Chronic Nicotine Selectively Enhances α4β2* Nicotinic Acetylcholine Receptors in the Nigrostriatal Dopamine Pathway

These electrophysiological experiments, in slices and intact animals, study the effects of in vivo chronic exposure to nicotine on functional α4β2* nAChRs in the nigrostriatal dopaminergic (DA) pathway. Recordings were made in wild-type and α4 nicotinic acetylcholine receptor (nAChR) subunit knock-out mice. Chronic nicotine enhanced methyllycaconitine citrate hydrate-resistant, dihydro-β-erythroidine hydrobromide-sensitive nicotinic currents elicited by 3–1000 µM ACh in GABAergic neurons of the substantia nigra pars reticulata (SNr), but not in DA neurons of the substantia nigra pars compacta (SNc). This enhancement leads to higher firing rates of SNr GABAergic neurons and consequently to increased GABAergic inhibition of the SNc DA neurons. In the dorsal striatum, functional α4* nAChRs were not found on the neuronal somata; however, nicotine acts via α4β2* nAChRs in the DA terminals to modulate glutamate release onto the medium spiny neurons. Chronic nicotine also increased the number and/or function of these α4β2* nAChRs. These data suggest that in nigrostriatal DA pathway, chronic nicotine enhancement of α4β2* nAChRs displays selectivity in cell type and in nAChR subtype as well as in cellular compartment. These selective events augment inhibition of SNc DA neurons by SNr GABAergic neurons and also temper the release of glutamate in the dorsal striatum. The effects may reduce the risk of excitotoxicity in SNc DA neurons and may also counteract the increased effectiveness of corticostriatal glutamatergic inputs during degeneration of the DA system. These processes may contribute to the inverse correlation between tobacco use and Parkinson's disease

Stem cells and fluid flow drive cyst formation in an invertebrate excretory organ.

Cystic kidney diseases (CKDs) affect millions of people worldwide. The defining pathological features are fluid-filled cysts developing from nephric tubules due to defective flow sensing, cell proliferation and differentiation. The underlying molecular mechanisms, however, remain poorly understood, and the derived excretory systems of established invertebrate models (Caenorhabditis elegans and Drosophila melanogaster) are unsuitable to model CKDs. Systematic structure/function comparisons revealed that the combination of ultrafiltration and flow-associated filtrate modification that is central to CKD etiology is remarkably conserved between the planarian excretory system and the vertebrate nephron. Consistently, both RNA-mediated genetic interference (RNAi) of planarian orthologues of human CKD genes and inhibition of tubule flow led to tubular cystogenesis that share many features with vertebrate CKDs, suggesting deep mechanistic conservation. Our results demonstrate a common evolutionary origin of animal excretory systems and establish planarians as a novel and experimentally accessible invertebrate model for the study of human kidney pathologies

Small Cities Blues: Looking for Growth Factors in Small and Medium-Sized Cities

The purpose of this exploratory study is to attempt to identify particular public policies which have the potential to increase the economic viability of smaller metropolitan areas and cities. We identify characteristics associated with smaller metro areas that performed better-than-expected (winners) and worse-than-expected (losers) during the 1990s, given their resources, industrial mix, and location as of 1990. Once these characteristics have been identified, we look for evidence that public policy choices may have promoted and enhanced a metro area\u27s ability to succeed and to regain control of its own economic destiny. Methodologically, we construct a regression model which identifies the small metro areas that achieved higher-than-expected economic prosperity (winners) and the areas that saw lower-than-expected economic prosperity (losers) according to the model. Next, we explore whether indications exist that winners and losers are qualitatively different from other areas in ways that may indicate consequences of policy choices. A cluster analysis is completed to group the metro areas based on changes in a host of social, economic, and demographic variables between 1990 and 2000. We then use contingency table analysis and ANOVA to see if winning or losing, as measured by the error term from the regression, is related to the grouping of metro areas in a way that may indicate the presence of deliberate and replicable government policy

Accretion of low angular momentum material onto black holes: 2D magnetohydrodynamical case

We report on the second phase of our study of slightly rotating accretion flows onto black holes. We consider magnetohydrodynamical (MHD) accretion flows with a spherically symmetric density distribution at the outer boundary, but with spherical symmetry broken by the introduction of a small, latitude-dependent angular momentum and a weak radial magnetic field. We study accretion flows by means of numerical 2D, axisymmetric, MHD simulations with and without resistive heating. Our main result is that the properties of the accretion flow depend mostly on an equatorial accretion torus which is made of the material that has too much angular momentum to be accreted directly. The torus accretes, however, because of the transport of angular momentum due to the magnetorotational instability (MRI). Initially, accretion is dominated by the polar funnel, as in the hydrodynamic inviscid case, where material has zero or very low angular momentum. At the later phase of the evolution, the torus thickens towards the poles and develops a corona or an outflow or both. Consequently, the mass accretion through the funnel is stopped. The accretion of rotating gas through the torus is significantly reduced compared to the accretion of non-rotating gas (i.e., the Bondi rate). It is also much smaller than the accretion rate in the inviscid, weakly rotating case.Our results do not change if we switch on or off resistive heating. Overall our simulations are very similar to those presented by Stone, Pringle, Hawley and Balbus despite different initial and outer boundary conditions. Thus, we confirm that MRI is very robust and controls the nature of radiatively inefficient accretion flows.Comment: submitted in Ap

Inferring hidden Markov models from noisy time sequences: a method to alleviate degeneracy in molecular dynamics

We present a new method for inferring hidden Markov models from noisy time sequences without the necessity of assuming a model architecture, thus allowing for the detection of degenerate states. This is based on the statistical prediction techniques developed by Crutchfield et al., and generates so called causal state models, equivalent to hidden Markov models. This method is applicable to any continuous data which clusters around discrete values and exhibits multiple transitions between these values such as tethered particle motion data or Fluorescence Resonance Energy Transfer (FRET) spectra. The algorithms developed have been shown to perform well on simulated data, demonstrating the ability to recover the model used to generate the data under high noise, sparse data conditions and the ability to infer the existence of degenerate states. They have also been applied to new experimental FRET data of Holliday Junction dynamics, extracting the expected two state model and providing values for the transition rates in good agreement with previous results and with results obtained using existing maximum likelihood based methods.Comment: 19 pages, 9 figure