Tag Archives: ARQ 621

We next sought insight regarding the mechanism

We next sought insight regarding the mechanism that links regulation of pluripotency with that of enhanced maintenance of genetic integrity in pluripotent cells. The discovery that fully pluripotent ARQ 621 can be derived by transduction of differentiated cells starting with four (Takahashi and Yamanaka, 2006), or fewer (Huangfu et al., 2008; Kim et al., 2009), key regulatory genes suggests that small numbers of factors control entire networks of downstream genes and gene products necessary to establish the fate of a cell. We tested the hypothesis that small numbers of pluripotency factors interact with large numbers of genetic integrity genes in pluripotent cells. We found evidence for extensive interactions between the pluripotency and genetic integrity gene networks. While further research will be needed to fully interrogate the functionality of each of the molecular interactions predicted by our analysis, the predicted interactions we report can account for the potential regulation of 22–50% of DNA repair gene and 21–35% of cell death gene differential expression in pluripotent cells. Undoubtedly, the extent of interactions between these two gene networks would be even greater if additional pluripotency factors and/or higher order interactions were considered. Indeed, the involvement of intermediary regulators linking the pluripotency and genetic integrity gene networks affords potential opportunities for additional levels of coordination of expression of downstream genetic integrity pathways.

In summary, our data indicate the Disposable Soma Theory (Kirkwood, 1977) applies to pluripotent cells as well as to germ cells. Further, we provide insight into the mechanism by which the pluripotency gene network interacts with the genetic integrity gene network to establish and maintain enhanced genetic integrity in pluripotent cells. This, in turn, suggests that key factors might be monitored and/or manipulated to maintain optimal genetic integrity in stem cells or their differentiated derivatives intended for use in therapeutic applications.
The following are the supplementary data related to this article.


Duchenne muscular dystrophy (DMD) is characterized by a progressive muscle degeneration caused by mutations in one of the largest gene known, that of dystrophin (Koenig et al., 1987). There is no curative treatment at present and death usually occurs within 10 to 15years of symptom onset, typically from breathing complications and cardiomyopathy (Emery, 1993). Current promising clinical and pre-clinical approaches include gene editing, exon skipping, gene therapy and stem cell therapies (Fairclough et al., 2013). Of these, ARQ 621 exon skipping is currently most advanced, where the delivery or expression of small RNAs affecting splicing is used to remove a mutated dystrophin mRNA exon. However, it may not offer a cure for all patients, depending on the type of the dystrophin gene mutation (Brolin and Shiraishi, 2011).
Other gene therapy strategies aim at the delivery of a functional dystrophin coding sequence into the dystrophic muscle of DMD patients. Viral vectors are commonly used in gene therapy for their efficient gene delivery and integration in the myofiber genomes, but their use may be limited to the expression of truncated dystrophin variants, due to cargo-size limitations of the viral capsid (Phelps et al., 1995; Duan et al., 1998). In addition, safety concerns were linked to malignant cell transformation due to insertional mutagenesis linked to certain viral vectors (Hacein-Bey-Abina et al., 2008; Lewinski and Bushman, 2005), whereas the immunogenicity of the viral particles is also a concern (Raper et al., 2003; Yei et al., 1994). Thus, alternatives to viral vector gene transfer are also currently assessed. For instance, an alternative gene transfer method is the in vivo electroporation of naked plasmids containing the dystrophin gene, which has little transgene size constraint and low immunogenicity. Plasmids or synthetic chromosomes can persist in the muscle fiber without genome integration and transgene expression can be relatively stable in the non-dividing myofibers (Puttini et al., 2009; Tedesco et al., 2011). However, the long-term expression of the transgene may be reduced by gradual silencing effects and/or by the loss of the episomal DNA.

br Materials and methods br Results and discussion br Conclusions

Materials and methods

Results and discussion

According to reaction-based kinetic models, the best correlation was obtained for the pseudo-second order model which presented higher values of R2 (greater than 0.99) and confirm that the protein sorption kinetics of OPN extract have followed this mechanism for protein adsorption. The results of pseudo-second order model were similar to the experimental observations with errors of −0.80, 7.89 and 10.02% for treatments at 30, 45 and 60 °C, respectively. Elovich model showed that desorption constant increases and initial adsorption rate decreases with increase of temperature which indicated that the process is endothermic, and that the protein adsorption by the activated carbon is intra-particle diffusion controlled. SEM demonstrated that the mechanism of non-diffusive sorption is involved in adsorbed protein of OPN extract on the porous matrix of activated carbon.

The authors wish to thank the Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG-Brazil), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq – Brazil) and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES – Brazil) for their financial support of this research.

The existence of colossal magnetoresistance (CMR), ferromagnetic (FM)–paramagnetic (PM) transition, and metal–insulator (MI) phase transitions (Shuyuan et al., 2013; Fan et al., 2014; Park et al., 2015) in R1−xAxMnO3 (R-trivalent rare earth ARQ 621 and A-divalent alkaline metal) perovskites culminates in significant anomalous magnetic and transport properties. The canonical type La1−xSrMnO3 (LSMO) perovskites has the double-exchange (DE) interactions along with Jahn–Teller (JT) distortions in the MnO6 octahedron (Mn atom is the center). The DE interaction and JT distortion is necessary to obtain the large magnetoresistance effects near the phase transition temperature (Von Helmolt et al., 1993; Dey et al., 2007). The literature indicates that the role of Mn atom on manganite perovskite is outstanding due to its wide application, catches the attention of comprehensive research (Zhong et al., 2015; Vaishnavi et al., 2015).
Several efforts have been made to examine the CMR associated with the lattice deformation and charge ordering (CO) of the crucial Mn–O–Mn network by doping the divalent alkaline atoms such ARQ 621 as Ca, Sr, Ba, and Pb (Agrestini et al., 2004; Siwach et al., 2008; Vikram et al., 2007) at the A-site in the manganite perovskite. It has been revealed that the magnetic and transport properties of manganite perovskites are devastated by the substitution of Mn at the B-site by any other atom (Izumi et al., 1999; Paraskevopoulos et al., 2000; Mellergard et al., 2000; Despina and Egami, 1997). The substitution on Mn-site affects the Mn3+–Mn4+ ratio and hence, the exchange interaction of Mn3+–Mn4+occurs. The mismatch of ionic radius between Mn and substituted ions has an impact on the lattice parameters of the crystal structure. Minorchange in Mn–O bond length and Mn–O–Mn bond angle in Mn3+–O–Mn4+ network (Thiele et al., 2007; Shimura et al., 1996) produces large variation in the magnetic and transport properties of manganite perovskite. Hence, the modification of Mn3+ and Mn4+ ratio generates the change in electron carrier density of Mn–O–Mn network.
Although, the stable state of Mg is Mg2+ (6 co-ordinations) having radius of 0.86 Å, which is larger than the radius of Mn3+ (0.645 Å) and Mn4+ (0.53 Å) (Thiele et al., 2007). Doping of Mg2+ replaces the Mn in manganite perovskite consequence an expansion of the unit cell than a reduction. In the present investigation, we found that, the upshot of substituting Mn by Mg on the structural and FM–PM phase transition properties of La0.7Sr0.3MnMgO3 manganite perovskite with 0.050 ≤ x ≤ 0.100.
The in-situ ultrasonic velocity/attenuation measurement is one of the exceptional and constructive methods for the comprehensive characterization of LSMMO manganite perovskites. The interaction between ultrasonic waves and the coupling in manganite perovskites, results a change in lattice. Any alteration occurring in the lattice degrees of freedom are reflected in the ultrasonic parameters like velocity and attenuation. Hence, ultrasonic parameters discovers (Sakthipandi et al., 2011; Kulandaivelu et al., 2013) the FM–PM phase exchange of any manganite perovskites.

br Influence of target hypersonic movement on radar measurements Since

Influence of target hypersonic movement on radar measurements
Since the LFM signal is one of the most famous radar signals, which is of large time-bandwidth product, and can significantly improve S/N ratio when the matching filter is performed. The PC (pulse compression) radar which emits LFM signal) is selected to discuss the problem of hypersonic target tracking in near space.
We assume that the PC radar emits the LFM signalwhere , , is the emitting pulse width, is the central carrier frequency, is the FM rate, B is the FM band width.
When the target moves at a radial speed of v, the received signal at time k can be expressed as followswhere , R0 is the target distance at time t0, c is the light speed, .
At this time, if the matched filtering technique is used to the received signal , the output of the matching filters can be expressed aswhere is the target Doppler shift. Then according to the maximum signal-to-noise ratio criterion, the signal has a maximum value at time . That is to say, the radar measurements are inevitably affected by the following dynamic biases
In order to evaluate the influence of target hypersonic movement on the tracking of near space target, the relative analysis is as follows.while the measurement errors of the conventional radar are around. That is to say, the high dynamic biases, which seriously affect the tracking of near space target, can not be neglected.

Tracking models of hypersonic sliding target in near space

Computer simulation is used to study the performance of the proposed tracking algorithm, and four methods in Section 4.1 are compared with the proposed method in this paper.


High energetic materials (HEMs) are rich sources of ARQ 621 stored in the form of chemical bonds [1]. They are thermodynamically unstable, but the kinetics of energy release can be controlled. They have found extensive use in explosives, rocket propellants and gas generators for automobile air bags [1,2]. Focus of research on HEMs has recently been to synthesize novel molecules with high energy density combined with insensitivity to hazardous stimuli [1,2]. Unfortunately, the research and development of new HECs has been very slow. RDX and HMX, which were developed many decades ago, are still being used as the main explosives due to their technological-economical characteristics such as their ready availability in large scale [2]. Powerful explosives such as CL-20 and octanitrocubane have much higher energetic performance than RDX and HMX [2,3]. But, their sensitivity to accidental stimuli is a matter of concern. Sensitivity of explosives is related to their chemical as well as physical characteristics [4]. The physical properties such as crystal size, shape, morphology, purity, inclusions and crystal defects can be altered to improve the performance of existing explosives [5,6]. Previous studies reported that the novel behaviour in deflagration to detonation transition was observed with submicron particles [7]. A few studies have indicated that the particle size of explosives influences the impact sensitivity and maximum energy output from a detonation [8]. Thus, the preparation of micrometer or sub-micrometer sized solid particles is of great interest in explosives.
However, the limited production strategies are only available for making organic nanoparticles in general compared to the large array of methods that are available for the preparation of inorganic nanoparticles. Some of the methods for the preparation of sub-micron sized HEMs includes rapid crystallisation from solvent by the addition of antisolvent [9,10], sol–gel method [11,12], rapid expansion of supercritical solution (RESS) [13,14], mechanical milling [15–17] and aero-sol method [18]. An excellent review on the various methods for the preparation of nanoenergetic materials was published recently [19]. Unfortunately, many of these techniques proved to be less attractive in large scale production of organic nano-sized materials. Among various techniques for the reduction of particle size, the antisolvent precipitation process is a simple and effective technique to produce the nanosized particles by introducing the organic solution containing an active substance to the antisolvent (e.g. water) that is solvent-miscible under rapid mixing, which generates high supersaturation leading to fast nucleation rates [20–25]. Instantaneous precipitation occurs by a rapid desolvation of the hydrophobic active ingredient in the antisolvent medium [26–29]. The antisolvent may contain hydrophilic stabilizers such as polymers or surfactants. The hydrophilic stabilizer in the antisolvent gets adsorbed on the particle surface to inhibit particle growth [20–25]. We have recently prepared nano-HECs by a simple evaporation assisted solvent-antisolvent interaction (EASAI) method using acetone as solvent at 70 °C [26,27]. The same method was also used to prepare nanodrugs [28,29]. It has been shown that the particle size can be controlled by varying a number of experimental parameters such as the concentration, ratio of solvent to antisolvent, temperature of the antisolvent during injection, stirring speed etc. Infact, a lot more experimental parameters such as ultrasonication, nozzle geometry, mixing rate, nature of solvent and nature of antisolvent also are known to affect the particle properties [30]. Although there has been some studies on the effect of many of these experimental parameters, only very few reports are there in the literature about the effects of different solvents on particle size and morphology of HECs. Here we demonstrate that particle size and even morphology of nano-HECs can be tuned by changing the solvent using the SAI method.

br Introduction The ability to anticipate where and when events

The ability to anticipate ‘where’ and ‘when’ events may occur stands as a fundamental skill which allows us to selectively orient our attention in space and time (Coull and Nobre, 1998), while ignoring a myriad of other irrelevant environmental stimuli. However, while the mechanisms underlying the orienting of attention in space (i.e., spatial orienting) have been thoroughly investigated in both adults (Corbetta and Shulman, 2002) and children (Amso and Scerif, 2015), the ability to orient attention in time (temporal orienting or TO) has slipped out of core attention research for many years (Nobre, 2001; Nobre and Kastner, 2014). This issue is of pivotal importance given the key role of temporal attention as a gating mechanism to select information for further computational processing, including perception, action, learning, memory and executive control (Correa, 2010).
Actually, attentional selection operates through time, but it ARQ 621 is also limited in time, since it depends on the structural constraints imposed by the limited capacity of the human neurocognitive system. In this sense, investigating the temporal orienting of attention from a developmental cognitive neuroscience perspective may constitute a powerful heuristic for shedding light onto the temporal attention constraints and the dynamics leading to the adult end-state. Moreover, from a clinical perspective, temporal attention has been claimed to be selectively impaired in several developmental disabilities, including dyslexia (Visser, 2014), language disorders (Dispaldro et al., 2013; Dispaldro and Corradi, 2015), Attention Deficit/Hyperactivity Disorder (Carelli and Wiberg, 2012), and autism (Ronconi et al., 2013). Therefore, a better understanding of the neurocognitive underpinnings of TO as a core selective attentional mechanism in typically developing children may open new lines of research to create early, specific intervention strategies for atypical development.
The existing literature on adult individuals shows that TO can be generated by establishing temporal expectancy a priori according to environmentally available cues, like a temporally regular structure or a discrete signal providing predictive information about the onset of a task-relevant stimulus. In both cases, TO operates by selectively biasing attentional resources at specific points in time, resulting in faster and better behavioural performance at multiple cognitive levels (Coull and Nobre, 1998; Correa and Nobre, 2008; Correa, 2010).
Once generated, temporal expectations can be further updated a posteriori as a function of (1) the sensory evidence sticky ends events actually occur when expected and (2) the elapsing time itself, which intrinsically biases the distribution of attentional and motor resources over time, a phenomenon also known as the Hazard Function or HF (Niemi and Näätänen, 1981; Luce, 1986; Nobre et al., 2007; Coull, 2009a).
In a recent event-related potential (ERP) study we showed dissociable neural signatures for expectancy generation driven by discrete, informative cues and HF-related expectancy updating (Mento et al., 2015). Specifically, the first relies on a larger centro-parietal Contingent Negative Variation (CNV) showing a modulation as a function of target predictability, with the largest CNVs for the targets with the highest predictability, in line with previous literature (Capizzi et al., 2013; Mento, 2013). By contrast, HF-related expectancy updating resulted in a sustained frontal activity, showing increasing amplitude with increasing boost of subjective expectancy as a function of the passage of time. Furthermore, the source reconstruction analyses allowed identification of the origin of the CNV in a left sensorimotor cortical network, while the HF-related ERP activity was mainly generated from the lateral prefrontal cortices. Remarkably, these findings provided converging evidence with the neuroimaging literature showing distinct parietal and frontal functional networks for generating and updating temporal expectancy, respectively (Coull et al., 2000; Vallesi et al., 2009; Vallesi, 2010; Coull, 2011).