K‐Lysine acetyltransferase 2a regulates a hippocampal gene expression network linked to memory formation

Neuronal histone acetylation has been linked to memory consolidation, and targeting histone acetylation has emerged as a promising therapeutic strategy for neuropsychiatric diseases. However, the role of histone‐modifying enzymes in the adult brain is still far from being understood. Here we use RNA sequencing to screen the levels of all known histone acetyltransferases (HATs) in the hippocampal CA1 region and find that K‐acetyltransferase 2a (Kat2a)—a HAT that has not been studied for its role in memory function so far—shows highest expression. Mice that lack Kat2a show impaired hippocampal synaptic plasticity and long‐term memory consolidation. We furthermore show that Kat2a regulates a highly interconnected hippocampal gene expression network linked to neuroactive receptor signaling via a mechanism that involves nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB). In conclusion, our data establish Kat2a as a novel and essential regulator of hippocampal memory consolidation.     

Vertebrate Hedgehog signaling: cilia rule

The Hedgehog (Hh) signaling pathway differentially utilizes the primary cilium in mammals and fruit flies. Recent work, including a study in BMC Biology, demonstrates that Hh signals through the cilium in zebrafish, clarifying the evolution of Hh signal transduction.     

Pyrrolizidine alkaloids from Echium glomeratum (Boraginaceae)

The methanolic extract of the whole plant of Echium glomeratum Poir. (Boraginaceae) has afforded five pyrrolizidine alkaloids, three that were (7S, 8R)-petranine (1), (7S, 8S)-petranine (2), and (7R, 8R)-petranine (3a) or (7R, 8S)-petranine (3b), comprising a tricyclic pyrrolizidine alkaloids subclass; and two that were known but to the species: 7-angeloylretronecine (4) and 9-angeloylretronecine (5). All compounds were tested against a human tumor panel for cytotoxicity; no activity was observed (EC(50) values>20mug/ml).     

Biologically-inspired humanoid postural control

This article presents a biologically-inspired framework for humanoid postural control. It complies with the main features of human postural control that are extracted from recent studies. In this article, the human body is abstracted as a single-inverted pendulum jointed with a foot that rests freely on a supporting surface. In particular, disturbances affecting posture are addressed and accommodated within the proposed framework. Among these are external forces and motion of support surface on which the body stands. The main components of this framework are: 1. A state-feedback mechanism for stabilizing the unstable dynamics of the body. 2. A tracking loop for robustly achieving desired voluntary orientations. 3. A feed-forward control primarily for improving the response to voluntary motions. 4. A stand-alone vestibular sensory fusion algorithm for estimating body orientation. 5. An external-disturbance estimator and a corresponding compensation for minimizing the effect of external disturbances. These components are interconnected in a way that qualifies this framework to modularly address the multi-segment body postural control problem. Although no postural stability measure is explicitly incorporated, experiments run on a special-purpose humanoid demonstrate the stability and the performance merits of the presented framework.     

Thiocyanate modulates the catalytic activity of mammalian peroxidases

We investigated the potential role of the co-substrate, thiocyanate (SCN-), in modulating the catalytic activity of myeloperoxidase (MPO) and other members of the mammalian peroxidase superfamily (lactoperoxidase (LPO) and eosinophil peroxidase (EPO)). Pre-incubation of SCN- with MPO generates a more complex biological setting, because SCN- serves as either a substrate or inhibitor, causing diverse impacts on the MPO heme iron microenvironment. Consistent with this hypothesis, the relationship between the association rate constant of nitric oxide binding to MPO-Fe(III) as a function of SCN- concentration is bell-shaped, with a trough comparable with normal SCN- plasma levels. Rapid kinetic measurements indicate that MPO, EPO, and LPO Compound I formation occur at rates slower than complex decay, and its formation serves to simultaneously catalyze SCN- via 1e- and 2e- oxidation pathways. For the three enzymes, Compound II formation is a fundamental feature of catalysis and allows the enzymes to operate at a fraction of their possible maximum activities. MPO and EPO Compound II is relatively stable and decays gradually within minutes to ground state upon H2O2 exhaustion. In contrast, LPO Compound II is unstable and decays within seconds to ground state, suggesting that SCN- may serve as a substrate for Compound II. Compound II formation can be partially or completely prevented by increasing SCN- concentration, depending on the experimental conditions. Collectively, these results illustrate for the first time the potential mechanistic differences of these three enzymes. A modified kinetic model, which incorporates our current findings with the mammalian peroxidases classic cycle, is presented.     

Kinetic evidence supports the existence of two halide binding sites that have a distinct impact on the heme iron microenvironment in myeloperoxidase

Myeloperoxidase (MPO) structural analysis has suggested that halides and pseudohalides bind to the distal binding site and serve as substrates or inhibitors, while others have concluded that there are two separate sites. Here, evidence for two distinct binding sites for halides comes from the bell-shaped effects observed when the second-order rate constant of nitric oxide (NO) binding to MPO was plotted versus Cl- concentration. The chloride level used in the X-ray structure that produced Cl- binding to the amino terminus of the helix halide binding site was insufficient to populate either of the two sites that appear to be responsible for the two phases. Biphasic effects were also observed when the I-, Br-, and SCN- concentrations were plotted against the NO combination rate constants. Interestingly, the trough concentrations obtained from the bell-shaped curves are comparable to normal plasma levels of halides and pseudohalides, suggesting the potential relevance of these molecules in modulating MPO function. The second-order rate constant of NO binding in the presence of plasma levels of I-, Br-, and SCN- is 1-2-fold lower compared to that obtained in the absence of these molecules and remains unaltered through the Cl- plasma level. When Cl- exceeded the plasma level, the NO combination rate becomes indistinguishable from the second phase of the bell-shaped curve that was obtained in the absence of halides. Our results are consistent with two halide binding sites that could be populated by two halides in which both display distinct effects on the MPO heme iron microenvironment.