Dynamics of Nucleation in the Ising Model

Reactive pathways to nucleation in a three-dimensional Ising model at 60% of the critical temperature are studied using transition path sampling of single spin flip Monte Carlo dynamics. Analysis of the transition state ensemble (TSE) indicates that the critical nuclei are rough and anisotropic. The TSE, projected onto the free energy surface characterized by cluster size, N, and surface area, S, indicates the significance of other variables in addition to these two traditional reaction coordinates for nucleation. The transmission coefficient along N is ~ 0.35, and this reduction of the transmission coefficient from unity is explained in terms of the stochastic nature of the dynamic model.Comment: In press at the Journal of Physical Chemistry B, 7 pages, 8 figure

Altered miRNA expression network in locus coeruleus of depressed suicide subjects

Norepinephrine (NE) is produced primarily by neurons in the locus coeruleus (LC). Retrograde and ultrastructural examinations reveal that the core of the LC and its surrounding region receives afferent projections from several brain areas which provide multiple neurochemical inputs to the LC with changes in LC neuronal firing, making it a highly coordinated event. Although NE and mediated signaling systems have been studied in relation to suicide and psychiatric disorders that increase the risk of suicide including depression, less is known about the corresponding changes in molecular network within LC. In this study, we examined miRNA networks in the LC of depressed suicide completers and healthy controls. Expression array revealed differential regulation of 13 miRNAs. Interaction between altered miRNAs and target genes showed dense interconnected molecular network. Functional clustering of predicated target genes yielded stress induced disorders that collectively showed the complex nature of suicidal behavior. In addition, 25 miRNAs were pairwise correlated specifically in the depressed suicide group, but not in the control group. Altogether, our study revealed for the first time the involvement of LC based dysregulated miRNA network in disrupting cellular pathways associated with suicidal behavior

A Mechanism for the Polarity Formation of Chemoreceptors at the Growth Cone Membrane for Gradient Amplification during Directional Sensing

Accurate response to external directional signals is essential for many physiological functions such as chemotaxis or axonal guidance. It relies on the detection and amplification of gradients of chemical cues, which, in eukaryotic cells, involves the asymmetric relocalization of signaling molecules. How molecular events coordinate to induce a polarity at the cell level remains however poorly understood, particularly for nerve chemotaxis. Here, we propose a model, inspired by single-molecule experiments, for the membrane dynamics of GABA chemoreceptors in nerve growth cones (GCs) during directional sensing. In our model, transient interactions between the receptors and the microtubules, coupled to GABA-induced signaling, provide a positive-feedback loop that leads to redistribution of the receptors towards the gradient source. Using numerical simulations with parameters derived from experiments, we find that the kinetics of polarization and the steady-state polarized distribution of GABA receptors are in remarkable agreement with experimental observations. Furthermore, we make predictions on the properties of the GC seen as a sensing, amplification and filtering module. In particular, the growth cone acts as a low-pass filter with a time constant ∼10 minutes determined by the Brownian diffusion of chemoreceptors in the membrane. This filtering makes the gradient amplification resistent to rapid fluctuations of the external signals, a beneficial feature to enhance the accuracy of neuronal wiring. Since the model is based on minimal assumptions on the receptor/cytoskeleton interactions, its validity extends to polarity formation beyond the case of GABA gradient sensing. Altogether, it constitutes an original positive-feedback mechanism by which cells can dynamically adapt their internal organization to external signals

Sp1 Expression Is Disrupted in Schizophrenia; A Possible Mechanism for the Abnormal Expression of Mitochondrial Complex I Genes, NDUFV1 and NDUFV2

The prevailing hypothesis regards schizophrenia as a polygenic disease, in which multiple genes combine with each other and with environmental stimuli to produce the variance of its clinical symptoms. We investigated whether the ubiquitous transcription factor Sp1 is abnormally expressed in schizophrenia, and consequently can affect the expression of genes implicated in this disorder. promoter by binding to its three GC-boxes. Both activation and binding were inhibited by mithramycin.These findings suggest that abnormality in Sp1, which can be the main activator/repressor or act in combination with additional transcription factors and is subjected to environmental stimuli, can contribute to the polygenic and clinically heterogeneous nature of schizophrenia

The density and distribution of six GABAA receptor subunits in primary cultures of rat cerebellar granule cells

In cultured cerebellar granule neurons (seven daysin vitro) the expression of GABAA receptor subunits was quantified by using freeze-fracture immunocytochemical techniques with antibodies that specifically recognize the α1, α6, β2-3, γ2 and δ subunits of the GABAA receptor. In some experiments we have also used a less specific antibody that recognizes several α receptor subunits (α-total). The specificity of these antibodies was verified in human embryonic kidney cell line no. 293 cells transfected with complementary DNAs codifying for various GABAA receptor subunits. The most abundant labeling in granule cells was generated by the antibody against the β2-3 subunits (∼44 colloidal gold particles/μm2), while the specific antibodies against α1 and α6 subunits show a labeling of about 16 colloidal gold particles/μm2. The α-total antibody shows a labeling of ∼37 gold particles/μm2. Both the γ2 and δ antibodies show a labeling of about 10 gold particles/μm2. In granule cells, the relative proportion of the label density revealed with antibodies against α-total, β2-3, γ2 and δ subunits is approximately 4:4:1:1. Assuming that one molecular form of the α subunit is assembled in a GABAA receptor, it can be estimated that in granule cells about 50% of receptors include the α1 subunit. A similar relative abundance can be estimated for the α6 subunit. The proportion of GABAA receptors containing the γ2 or δ subunits can be estimated to be about 50% in each case. Cerebellar granule cells express various abundances of GABAA receptor subunits which can be estimated by freeze-fracture immunocytochemistry. Fifty to sixty percent of these subunits form small receptor clusters, which appear to be associated with neuronal cytoskeleton proteins. © 1995 IBRO

Freeze-fracture immunocytochemical study of the expression of native and recombinant GABAA receptors

To assess the density and distribution of native and recombinant GABAA receptors we used label-fracture and fracture-flip technologies combined with immunocytochemistry using monoclonal and polyclonal Abs directed against the extracellular domain of the GABAA receptor protein located in the freeze-fracture replicas. In cortical neurons there is a high density of GABAA receptors on both soma and dendrites with some areas were the density of receptors is higher, but there are no well defined clusters. In cerebellar granule cells most of the receptors are distributed in round clusters both in neurites and soma. In astroglial cells the receptor density is lower than in neurons and only occasionally they appear in clusters. In cells transfected with cDNAs encoding for various molecular forms of GABAA receptor subunits, the receptor density is moderate when cDNAs for \u3b1, \u3b2 and \u3b3 subnits are cotransfected; however, on cells cotransfected with cDNAs for \u3b2 and \u3b3 subunits the receptor density is significantly lower. Recombinant receptors appear randomly distributed and occasionally they aggregate in small groups. \ua9 1993

Intravenous Reelin rescues despair-like behavior, Reelin cells in the dentate sub-granular zone, and spleen atrophy in the cyclic corticosterone model of recurring depressive episodes

Novel antidepressants are predominantly evaluated preclinically in rodent models of chronic stress in which animals experience a single prolonged exposure to chronic stress prior to treatment. Rodent models of a single episode of chronic stress translate poorly to human depressive disorders, which are commonly marked by recurring depressive episodes. Intravenous administration of Reelin has previously been shown to resolve immobility in the forced swim test of rats exposed to a single prolonged exposure to chronic stress. To determine whether Reelin has antidepressant-like properties in a model of recurring depressive episodes, Long–Evans rats (N = 57) were exposed to multiple cycles of chronic stress and stress-free periods before the administration of a single injection of Reelin during the final cycle of chronic stress. The animals then performed in the forced swim test and open field test before the post-mortem evaluation of Reelin cell counts in the sub-granular zone of the dentate gyrus to determine the impact of treatment on hippocampal Reelin levels and spleen white pulp to evaluate the role of Reelin treatment in peripheral inflammation. The results show a single Reelin injection reversed elevated levels of immobility in the forced swim test in both male and female subjects exposed to the cyclic chronic stress model of recurring depressive episodes. Treatment with Reelin also restored Reelin-positive cell counts in the dentate gyrus sub-granular zone and reversed atrophy of spleen white pulp. The results shown here indicate that treatment with Reelin could effectively resolve alterations in forced swim test behavior caused by the cyclic corticosterone model of recurring depressive episodes and that Reelin homeostasis is important for regulating stress-related inflammation. Future preclinical antidepressant research should incorporate models of multiple depressive episodes to improve the translation of preclinical rodent research to human depressive disorders