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Sensory disabilities have been identified as significant risk factors for dementia but underlying molecular mechanisms are unknown. In different Drosophila models with loss of sensory input, we observe non-autonomous induction of the integrated stress response (ISR) deep in the brain, as indicated by eIF2α S50 phosphorylation-dependent elevated levels of the ISR effectors ATF4 and XRP1. Unlike during canonical ISR, however, the ATF4 and XRP1 transcription factors are enriched in cytosolic granules that are positive for RNA and the stress granule markers Caprin, FMR1, and p62, and are reversible upon restoration of vision for blind flies. Cytosolic restraint of the ATF4 and XRP1 transcription factors dampens expression of their downstream targets including genes of cell death pathways activated during chronic cellular stress and thus constitutes a chronic stress protective response (CSPR). Cytosolic granules containing both p62 and ATF4 are also evident in the thalamus and hippocampus of mouse models of congenital or degenerative blindness. These data indicate a conserved link between loss of sensory input and curbed stress responses critical for protein quality control in the brain. Chronic stress responses can be as damaging as the hazards they counteract. Here the authors show how a blindness-induced brain-wide stress response is dampened by sequestration of transcription factors in cytosolic granules.

In nervous systems, retrograde signals are key for organizing circuit activity and maintaining neuronal homeostasis. We identify the conserved Allnighter (Aln) pseudokinase as a cell non-autonomous regulator of proteostasis responses necessary for normal sleep and structural plasticity of Drosophila photoreceptors. In aln mutants exposed to extended ambient light, proteostasis is dysregulated and photoreceptors develop striking, but reversible, dysmorphology. The aln gene is widely expressed in different neurons, but not photoreceptors. However, secreted Aln protein is retrogradely endocytosed by photoreceptors. Inhibition of photoreceptor synaptic release reduces Aln levels in lamina neurons, consistent with secreted Aln acting in a feedback loop. In addition, aln mutants exhibit reduced night time sleep, providing a molecular link between dysregulated proteostasis and sleep, two characteristics of ageing and neurodegenerative diseases. For homeostatic plasticity, neuronal circuits rely on poorly understood retrograde signals. Here, the authors identify a visual activity-dependent feedback loop mediated by the secreted Allnighter pseudokinase with effects on brain-wide proteostasis and sleep.

Neuronal health depends on quality control functions of autophagy, but mechanisms regulating neuronal autophagy are poorly understood. Previously, we showed that in Drosophila starvation-independent quality control autophagy is regulated by acinus (acn) and the Cdk5-dependent phosphorylation of its serine 437 (Nandi et al., 2017). Here, we identify the phosphatase that counterbalances this activity and provides for the dynamic nature of acinus-serine 437 (acn-S437) phosphorylation. A genetic screen identified six phosphatases that genetically interacted with an acn gain-of-function model. Among these, loss of function of only one, the PPM-type phosphatase Nil (CG6036), enhanced pS437-acn levels. Cdk5-dependent phosphorylation of acn-S437 in nil 1 animals elevates neuronal autophagy and reduces the accumulation of polyQ proteins in a Drosophila Huntington’s disease model. Consistent with previous findings that Cd 2+ inhibits PPM-type phosphatases, Cd 2+ exposure elevated acn-S437 phosphorylation which was necessary for increased neuronal autophagy and protection against Cd 2+ -induced cytotoxicity. Together, our data establish the acn-S437 phosphoswitch as critical integrator of multiple stress signals regulating neuronal autophagy.

Neuronal health depends on quality control functions of autophagy, but mechanisms regulating neuronal autophagy are poorly understood. Previously, we showed that in starvation-independent quality control autophagy is regulated by acinus (acn) and the Cdk5-dependent phosphorylation of its serine (Nandi et al., 2017). Here, we identify the phosphatase that counterbalances this activity and provides for the dynamic nature of acinus-serine (acn-S437) phosphorylation. A genetic screen identified six phosphatases that genetically interacted with an acn gain-of-function model. Among these, loss of function of only one, the PPM-type phosphatase Nil (CG6036), enhanced pS437-acn levels. Cdk5-dependent phosphorylation of acn-S437 in animals elevates neuronal autophagy and reduces the accumulation of polyQ proteins in a Huntington's disease model. Consistent with previous findings that Cd inhibits PPM-type phosphatases, Cd exposure elevated acn-S437 phosphorylation which was necessary for increased neuronal autophagy and protection against Cd -induced cytotoxicity. Together, our data establish the acn-S437 phosphoswitch as critical integrator of multiple stress signals regulating neuronal autophagy.

The roof vaulting, the surviving components of the Pietà, formerly standing behind the altar, the sculptural elements in the apse ceiling above, as well as the north Italian mural paintings of Mary Cleophas and Mary Salome (discussed by Cécile Scailliérez), and the sole surviving stained-glass window (Sophie Lagabrielle), convince one of the outstanding artistic importance of the ensemble. [...]the original siting of this screen is unknown, and, in any case, even if the stalls had abutted it in this way, the chancel area would have been uncomfortably crowded. A more convincing estimate of the original tally of stalls might be arrived at through the careful measurement of the five refugee panels from the Gaillon seat backs, now at Écouen, Berlin and New York, an archaeological examination of Viollet-le-Duc's reassemblage at St Denis, and a search through his papers in the Bibliothèque Nationale. In spite of the depredations of the French Revolution, however, it is still possible to affirm that four clerical members of the older generation of the d'Amboise family were probably responsible for creating the most important episcopal chapels of their time.

A book that accompanied an exhibition presented at the Musée national du Moyen Âge in Paris and the Musée national de la Renaissance at the château d'Écouen in Ecouen, from October 3, 2007-January 14, 2008, is reviewed (Éditions de la Réunion des musées nationaux, 2007). It explores the lavish artistic patronage of two generations of the d'Amboise family, focusing on chapel architecture and furniture.

A handbook that takes a forensic approach to the medieval and post-medieval chests found in the churches of Suffolk is reviewed (Suffolk Institute of Archaeology and History, 2007).