Cortical neurons receive balanced excitatory and inhibitory synaptic currents. Such a balance could be established and maintained in an experience-dependent manner by synaptic plasticity at ...inhibitory synapses. We show that this mechanism provides an explanation for the sparse firing patterns observed in response to natural stimuli and fits well with a recently observed interaction of excitatory and inhibitory receptive field plasticity. The introduction of inhibitory plasticity in suitable recurrent networks provides a homeostatic mechanism that leads to asynchronous irregular network states. Further, it can accommodate synaptic memories with activity patterns that become indiscernible from the background state but can be reactivated by external stimuli. Our results suggest an essential role of inhibitory plasticity in the formation and maintenance of functional cortical circuitry.
While the plasticity of excitatory synaptic connections in the brain has been widely studied, the plasticity of inhibitory connections is much less understood. Here, we present recent experimental ...and theoretical findings concerning the rules of spike timing-dependent inhibitory plasticity and their putative network function. This is a summary of a workshop at the COSYNE conference 2012.
Summary
Background
The kinesin spindle protein Eg5 is involved in mitosis, and its inhibition promotes mitotic arrest. EMD 534085, a potent, reversible Eg5 inhibitor, demonstrated significant ...preclinical antitumor activity.
Methods
This first-in-man, single-center, open-label, phase I dose-escalation study (3 + 3 design) investigated EMD 534085 safety, pharmacokinetics and antitumor activity in refractory solid tumors, Hodgkin’s lymphoma, or non-Hodgkin’s lymphoma. EMD 534085 (starting dose 2 mg/m
2
/day) was administered intravenously every 3 weeks. Doses were escalated in 100 % steps in successive cohorts of 3 patients until grade 2 toxicity occurred, followed by 50 % until the first dose-limiting toxicity (DLT) arose. If <2 of 6 patients experienced a DLT, doses were further increased by 25 %. Dose-escalation was stopped if a DLT occurred in ≥2 of 6 patients.
Results
Forty-four patients received EMD 534085. Median treatment duration was 43 days (range, 21–337). Thirty-eight patients (86 %) received ≥2 cycles. DLTs were grade 4 neutropenia (1 patient each at 108 and 135 mg/m
2
/day), and grade 3 acute coronary syndrome with troponin I elevation (1 patient at 135 mg/m
2
/day). The maximum tolerated dose (MTD) was 108 mg/m
2
/day. The most common treatment-related adverse events were asthenia (50 %) and neutropenia (32 %). EMD 534085 appeared to have linear pharmacokinetics. Increase in phospho-histone H3 positive cells in paired pre- and on-treatment biopsies showed evidence of target modulation. No complete or partial responses were observed. Best response was stable disease in 23 patients (52 %).
Conclusions
EMD 534085 appeared to be well tolerated; MTD was 108 mg/m
2
/day. Preliminary antitumor results suggested limited activity in monotherapy.
In a search for ω mesic states, the production of ω-mesons in coincidence with forward going protons has been studied in photon induced reactions on 12C for incident photon energies of 1250–3100 MeV. ...The π0γ pairs from decays of bound or quasi-free ω-mesons have been measured with the CBELSA/TAPS detector system in coincidence with protons registered in the MiniTAPS forward array. Structures in the total energy distribution of the π0γ pairs, which would indicate the population and decay of bound ω11B states, are not observed. The π0γ cross section of 0.3 nb MeV−1 sr−1 observed in the bound state energy regime between −100 and 0 MeV may be accounted for by yield leaking into the bound state regime because of the large in-medium width of the ω-meson. A comparison of the measured total energy distribution with calculations suggests the real part V0 of the ω11B potential to be small and only weakly attractive with V0(ρ=ρ0)=−15±35(stat)±20(syst) MeV in contrast to some theoretical predictions of attractive potentials with a depth of 100–150 MeV.
GEF-H1 is a guanine nucleotide exchange factor for Rho whose activity is regulated through a cycle of microtubule binding
and release. Here we identify a region in the carboxyl terminus of GEF-H1 ...that is important for suppression of its guanine
nucleotide exchange activity by microtubules. This portion of the protein includes a coiled-coil motif, a proline-rich motif
that may interact with Src homology 3 domain-containing proteins, and a potential binding site for 14-3-3 proteins. We identify
GEF-H1 as a binding target and substrate for p21-activated kinase 1 (PAK1), an effector of Rac and Cdc42 GTPases, using an
affinity-based screen and localize a PAK1 phosphorylation site to the inhibitory carboxylterminal region of GEF-H1. We show
that phosphorylation of GEF-H1 at Ser 885 by PAK1 induces 14-3-3 binding to the exchange factor and relocation of 14-3-3 to microtubules. Phosphorylation of GEF-H1
by PAK may be involved in regulation of GEF-H1 activity and may serve to coordinate Rho-, Rac-, and Cdc42-mediated signaling
pathways.
Yeast galactokinase (Gal1p) is an enzyme and a regulator of transcription. In addition to phosphorylating galactose, Gal1p activates Gal4p, the activator of GAL genes, but the mechanism of this ...regulation has been unclear. Here, biochemical and genetic evidence is presented to show that Gal1p activates Gal4p by direct interaction with the Gal4p inhibitor Gal80p. Interaction requires galactose, adenosine triphosphate, and the regulatory function of Gal1p. These data indicate that Gal1p-Gal80p complex formation results in the inactivation of Gal80p, thereby transmitting the galactose signal to Gal4p.
Nitric oxide, generated from S-nitrosocysteine or applied as gas mediates metal ion release from the Zn2+/Cd(2+)-complexing protein metallothionein via oxidation of SH-groups. Time-dependent ...S-nitrosylation and subsequent disulfide formation of metallothionein are demonstrated. Furthermore, nitric oxide inhibits DNA binding activity of the yeast transcription factor LAC9 containing a zinc finger like DNA binding domain. These results show that nitric oxide interacts with and destroys zinc-sulfur clusters in proteins.
p21-activated kinases (Pak)/Ste20 kinases are regulated in vitro and in vivo by the small GTP-binding proteins Rac and Cdc42 and lipids, such as sphingosine, which stimulate autophosphorylation and ...phosphorylation of exogenous substrates. The mechanism of Pak activation by these agents remains unclear. We investigated Pak kinase activation in more detail to gain insight into the interplay between the GTPase/sphingosine binding, an intramolecular inhibitory interaction, and autophosphorylation. We present biochemical evidence that an autoinhibitory domain (ID) contained within amino acid residues 67–150 of Pak1 interacts with the carboxyl-terminal kinase domain and that this interaction is regulated in a GTPase-dependent fashion. Cdc42- and sphingosine-stimulated Pak1 activity can be inhibited intrans by recombinant ID peptide, indicating similarities in their mode of activation. However, Pak1, which was autophosphorylated in response to either GTPase or sphingosine, is highly active and is insensitive to inhibition by the ID peptide. We identified phospho-acceptor site threonine 423 in the kinase activation loop as a critical determinant for the sensitivity to autoinhibition and enzymatic activity. Phosphorylation studies suggested that the stimulatory effect of both GTPase and sphingosine results in exposure of the activation loop, making it accessible for intermolecular phosphorylation.
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