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The results show that taking cAMP levels and the endogenous adenosine agonist as references, the main difference in bias was obtained with PSB-0777 and LUF-5834. The C-terminus is dispensable for both G-protein and β-arrestin recruitment and also for MAPK activation. Unrestrained molecular dynamics simulations, at the μs timescale, were used to understand the structural arrangements of the binding cavity, triggered by these chemically different agonists, facilitating G protein binding with different efficacy.A series of complex transport, storage and regulation mechanisms control iron metabolism and thereby maintain iron homeostasis in plants. Despite several studies on iron deficiency responses in different plant species, these mechanisms remain unclear in the allohexaploid wheat, which is the most widely cultivated commercial crop. We used RNA sequencing to reveal transcriptomic changes in the wheat flag leaves and roots, when subjected to iron limited conditions. We identified 5969 and 2591 differentially expressed genes (DEGs) in the flag leaves and roots, respectively. Genes involved in the synthesis of iron ligands i.e., nicotianamine (NA) and deoxymugineic acid (DMA) were significantly up-regulated during iron deficiency. In total, 337 and 635 genes encoding transporters exhibited altered expression in roots and flag leaves, respectively. Several genes related to MAJOR FACILITATOR SUPERFAMILY (MFS), ATP-BINDING CASSETTE (ABC) transporter superfamily, NATURAL RESISTANCE ASSOCIATED MACROPHAGE PROTEIN (NRAMP) family and OLIGOPEPTIDE TRANSPORTER (OPT) family were regulated, indicating their important roles in combating iron deficiency stress. Among the regulatory factors, the genes encoding for transcription factors of BASIC HELIX-LOOP-HELIX (bHLH) family were highly up-regulated in both roots and the flag leaves. The jasmonate biosynthesis pathway was significantly altered but with notable expression differences between roots and flag leaves. Homoeologs expression and induction bias analysis revealed subgenome specific differential expression. Our findings provide an integrated overview on regulated molecular processes in response to iron deficiency stress in wheat. This information could potentially serve as a guideline for breeding iron deficiency stress tolerant crops as well as for designing appropriate wheat iron biofortification strategies.The brain can be regarded as an information processing system in which neurons store and propagate information about external stimuli and internal processes. Therefore, estimating interactions between neural activity at the cellular scale has significant implications in understanding how neuronal circuits encode and communicate information across brain areas to generate behavior. While the number of simultaneously recorded neurons is growing exponentially, current methods relying only on pairwise statistical dependencies still suffer from a number of conceptual and technical challenges that preclude experimental breakthroughs describing neural information flows. In this review, we examine the evolution of the field over the years, starting from descriptive statistics to model-based and model-free approaches. Then, we discuss in detail the Granger Causality framework, which includes many popular state-of-the-art methods and we highlight some of its limitations from a conceptual and practical estimation perspective. Finally, we discuss directions for future research, including the development of theoretical information flow models and the use of dimensionality reduction techniques to extract relevant interactions from large-scale recording datasets.Protein kinases are crucial components of the cell-signalling machinery that orchestrate and convey messages to their downstream targets. Most often, kinases are activated upon a phosphorylation to their activation loop, which will shift the kinase into the active conformation. The Dual specificity mitogen-activated protein kinase kinase 4 (MKK4) exists in a unique conformation in its inactive unphosphorylated state, where its activation segment appears in a stable α-helical conformation. However, the precise role of this unique conformational state of MKK4 is unknown. [https://www.selleckchem.com/products/sy-5609.html SY-5609 ic50] Here, by all-atom molecular dynamics simulations (MD simulations), we show that this inactive state is unstable as monomer even when unphosphorylated and that the phosphorylation of the activation segment further destabilizes the autoinhibited α-helix. The specific phosphorylation pattern of the activation segment has also a unique influence on MKK4 dynamics. Furthermore, we observed that this specific inactive state is stable as a dimer, which becomes destabilized upon phosphorylation. Finally, we noticed that the most frequent MKK4 mutation observed in cancer, R134W, which role has not been disclosed to date, contributes to the dimer stability. Based on these data we postulate that MKK4 occurs as a dimer in its inactive autoinhibited state, providing an additional layer for its activity regulation.Protein-protein interactions regulate almost all cellular functions and rely on a fine tune of surface amino acids properties involved on both molecular partners. The disruption of a molecular association can be caused even by a single residue mutation, often leading to a pathological modification of a biochemical pathway. Therefore the evaluation of the effects of amino acid substitutions on binding, and the ad hoc design of protein-protein interfaces, is one of the biggest challenges in computational biology. Here, we present a novel strategy for computational mutation and optimization of protein-protein interfaces. Modeling the interaction surface properties using the Zernike polynomials, we describe the shape and electrostatics of binding sites with an ordered set of descriptors, making possible the evaluation of complementarity between interacting surfaces. With a Monte Carlo approach, we obtain protein mutants with controlled molecular complementarities. Applying this strategy to the relevant case of the interaction between Ferritin and Transferrin Receptor, we obtain a set of Ferritin mutants with increased or decreased complementarity. The extensive molecular dynamics validation of the method results confirms its efficacy, showing that this strategy represents a very promising approach in designing correct molecular interfaces.