Latest Articles Include:
- Multiple Sulfur Acceptors Dock at IscS
Heller K - PLoS Biol 8(4):e1000353 (2010)
- Adaptation, Plasticity, and Extinction in a Changing Environment: Towards a Predictive Theory
- PLoS Biol 8(4):e1000357 (2010)
- The MAHB, the Culture Gap, and Some Really Inconvenient Truths
Ehrlich PR - PLoS Biol 8(4):e1000330 (2010)
Humanity's failure to take adequate actions to stem a likely environmental collapse calls for extraordinary measures to understand and alter human behavior, argues Paul Ehrlich. His Millennium Assessment of Human Behavior (MAHB) aims to chart the path to a sustainable future. - The Light-Driven Proton Pump Proteorhodopsin Enhances Bacterial Survival during Tough Times
- PLoS Biol 8(4):e1000359 (2010)
- Proteorhodopsin Phototrophy Promotes Survival of Marine Bacteria during Starvation
- PLoS Biol 8(4):e1000358 (2010)
Proteorhodopsins are globally abundant photoproteins found in bacteria in the photic zone of the ocean. Although their function as proton pumps with energy-yielding potential has been demonstrated, the ecological role of proteorhodopsins remains largely unexplored. Here, we report the presence and function of proteorhodopsin in a member of the widespread genus Vibrio, uncovered through whole-genome analysis. Phylogenetic analysis suggests that the Vibrio strain AND4 obtained proteorhodopsin through lateral gene transfer, which could have modified the ecology of this marine bacterium. We demonstrate an increased long-term survival of AND4 when starved in seawater exposed to light rather than held in darkness. Furthermore, mutational analysis provides the first direct evidence, to our knowledge, linking the proteorhodopsin gene and its biological function in marine bacteria. Thus, proteorhodopsin phototrophy confers a fitness advantage to marine bacteria, representing a ! novel mechanism for bacterioplankton to endure frequent periods of resource deprivation at the ocean's surface. - Carbon Dioxide Sensing Modulates Lifespan and Physiology in Drosophila
Poon PC Kuo TH Linford NJ Roman G Pletcher SD - PLoS Biol 8(4):e1000356 (2010)
For nearly all life forms, perceptual systems provide access to a host of environmental cues, including the availability of food and mates as well as the presence of disease and predators. Presumably, individuals use this information to assess the current and future states of the environment and to enact appropriate developmental, behavioral, and regulatory decisions. Recent work using the nematode worm, Caenorhabditis elegans, and the fruit fly, Drosophila melanogaster, has established that aging is subject to modulation through neurosensory systems and that this regulation is evolutionarily conserved. To date, sensory manipulations shown to impact Drosophila aging have involved general loss of function or manipulation of complex stimuli. We therefore know little about the specific inputs, sensors, or associated neural circuits that affect these life and death decisions. We find that a specialized population of olfactory neurons that express receptor Gr63a (a componen! t of the olfactory receptor for gaseous phase CO2) affects fly lifespan and physiology. Gr63a loss of function leads to extended lifespan, increased fat deposition, and enhanced resistance to some (but not all) environmental stresses. Furthermore, we find that the reduced lifespan that accompanies exposure to odors from live yeast is dependent on Gr63a. Together these data implicate a specific sensory cue (CO2) and its associated receptor as having the ability to modulate fly lifespan and alter organism stress response and physiology. Because Gr63a is expressed in a well-defined population of neurons, future work may now be directed at dissecting more complex neurosensory and neuroendocrine circuits that modulate aging in Drosophila. - Environmental Change Enhances Cognitive Abilities in Fish
Kotrschal A Taborsky B - PLoS Biol 8(4):e1000351 (2010)
Flexible or innovative behavior is advantageous, especially when animals are exposed to frequent and unpredictable environmental perturbations. Improved cognitive abilities can help animals to respond quickly and adequately to environmental dynamics, and therefore changing environments may select for higher cognitive abilities. Increased cognitive abilities can be attained, for instance, if environmental change during ontogeny triggers plastic adaptive responses improving the learning capacity of exposed individuals. We tested the learning abilities of fishes in response to experimental variation of environmental quality during ontogeny. Individuals of the cichlid fish Simochromis pleurospilus that experienced a change in food ration early in life outperformed fish kept on constant rations in a learning task later in life—irrespective of the direction of the implemented change and the mean rations received. This difference in learning abilities between individuals re! mained constant between juvenile and adult stages of the same fish tested 1 y apart. Neither environmental enrichment nor training through repeated neural stimulation can explain our findings, as the sensory environment was kept constant and resource availability was changed only once. Instead, our results indicate a pathway by which a single change in resource availability early in life permanently enhances the learning abilities of animals. Early perturbations of environmental quality may signal the developing individual that it lives in a changing world, requiring increased cognitive abilities to construct adequate behavioral responses. - Cholinergic Activation of M2 Receptors Leads to Context-Dependent Modulation of Feedforward Inhibition in the Visual Thalamus
Antal M Acuna-Goycolea C Pressler RT Blitz DM Regehr WG - PLoS Biol 8(4):e1000348 (2010)
In many brain regions, inhibition is mediated by numerous classes of specialized interneurons, but within the rodent dorsal lateral geniculate nucleus (dLGN), a single class of interneuron is present. dLGN interneurons inhibit thalamocortical (TC) neurons and regulate the activity of TC neurons evoked by retinal ganglion cells (RGCs), thereby controlling the visually evoked signals reaching the cortex. It is not known whether neuromodulation can regulate interneuron firing mode and the resulting inhibition. Here, we examine this in brain slices. We find that cholinergic modulation regulates the output mode of these interneurons and controls the resulting inhibition in a manner that is dependent on the level of afferent activity. When few RGCs are activated, acetylcholine suppresses synaptically evoked interneuron spiking, and strongly reduces disynaptic inhibition. In contrast, when many RGCs are coincidently activated, single stimuli promote the generation of a calciu! m spike, and stimulation with a brief train evokes prolonged plateau potentials lasting for many seconds that in turn lead to sustained inhibition. These findings indicate that cholinergic modulation regulates feedforward inhibition in a context-dependent manner. - Pro-Survival Role for Parkinson's Associated Gene DJ-1 Revealed in Trophically Impaired Dopaminergic Neurons
Aron L Klein P Pham TT Kramer ER Wurst W Klein R - PLoS Biol 8(4):e1000349 (2010)
The mechanisms underlying the selective death of substantia nigra (SN) neurons in Parkinson disease (PD) remain elusive. While inactivation of DJ-1, an oxidative stress suppressor, causes PD, animal models lacking DJ-1 show no overt dopaminergic (DA) neuron degeneration in the SN. Here, we show that aging mice lacking DJ-1 and the GDNF-receptor Ret in the DA system display an accelerated loss of SN cell bodies, but not axons, compared to mice that only lack Ret signaling. The survival requirement for DJ-1 is specific for the GIRK2-positive subpopulation in the SN which projects exclusively to the striatum and is more vulnerable in PD. Using Drosophila genetics, we show that constitutively active Ret and associated Ras/ERK, but not PI3K/Akt, signaling components interact genetically with DJ-1. Double loss-of-function experiments indicate that DJ-1 interacts with ERK signaling to control eye and wing development. Our study uncovers a conserved interaction between DJ-1 an! d Ret-mediated signaling and a novel cell survival role for DJ-1 in the mouse. A better understanding of the molecular connections between trophic signaling, cellular stress and aging could uncover new targets for drug development in PD. - An Excitatory Loop with Astrocytes Contributes to Drive Neurons to Seizure Threshold
Gómez-Gonzalo M Losi G Chiavegato A Zonta M Cammarota M Brondi M Vetri F Uva L Pozzan T de Curtis M Ratto GM Carmignoto G - PLoS Biol 8(4):e1000352 (2010)
Seizures in focal epilepsies are sustained by a highly synchronous neuronal discharge that arises at restricted brain sites and subsequently spreads to large portions of the brain. Despite intense experimental research in this field, the earlier cellular events that initiate and sustain a focal seizure are still not well defined. Their identification is central to understand the pathophysiology of focal epilepsies and to develop new pharmacological therapies for drug-resistant forms of epilepsy. The prominent involvement of astrocytes in ictogenesis was recently proposed. We test here whether a cooperation between astrocytes and neurons is a prerequisite to support ictal (seizure-like) and interictal epileptiform events. Simultaneous patch-clamp recording and Ca2+ imaging techniques were performed in a new in vitro model of focal seizures induced by local applications of N-methyl-D-aspartic acid (NMDA) in rat entorhinal cortex slices. We found that a Ca2+ elevation in ! astrocytes correlates with both the initial development and the maintenance of a focal, seizure-like discharge. A delayed astrocyte activation during ictal discharges was also observed in other models (including the whole in vitro isolated guinea pig brain) in which the site of generation of seizure activity cannot be precisely monitored. In contrast, interictal discharges were not associated with Ca2+ changes in astrocytes. Selective inhibition or stimulation of astrocyte Ca2+ signalling blocked or enhanced, respectively, ictal discharges, but did not affect interictal discharge generation. Our data reveal that neurons engage astrocytes in a recurrent excitatory loop (possibly involving gliotransmission) that promotes seizure ignition and sustains the ictal discharge. This neuron–astrocyte interaction may represent a novel target to develop effective therapeutic strategies to control seizures. - Spadin, a Sortilin-Derived Peptide, Targeting Rodent TREK-1 Channels: A New Concept in the Antidepressant Drug Design
Mazella J Pétrault O Lucas G Deval E Béraud-Dufour S Gandin C El-Yacoubi M Widmann C Guyon A Chevet E Taouji S Conductier G Corinus A Coppola T Gobbi G Nahon JL Heurteaux C Borsotto M - PLoS Biol 8(4):e1000355 (2010)
Current antidepressant treatments are inadequate for many individuals, and when they are effective, they require several weeks of administration before a therapeutic effect can be observed. Improving the treatment of depression is challenging. Recently, the two-pore domain potassium channel TREK-1 has been identified as a new target in depression, and its antagonists might become effective antidepressants. In mice, deletion of the TREK-1 gene results in a depression-resistant phenotype that mimics antidepressant treatments. Here, we validate in mice the antidepressant effects of spadin, a secreted peptide derived from the propeptide generated by the maturation of the neurotensin receptor 3 (NTSR3/Sortilin) and acting through TREK-1 inhibition. NTSR3/Sortilin interacted with the TREK-1 channel, as shown by immunoprecipitation of TREK-1 and NTSR3/Sortilin from COS-7 cells and cortical neurons co-expressing both proteins. TREK-1 and NTSR3/Sortilin were colocalized in mous! e cortical neurons. Spadin bound specifically to TREK-1 with an affinity of 10 nM. Electrophysiological studies showed that spadin efficiently blocked the TREK-1 activity in COS-7 cells, cultured hippocampal pyramidal neurons, and CA3 hippocampal neurons in brain slices. Spadin also induced in vivo an increase of the 5-HT neuron firing rate in the Dorsal Raphe Nucleus. In five behavioral tests predicting an antidepressant response, spadin-treated mice showed a resistance to depression as found in TREK-1 deficient mice. More importantly, an intravenous 4-d treatment with spadin not only induced a strong antidepressant effect but also enhanced hippocampal phosphorylation of CREB protein and neurogenesis, considered to be key markers of antidepressant action after chronic treatment with selective serotonin reuptake inhibitors. This work also shows the development of a reliable method for dosing the propeptide in serum of mice by using AlphaScreen technology. These findings poi! nt out spadin as a putative antidepressant of new generation w! ith a rapid onset of action. Spadin can be regarded as the first natural antidepressant peptide identified. It corresponds to a new concept to address the treatment of depression. - Bicaudal D2, Dynein, and Kinesin-1 Associate with Nuclear Pore Complexes and Regulate Centrosome and Nuclear Positioning during Mitotic Entry
Splinter D Tanenbaum ME Lindqvist A Jaarsma D Flotho A Yu KL Grigoriev I Engelsma D Haasdijk ED Keijzer N Demmers J Fornerod M Melchior F Hoogenraad CC Medema RH Akhmanova A - PLoS Biol 8(4):e1000350 (2010)
BICD2 is one of the two mammalian homologues of the Drosophila Bicaudal D, an evolutionarily conserved adaptor between microtubule motors and their cargo that was previously shown to link vesicles and mRNP complexes to the dynein motor. Here, we identified a G2-specific role for BICD2 in the relative positioning of the nucleus and centrosomes in dividing cells. By combining mass spectrometry, biochemical and cell biological approaches, we show that the nuclear pore complex (NPC) component RanBP2 directly binds to BICD2 and recruits it to NPCs specifically in G2 phase of the cell cycle. BICD2, in turn, recruits dynein-dynactin to NPCs and as such is needed to keep centrosomes closely tethered to the nucleus prior to mitotic entry. When dynein function is suppressed by RNA interference-mediated depletion or antibody microinjection, centrosomes and nuclei are actively pushed apart in late G2 and we show that this is due to the action of kinesin-1. Surprisingly, depletion ! of BICD2 inhibits both dynein and kinesin-1-dependent movements of the nucleus and cytoplasmic NPCs, demonstrating that BICD2 is needed not only for the dynein function at the nuclear pores but also for the antagonistic activity of kinesin-1. Our study demonstrates that the nucleus is subject to opposing activities of dynein and kinesin-1 motors and that BICD2 contributes to nuclear and centrosomal positioning prior to mitotic entry through regulation of both dynein and kinesin-1. - Functional Crosstalk between Type I and II Interferon through the Regulated Expression of STAT1
- PLoS Biol 8(4):e1000361 (2010)
Autocrine priming of cells by small quantities of constitutively produced type I interferon (IFN) is a well-known phenomenon. In the absence of type I IFN priming, cells display attenuated responses to other cytokines, such as anti-viral protection in response to IFNγ. This phenomenon was proposed to be because IFNα/β receptor1 (IFNAR1) is a component of the IFNγ receptor (IFNGR), but our new data are more consistent with a previously proposed model indicating that regulated expression of STAT1 may also play a critical role in the priming process. Initially, we noticed that DNA binding activity of STAT1 was attenuated in c-Jun−/− fibroblasts because they expressed lower levels of STAT1 than wild-type cells. However, expression of STAT1 was rescued by culturing c-Jun−/− fibroblasts in media conditioned by wild-type fibroblasts suggesting they secreted a STAT1-inducing factor. The STAT1-inducing factor in fibroblast-conditioned media was IFNβ, as it was inhi! bited by antibodies to IFNAR1, or when IFNβ expression was knocked down in wild-type cells. IFNAR1−/− fibroblasts, which cannot respond to this priming, also expressed reduced levels of STAT1, which correlated with their poor responses to IFNγ. The lack of priming in IFNAR1−/− fibroblasts was compensated by over-expression of STAT1, which rescued molecular responses to IFNγ and restored the ability of IFNγ to induce protective anti-viral immunity. This study provides a comprehensive description of the molecular events involved in priming by type I IFN. Adding to the previous working model that proposed an interaction between type I and II IFN receptors, our work and that of others demonstrates that type I IFN primes IFNγ-mediated immune responses by regulating expression of STAT1. This may also explain how type I IFN can additionally prime cells to respond to a range of other cytokines that use STAT1 (e.g., IL-6, M-CSF, IL-10) and suggests a potential mechanism! for the changing levels of STAT1 expression observed during v! iral infection. - Degradation of YRA1 Pre-mRNA in the Cytoplasm Requires Translational Repression, Multiple Modular Intronic Elements, Edc3p, and Mex67p
- PLoS Biol 8(4):e1000360 (2010)
Intron-containing pre-mRNAs are normally retained and processed in the nucleus but are sometimes exported to the cytoplasm and degraded by the nonsense-mediated mRNA decay (NMD) pathway as a consequence of their inclusion of intronic in-frame termination codons. When shunted to the cytoplasm by autoregulated nuclear export, the intron-containing yeast YRA1 pre-mRNA evades NMD and is targeted by a cytoplasmic decay pathway mediated by the decapping activator Edc3p. Here, we have elucidated this transcript-specific decay mechanism, showing that Edc3p-mediated YRA1 pre-mRNA degradation occurs independently of translation and is controlled through five structurally distinct but functionally interdependent modular elements in the YRA1 intron. Two of these elements target the pre-mRNA as an Edc3p substrate and the other three mediate transcript-specific translational repression. Translational repression of YRA1 pre-mRNA also requires the heterodimeric Mex67p/Mtr2p general mR! NA export receptor, but not Edc3p, and serves to enhance Edc3p substrate specificity by inhibiting the susceptibility of this pre-mRNA to NMD. Collectively, our data indicate that YRA1 pre-mRNA degradation is a highly regulated process that proceeds through translational repression, substrate recognition by Edc3p, recruitment of the Dcp1p/Dcp2p decapping enzyme, and activation of decapping. - Structural Basis for Fe–S Cluster Assembly and tRNA Thiolation Mediated by IscS Protein–Protein Interactions
Shi R Proteau A Villarroya M Moukadiri I Zhang L Trempe JF Matte A Armengod ME Cygler M - PLoS Biol 8(4):e1000354 (2010)
The cysteine desulfurase IscS is a highly conserved master enzyme initiating sulfur transfer via persulfide to a range of acceptor proteins involved in Fe-S cluster assembly, tRNA modifications, and sulfur-containing cofactor biosynthesis. Several IscS-interacting partners including IscU, a scaffold for Fe-S cluster assembly; TusA, the first member of a sulfur relay leading to sulfur incorporation into the wobble uridine of several tRNAs; ThiI, involved in tRNA modification and thiamine biosynthesis; and rhodanese RhdA are sulfur acceptors. Other proteins, such as CyaY/frataxin and IscX, also bind to IscS, but their functional roles are not directly related to sulfur transfer. We have determined the crystal structures of IscS-IscU and IscS-TusA complexes providing the first insight into their different modes of binding and the mechanism of sulfur transfer. Exhaustive mutational analysis of the IscS surface allowed us to map the binding sites of various partner proteins! and to determine the functional and biochemical role of selected IscS and TusA residues. IscS interacts with its partners through an extensive surface area centered on the active site Cys328. The structures indicate that the acceptor proteins approach Cys328 from different directions and suggest that the conformational plasticity of a long loop containing this cysteine is essential for the ability of IscS to transfer sulfur to multiple acceptor proteins. The sulfur acceptors can only bind to IscS one at a time, while frataxin and IscX can form a ternary complex with IscU and IscS. Our data support the role of frataxin as an iron donor for IscU to form the Fe-S clusters.
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