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The level of arousal in mammals is correlated with metabolic state and specific patterns of cortical neuronal responsivity. In particular, rhythmic transitions between periods of high activity (up phases) and low activity (down phases) vary between wakefulness and deep sleep/anesthesia. Current opinion about changes in cortical response state between sleep and wakefulness is split between neuronal network-mediated mechanisms and neuronal metabolism-related mechanisms. Here, we demonstrate that slow oscillations in network state are a consequence of interactions between both mechanisms. Specifically, recurrent networks of excitatory neurons, whose membrane potential is partly governed by ATPmodulated potassium $(K_{ATP})$ channels, mediate response-state oscillations via the interaction between excitatory network activity involving slow, kainate receptor-mediated events and the resulting activation of ATP-dependent homeostatic mechanisms. These findings suggest that $K^{ATP}$ channels function as an interface between neuronal metabolic state and network responsivity in mammalian cortex.

Krüppel-like factor 6 (KLF6) is a transcription factor involved in the regulation of several cellular processes. Regarding its role in tumorigenesis, KLF6 is considered a tumor suppressor. Numerous reports demonstrate its frequent genomic loss or down-regulation, implying a functional inactivation in a broad range of human cancers. Previous work from our laboratory showed that the down-regulation of KLF6 expression in normal fibroblasts leads to cellular transformation, while its ectopic expression interferes with the oncogenic transformation triggered by activated Ras through a cell cycle arrest. We hypothesize that the growth suppressor activity of KLF6 may involve the induction of cellular senescence thereby helping to prevent the proliferation of cells at risk of neoplastic transformation. Here, we explored the association of KLF6 up-regulation in two different cellular senescence scenarios. We found that KLF6 silencing bypasses both oxidative and oncogene-induced senescence. In this context, KLF6 expression was capable to trigger cellular senescence in both normal and tumoral contexts. As such, the findings presented in this report provide insights into a potential mechanism by which KLF6 may play a suppressing role of uncontrolled or damaged cell proliferation.

Lysine acetylation is an important post-translational modification that plays a central role in eukaryotic transcriptional activation by modifying chromatin and transcription-related factors. Human pregnancy-specific glycoproteins (PSG) are the major secreted placental proteins expressed by the syncytiotrophoblast at the end of pregnancy and represent early markers of cytotrophoblast differentiation. Low PSG levels are associated with complicated pregnancies, thus highlighting the importance of studying the mechanisms that control their expression. Despite several transcription factors having been implicated as key regulators of PSG gene family expression; the role of protein acetylation has not been explored. Here, we explored the role of acetylation on PSG gene expression in the human placental-derived JEG-3 cell line. Pharmacological inhibition of histone deacetylases (HDACs) up-regulated PSG protein and mRNA expression levels, and augmented the amount of acetylated histone H3 associated with PSG 5'regulatory regions. Moreover, PSG5 promoter activation mediated by Sp1 and KLF6, via the core promoter element motif (CPE, -147/-140), was markedly enhanced in the presence of the HDAC inhibitor trichostatin A (TSA). This effect correlated with an increase in Sp1 acetylation and KLF6 nuclear localization as revealed by immunoprecipitation and subcellular fractionation assays. The co-activators PCAF, p300, and CBP enhanced Sp1-dependent PSG5 promoter activation through their histone acetylase (HAT) function. Instead, p300 and CBP acetyltransferase domain was dispensable for sustaining co-activation of PSG5 promoter by KLF6. Results are consistent with a regulatory role of lysine acetylation on PSG expression through a relaxed chromatin state and an increase in the transcriptional activity of Sp1 and KLF6 following an augmented Sp1 acetylation and KLF6 nuclear localization.

Krüppel-like factor-6 (KLF6) is a widely expressed member of the Sp1/KLF family of transcriptional regulators involved in differentiation, cell cycle control and proliferation in several cell systems. Even though the highest expression level of KLF6 has been detected in human and mice placenta, its function in trophoblast physiology is still unknown. Herein, we explored KLF6 expression and sub-cellular distribution in human trophoblast cells differentiating into the syncytial pathway, and its role in the regulation of genes associated with placental development and pregnancy maintenance. Confocal immunofluorescence microscopy demonstrated that KLF6 is expressed throughout human cytotrophoblast differentiation showing no evident modifications in its nuclear and cytoplasmic localization pattern. KLF6 transcript and protein peaked early during the syncytialization process as determined by qRT-PCR and western blot assays. Overexpression of KLF6 in trophoblast-derived JEG-3 cells showed a preferential nuclear signal correlating with enhanced expression of human β-chorionic gonadotropin (βhCG) and pregnancy-specific glycoprotein (PSG) genes. Moreover, KLF6 transactivated βhCG5, PSG5 and PSG3 gene promoters. Deletion of KLF6 Zn-finger DNA binding domain or mutation of the consensus KLF6 binding site abolished transactivation of the PSG5 promoter. Results are consistent with KLF6 playing a role as transcriptional regulator of relevant genes for placental differentiation and physiology such as βhCG and PSG, in agreement with an early and transient increase of KLF6 expression during trophoblast syncytialization.

c-Jun is a member of the early mammalian transcriptional regulators belonging to the AP-1 family, which participates in a wide range of cellular processes such as proliferation, apoptosis, tumorigenesis, and differentiation. Despite its established role in cell survival upon stress, its participation in the stress response induced by bacterial infections has been poorly investigated. To study the potential role of c-Jun in this context we choose the widely studied α-toxin produced by , a pore-forming toxin that is a critical virulence factor in the pathogenesis of these bacteria. We analyzed the effect of α-toxin treatment in the activation, expression, and protein levels of c-Jun in A549 lung epithelial cells. Furthermore, we explored the role of c-Jun in the cellular fate after exposure to α-toxin. Our results show that staphylococcal α-toxin is able to activate c-Jun by inducing phosphorylation of its Serine 73 residue. Silencing of the JNK (c-Jun N-terminal Kinase) signaling pathway abrogated most of this activation. On the contrary, silencing of the ERK (Extracellular Signal-Regulated Kinase) pathway exacerbated this response. Intriguingly, while the exposure to α-toxin induced a marked increase in the levels of c-Jun transcripts, c-Jun protein levels noticeably decreased in the same time-frame as a consequence of active proteolytic degradation through the proteasome-dependent pathway. In addition, we established that c-Jun promoted cell survival when cells were challenged with α-toxin. Similarly, c-Jun phosphorylation was also induced in cells upon intoxication with the cytolysin produced by in a JNK-dependent manner, suggesting that c-Jun-JNK axis would be a conserved responsive cellular pathway to pore-forming toxins. This study contributes to understanding the role of the multifaceted c-Jun proto-oncoprotein in cell response to bacterial pore-forming toxins, positioning it as a relevant component of the complex early machinery mounted to deal with staphylococcal infections.

NMDA ( N -methyl- D -aspartate) receptors (NMDARs) are targeted to dendrites and anchored at the post-synaptic density (PSD) through interactions with PDZ proteins. However, little is known about how these receptors are sorted from the endoplasmic reticulum and Golgi apparatus to the synapse. Here, we find that synapse-associated protein 102 (SAP102) interacts with the PDZ-binding domain of Sec8, a member of the exocyst complex. Our results show that interactions between SAP102 and Sec8 are involved in the delivery of NMDARs to the cell surface in heterologous cells and neurons. Furthermore, they suggest that an exocyst–SAP102–NMDAR complex is an important component of NMDAR trafficking.

(ProQuest: ... denotes formulae and/or non-USASCII text omitted; see image).Atmospheric neutrinos are produced during cascades initiated by the interaction of primary cosmic rays with air nuclei. In this paper, a measurement of the atmospheric ... energy spectrum in the energy range 0.1-200 TeV is presented, using data collected by the ANTARES underwater neutrino telescope from 2008 to 2011. Overall, the measured flux is 25 % higher than predicted by the conventional neutrino flux, and compatible with the measurements reported in ice. The flux is compatible with a single power-law dependence with spectral index gamma sub(meas)=3.58 plus or minus 0.12. With the present statistics the contribution of prompt neutrinos cannot be established.

Many criticisms have been leveled at the dominant positivist accounting research paradigm. This paper links this modern research paradigm to the development of double entry bookkeeping, which itself was part of a larger intellectual movement toward quantitative knowledge production, referred to herein as the quantification paradigm shift. Among the items discussed are the socio-economic forces that facilitated this shift, the role played by this movement in the development of accounting techniques, the advent of the concept of profit, and the emergence of positivism in accounting research. These items will be analyzed in the light of historical changes in philosophy and science, critical perspectives on the dominant research paradigm, and calls for alternative research programs.

Cherenkov light induced by radioactive decay products is one of the major sources of background light for deep-sea neutrino telescopes such as ANTARES. These decays are at the same time a powerful calibration source. Using data collected by the ANTARES neutrino telescope from mid 2008 to 2017, the time evolution of the photon detection efficiency of optical modules is studied. A modest loss of only 20% in 9 years is observed. The relative time calibration between adjacent modules is derived as well.

Distance (i.e., online) education has become an increasingly popular form of higher-education instruction. A Pew Research Center survey conducted in 2011 revealed that a majority of colleges and universities now offer online courses; this trend was most pervasive among public universities (at 89 percent). Online (vs. in-class) instruction is considered more cost effective and has the potential to educate larger portions of the population. However, while some prior studies have focused on the efficacy of various educational delivery methods, some self-selection bias has generally been present in comparisons of online and traditional, in-classroom instruction. This paper provides preliminary evidence about the outcomes when students are not allowed to self-select between online and traditional instruction for an upper-level accounting course and instead are offered only an online course; our results suggest that when students are provided with this option, their exam performance and instructor-evaluation scores are higher. This suggests that upper-level accounting students self-select well between online and traditional instruction and that online education is not suitable for all students. This should be important to academic institutions and accounting researchers as we continue to explore issues pertaining to online education.