory effects.

Specialised literature presents education and training as a determining factor for entrepreneurship. However, time and time again experts at the Global Entrepreneurship Monitor (GEM) have stated that it’s one lowest, and sometimes the least, valued elements in this area. Therefore, the objective of this study is to analyse the state of entrepreneurship education and training in its different stages within the countries and regions that participated in GEM 2012. Specifically, what is sought is, based on the opinion of the experts, the state of entrepreneurship training and education in each level analysed in GEM, generically as well as by country, while looking at the possible differences (strengths and weaknesses) that appear in each one. Furthermore, this is paired with a national analysis that examines the situation of the different participating regions in the study. In order to carry out the analysis, the 2012 NES database is used. In that edition, a total of 69 countries participated and, in the case of Spain, there were 14 regions all with 36 experts in each. The data processing is carried out using the Rasch model for measurement. The preliminary results show that, in general, university level education geared towards entrepreneurship is more highly developed than at the lower levels of education, such as in secondary and primary education. Nevertheless, the individual analysis makes it possible to detect differences between countries and regions.

Contact occurrence between disk and stator as result of undesirable vibrations produced by eccentricity of the disk is one of the most destructive and common phenomena in rotor dynamics systems. In this work, utilizing tuned mass damper (TMD) and nonlinear energy sink (NES) are suggested as a solution for preventing contact occurrence. The mass and angular position of absorbers determine their efficiency for resisting the eccentricity force produced by the disk, and their stiffness and damping coefficients determine the displacement scope of the absorber. In order to efficiently design absorbers, optimization is proposed. In this suggested optimization process, complex averaging method is used in order for deriving the equations of motion of the system in presence of dynamic absorbers at the steady state condition. Afterwards, for determining trustworthiness of each absorber’s performance, system’s behavior is studied for different values of its parameters such as rotational speed, stiffness, clearance and eccentricity in presence of each absorber. From the obtained results, it can be perceived that TMD and NES are as efficient as possible and they have exactly the same positive influence on the system’s vibrations. The reliability of the proposed optimization process can be determined by the results. [ABSTRACT FROM AUTHOR]

Nuclear export receptor CRM1 binds highly variable nuclear export signals (NESs) in hundreds of different cargoes. Previously we have shown that CRM1 binds NESs in both polypeptide orientations (Fung et al., 2015). Here, we show crystal structures of CRM1 bound to eight additional NESs which reveal diverse conformations that range from loop-like to all-helix, which occupy different extents of the invariant NES-binding groove. Analysis of all NES structures show 5-6 distinct backbone conformations where the only conserved secondary structural element is one turn of helix that binds the central portion of the CRM1 groove. All NESs also participate in main chain hydrogen bonding with human CRM1 Lys568 side chain, which acts as a specificity filter that prevents binding of non-NES peptides. The large conformational range of NES backbones explains the lack of a fixed pattern for its 3-5 hydrophobic anchor residues, which in turn explains the large array of peptide sequences that can function as NESs.

DEAD-box helicase 3, X-linked (DDX3X) regulates the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)-mediated antiviral response, but can also be a host factor contributing to the replication of viruses of significance to human health, such as human immunodeficiency virus type 1 (HIV-1). These roles are mediated in part through its ability to actively shuttle between the nucleus and the cytoplasm to modulate gene expression, although the trafficking mechanisms, and impact thereof on immune signaling and viral infection, are incompletely defined. We confirm that DDX3X nuclear export is mediated by the nuclear transporter exportin-1/CRM1, dependent on an N-terminal, leucine-rich nuclear export signal (NES) and the monomeric guanine nucleotide binding protein Ran in activated GTP-bound form. Transcriptome profiling and ELISA show that exportin-1-dependent export of DDX3X to the cytoplasm strongly impacts IFN-β production and the upregulation of immune genes in response to infection. That this is key to DDX3X’s antiviral role was indicated by enhanced infection by human parainfluenza virus-3 (hPIV-3)/elevated virus production when the DDX3X NES was inactivated. Our results highlight a link between nucleocytoplasmic distribution of DDX3X and its role in antiviral immunity, with strong relevance to hPIV-3, as well as other viruses such as HIV-1.

The bHLH-PAS (basic helix-loop-helix/ Period-ARNT-Single minded) proteins are a family of transcriptional regulators commonly occurring in living organisms. bHLH-PAS members act as intracellular and extracellular “signals” sensors, initiating response to endo- and exogenous signals, including toxins, redox potential, and light. The activity of these proteins as transcription factors depends on nucleocytoplasmic shuttling: the signal received in the cytoplasm has to be transduced, via translocation, to the nucleus. It leads to the activation of transcription of particular genes and determines the cell response to different stimuli. In this review, we aim to present the current state of knowledge concerning signals that affect shuttling of bHLH-PAS transcription factors. We summarize experimentally verified and published nuclear localization signals/nuclear export signals (NLSs/NESs) in the context of performed in silico predictions. We have used most of the available NLS/NES predictors. Importantly, all our results confirm the existence of a complex system responsible for protein localization regulation that involves many localization signals, which activity has to be precisely controlled. We conclude that the current stage of knowledge in this area is still not complete and for most of bHLH-PAS proteins an experimental verification of the activity of further NLS/NES is needed.

ZO-2 is a cytoplasmic protein of tight junctions (TJs). Here, we describe ZO-2 involvement in the formation of the apical junctional complex during early development and in TJ biogenesis in epithelial cultured cells. ZO-2 acts as a scaffold for the polymerization of claudins at TJs and plays a unique role in the blood−testis barrier, as well as at TJs of the human liver and the inner ear. ZO-2 movement between the cytoplasm and nucleus is regulated by nuclear localization and exportation signals and post-translation modifications, while ZO-2 arrival at the cell border is triggered by activation of calcium sensing receptors and corresponding downstream signaling. Depending on its location, ZO-2 associates with junctional proteins and the actomyosin cytoskeleton or a variety of nuclear proteins, playing a role as a transcriptional repressor that leads to inhibition of cell proliferation and transformation. ZO-2 regulates cell architecture through modulation of Rho proteins and its absence induces hypertrophy due to inactivation of the Hippo pathway and activation of mTOR and S6K. The interaction of ZO-2 with viral oncoproteins and kinases and its silencing in diverse carcinomas reinforce the view of ZO-2 as a tumor regulator protein.