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Placental insufficiency is implicated in spontaneous preterm birth (SPTB) associated with intrauterine inflammation. We hypothesized that intrauterine inflammation leads to deficits in the capacity of the placenta to maintain bioenergetic and metabolic stability during pregnancy ultimately resulting in SPTB. Using a mouse model of intrauterine inflammation that leads to preterm delivery, we performed RNA-seq and metabolomics studies to assess how intrauterine inflammation alters gene expression and/or modulates metabolite production and abundance in the placenta. 1871 differentially expressed genes were identified in LPS-exposed placenta. Among them, 1,149 and 722 transcripts were increased and decreased, respectively. Ingenuity pathway analysis showed alterations in genes and canonical pathways critical for regulating oxidative stress, mitochondrial function, metabolisms of glucose and lipids, and vascular reactivity in LPS-exposed placenta. Many upstream regulators and master regulators important for nutrient-sensing and mitochondrial function were also altered in inflammation exposed placentae, including STAT1, HIF1α, mTOR, AMPK, and PPARα. Comprehensive quantification of metabolites demonstrated significant alterations in the glucose utilization, metabolisms of branched-chain amino acids, lipids, purine and pyrimidine, as well as carbon flow in TCA cycle in LPS-exposed placenta compared to control placenta. The transcriptome and metabolome were also integrated to assess the interactions of altered genes and metabolites. Collectively, significant and biologically relevant alterations in the placenta transcriptome and metabolome were identified in placentae exposed to intrauterine inflammation. Altered mitochondrial function and energy metabolism may underline the mechanisms of inflammation-induced placental dysfunction.Understanding the mechanism by which plants respond to cold stress and strengthen their tolerance to low temperatures is an important and challenging task in plant sciences. Experiments have established that the first step in the perception and transduction of the cold stress signal consists of a transient influx of Ca2+. This Ca2+ influx triggers the activation of a cascade of phosphorylation-dephosphorylation reactions that eventually affects the expression of C-repeat-binding factors (CBFs, notably CBF3), which were shown in many plants to control resistance to cold stress by regulating the expression of cold-regulated (COR) genes. Based on experimental observations mostly made on Arabidopsis thaliana, we build a computational model for the cold response pathway in plants, from the transduction of the cold signal via the transient influx of Ca2+ to the activation of the phosphorylation cascade leading to CBF3 expression. We explore the dynamics of this regulatory network by means of numerical simulations aold stress by the plant circadian clock.Anoctamin-1 (ANO1), also known as TMEM16A, is the most studied member of anoctamin family of calcium-activated chloride channels with diverse cellular functions. ANO1 controls multiple cell functions including cell proliferation, survival, migration, contraction, secretion, and neuronal excitation. This review summarizes the current knowledge of the cellular mechanisms governing the regulation of ANO1 expression and of ANO1-mediated intracellular signaling. This includes the stimuli and mechanisms controlling ANO1 expression, agonists and processes that activate ANO1, and signal transduction mediated by ANO1. The major conclusion is that this field is poorly understood, remains highly controversial, and requires extensive and rigorous further investigation.

Na

1.5 cardiac Na

channel mutations can cause arrhythmogenic syndromes. Some of these mutations exert a dominant negative effect on wild-type channels. Recent studies showed that Na

channels can dimerize, allowing coupled gating. This leads to the hypothesis that allosteric interactions between Na

channels modulate their function and that these interactions may contribute to the negative dominance of certain mutations.

To investigate how allosteric interactions affect microscopic and macroscopic channel function, we developed a modeling paradigm in which Markovian models of two channels are combined. this website Allosteric interactions are incorporated by modifying the free energies of the composite states and/or barriers between states.

Simulations using two generic 2-state models (C-O, closed-open) revealed that increasing the free energy of the composite states CO/OC leads to coupled gating. Simulations using two 3-state models (closed-open-inactivated) revealed that coupled closings must also involve interactions between further composite states. Using two 6-state cardiac Na

channel models, we replicated previous experimental results mainly by increasing the energies of the CO/OC states and lowering the energy barriers between the CO/OC and the CO/OO states. The channel model was then modified to simulate a negative dominant mutation (Na

1.5 p.L325R). Simulations of homodimers and heterodimers in the presence and absence of interactions showed that the interactions with the variant channel impair the opening of the wild-type channel and thus contribute to negative dominance.

Our new modeling framework recapitulates qualitatively previous experimental observations and helps identifying possible interaction mechanisms between ion channels.

Our new modeling framework recapitulates qualitatively previous experimental observations and helps identifying possible interaction mechanisms between ion channels.Alpha-arbutin (4-hydroxyphenyl alpha-glucopyranoside) is a known inhibitor of tyrosinase in keratinocytes; however, its effect on other genes and pathways in other skin cells has not been thoroughly investigated. In this study, we investigate the mechanism of alpha-arbutin activity in human dermal fibroblast cultures for 48 h. Results showed that the oxidative stress pathway was activated as alpha-arbutin reduced reactive oxygen species. In addition, we found a high possibility of wound healing and the upregulation of the insulin-like growth factor 1 receptor (IFG1R) pathway. We also investigated the role of the NRF2 gene in mediating the alpha-arbutin response. In silico comparative genomics analysis conducted using our original tool, SHOE, suggested transcription factors with a role in tumor suppression and toxicity response as candidates for regulating the alpha-arbutin-mediated pathway.