Niemann-Pick type C is a neurodegenerative lysosomal storage disorder caused by mutations in either of two genes, npc1 and npc2. Cells lacking Npc1, which is a transmembrane protein related to the Hedgehog receptor Patched, or Npc2, which is a secreted cholesterol-binding protein, have aberrant organelle trafficking and accumulate large quantities of cholesterol and other lipids. Though the Npc proteins are produced by all cells, cerebellar Purkinje neurons are especially sensitive to loss of Npc function. Since Niemann-Pick type C disease involves circulating molecules such as sterols and steroids and a robust inflammatory response within the brain parenchyma, it is crucial to determine whether external factors affect the survival of Purkinje cells (PCs). We investigated the basis of neurodegeneration in chimeric mice that have functional npc1 in only some cells. Death of mutant npc1 cells was not prevented by neighboring wild-type cells, and wild-type PCs were not poisoned by surrounding mutant npc1 cells. PCs undergoing cell-autonomous degeneration have features consistent with autophagic cell death. Chimeric mice exhibited a remarkable delay and reduction of wasting and ataxia despite their substantial amount of mutant tissue and dying cells, revealing a robust mechanism that partially compensates for massive PC death.

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Acetylcholine is a regulatory cofactor for numerous activity‐dependent processes of central nervous system development and plasticity in which increases in cytosolic calcium ion concentration ([Ca2+]cyto) couple membrane excitation to cellular changes. We examined how cholinergic receptor activation affects temporal and spatial aspects of increases in [Ca2+]cyto during short trains of action potentials in hippocampal CA1 pyramidal neurones. Membrane‐impermeant Ca2+‐sensitive dye was introduced into the cytosol during whole‐cell recordings, and Ca2+‐dependent fluorescence was recorded from somatic, nuclear and proximal dendrite regions with high temporal resolution. In all neuronal compartments, the cholinergic agonist carbachol (5 μM) increased resting [Ca2+]cyto and the maximum [Ca2+]cyto attained during a short action potential train. Carbachol also slowed the recovery of [Ca2+]cyto towards resting levels. The largest increases in peak cytosolic Ca2+ concentration (Δ[Ca2+]cyto) were seen in the dendrite and apical cell body, while relaxations of the carbachol‐induced increase in Δ[Ca2+]cyto showed greater prolongation in the nucleus and basal cell body. Most significantly, the difference between Ca2+ signals recorded before and during exposure to carbachol consistently showed a monotonic rise and smooth fall in all cell compartments, suggesting that the increase in [Ca2+]cyto associated with each action potential was not altered by carbachol. Consistent with this view, changes in Ca2+ signalling were not accompanied by changes in action potential waveforms. The effects of carbachol were partially reversed by simultaneous exposure to atropine, or partially inhibited by inclusion of heparin in the intracellular solution, indicating the involvement of muscarinic acetylcholine receptors and InsP3‐sensitive Ca2+‐release channels. Our data indicate that carbachol‐induced slowing of [Ca2+]cyto relaxations after each action potential results in enhanced accumulation of Ca2+ in the cytosol in the absence of changes in action potential‐driven Ca2+ entry. By modulating the time course of Ca2+ signals, cholinergic stimulation may regulate the activation of Ca2+‐dependent intracellular processes dependent on patterns of [Ca2+]cyto changes.

Three experiments studied the influence on hiring decisions of the nonverbal communication of female job applicants. The first experiment found ratings of the applicants' subtle cues to be significant predictors of the hiring decisions made by college‐student judges. Professional employment interviewers served as judges in the second study to cross‐validate the first experiment. The third study measured the relative contributions of work histories and nonverbal behavior to hiring decisions. Regardless of the work history preceding the applicant, nonverbal style had a statistically significant effect on hiring decisions.