Sleep in Drosophila is regulated by adult mushroom bodies

Sleep is one of the few major whole-organ phenomena for which no function and no underlying mechanism have been conclusively demonstrated. Sleep could result from global changes in the brain during wakefulness or it could be regulated by specific loci that recruit the rest of the brain into the electrical and metabolic states characteristic of sleep. Here we address this issue by exploiting the genetic tractability of the fruitfly, Drosophila melanogaster, which exhibits the hallmarks of vertebrate sleep. We show that large changes in sleep are achieved by spatial and temporal enhancement of cyclic-AMP-dependent protein kinase (PKA) activity specifically in the adult mushroom bodies of Drosophila. Other manipulations of the mushroom bodies, such as electrical silencing, increasing excitation or ablation, also alter sleep. These results link sleep regulation to an anatomical locus known to be involved in learning and memory.     

CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death

The 'help' provided by CD4+ T lymphocytes during the priming of CD8+ T lymphocytes confers a key feature of immune memory: the capacity for autonomous secondary expansion following re-encounter with antigen. Once primed in the presence of CD4+ T cells, 'helped' CD8+ T cells acquire the ability to undergo a second round of clonal expansion upon restimulation in the absence of T-cell help. 'Helpless' CD8+ T cells that are primed in the absence of CD4+ T cells, in contrast, can mediate effector functions such as cytotoxicity and cytokine secretion upon restimulation, but do not undergo a second round of clonal expansion. These disparate responses have features of being 'programmed', that is, guided by signals that are transmitted to naive CD8+ T cells during priming, which encode specific fates for their clonal progeny. Here we explore the instructional programme that governs the secondary response of CD8+ T cells and find that helpless cells undergo death by activation-induced cell death upon secondary stimulation. This death is mediated by tumour-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). Regulation of Trail expression can therefore account for the role of CD4+ T cells in the generation of CD8+ T cell memory and represents a novel mechanism for controlling adaptive immune responses.     

MicroRNA expression profiles classify human cancers

Recent work has revealed the existence of a class of small non-coding RNA species, known as microRNAs (miRNAs), which have critical functions across various biological processes. Here we use a new, bead-based flow cytometric miRNA expression profiling method to present a systematic expression analysis of 217 mammalian miRNAs from 334 samples, including multiple human cancers. The miRNA profiles are surprisingly informative, reflecting the developmental lineage and differentiation state of the tumours. We observe a general downregulation of miRNAs in tumours compared with normal tissues. Furthermore, we were able to successfully classify poorly differentiated tumours using miRNA expression profiles, whereas messenger RNA profiles were highly inaccurate when applied to the same samples. These findings highlight the potential of miRNA profiling in cancer diagnosis.     

An SCF-like ubiquitin ligase complex that controls presynaptic differentiation

During synapse formation, specialized subcellular structures develop at synaptic junctions in a tightly regulated fashion. Cross-signalling initiated by ephrins, Wnts and transforming growth factor-beta family members between presynaptic and postsynaptic termini are proposed to govern synapse formation. It is not well understood how multiple signals are integrated and regulated by developing synaptic termini to control synaptic differentiation. Here we report the identification of FSN-1, a novel F-box protein that is required in presynaptic neurons for the restriction and/or maturation of synapses in Caenorhabditis elegans. Many F-box proteins are target recognition subunits of SCF (Skp, Cullin, F-box) ubiquitin-ligase complexes. fsn-1 functions in the same pathway as rpm-1, a gene encoding a large protein with RING finger domains. FSN-1 physically associates with RPM-1 and the C. elegans homologues of SKP1 and Cullin to form a new type of SCF complex at presynaptic periactive zones. We provide evidence that T10H9.2, which encodes the C. elegans receptor tyrosine kinase ALK (anaplastic lymphoma kinase), may be a target or a downstream effector through which FSN-1 stabilizes synapse formation. This neuron-specific, SCF-like complex therefore provides a localized signal to attenuate presynaptic differentiation.     

Stellar encounters as the origin of distant Solar System objects in highly eccentric orbits

The Kuiper belt extends from the orbit of Neptune at 30 au to an abrupt outer edge about 50 au from the Sun. Beyond the edge is a sparse population of objects with large orbital eccentricities. Neptune shapes the dynamics of most Kuiper belt objects, but the recently discovered planet 2003 VB12 (Sedna) has an eccentric orbit with a perihelion distance of 70 au, far beyond Neptune's gravitational influence. Although influences from passing stars could have created the Kuiper belt's outer edge and could have scattered objects into large, eccentric orbits, no model currently explains the properties of Sedna. Here we show that a passing star probably scattered Sedna from the Kuiper belt into its observed orbit. The likelihood that a planet at 60-80 au can be scattered into Sedna's orbit is about 50 per cent; this estimate depends critically on the geometry of the fly-by. Even more interesting is the approximately 10 per cent chance that Sedna was captured from the outer disk of the passing star. Most captures have very high inclination orbits; detection of such objects would confirm the presence of extrasolar planets in our own Solar System.     

A Taylor vortex analogy in granular flows

Fluids sheared between concentric rotating cylinders undergo a series of three-dimensional instabilities. Since Taylor's archetypal 1923 study, these have proved pivotal to understanding how fluid flows become unstable and eventually undergo transitions to chaotic or turbulent states. In contrast, predicting the dynamics of granular systems--from nano-sized particles to debris flows--is far less reliable. Under shear these materials resemble fluids, but solid-like responses, non-equilibrium structures and segregation patterns develop unexpectedly. As a result, the analysis of geophysical events and the performance of largely empirical particle technologies might suffer. Here, using gas fluidization to overcome jamming, we show experimentally that granular materials develop vortices consistent with the primary Taylor instability in fluids. However, the vortices observed in our fluidized granular bed are unlike those in fluids in that they are accompanied by novel mixing-segregation transitions. The vortices seem to alleviate increased strain by spawning new vortices, directly modifying the scale of kinetic interactions. Our observations provide insights into the mechanisms of shear transmission by particles and their consequent convective mixing.     

The histone H3.3 chaperone HIRA is essential for chromatin assembly in the male pronucleus

In sexually reproducing animals, a crucial step in zygote formation is the decondensation of the fertilizing sperm nucleus into a DNA replication-competent male pronucleus. Genome-wide nucleosome assembly on paternal DNA implies the replacement of sperm chromosomal proteins, such as protamines, by maternally provided histones. This fundamental process is specifically impaired in sésame (ssm), a unique Drosophila maternal effect mutant that prevents male pronucleus formation. Here we show that ssm is a point mutation in the Hira gene, thus demonstrating that the histone chaperone protein HIRA is required for nucleosome assembly during sperm nucleus decondensation. In vertebrates, HIRA has recently been shown to be critical for a nucleosome assembly pathway independent of DNA synthesis that specifically involves the H3.3 histone variant. We also show that nucleosomes containing H3.3, and not H3, are specifically assembled in paternal Drosophila chromatin before the first round of DNA replication. The exclusive marking of paternal chromosomes with H3.3 represents a primary epigenetic distinction between parental genomes in the zygote, and underlines an important consequence of the critical and highly specialized function of HIRA at fertilization.