Current Biology

Patrick H. O'Farrell.

Publication Date: 2010 Feb 23 PMID: 20213891
Authors: O'Farrell, P. H.
Journal: Curr Biol

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Merchants and ivory.

Publication Date: 2010 Feb 23 PMID: 20213890
Authors: Williams, N.
Journal: Curr Biol

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Darwin's enduring finches.

Publication Date: 2010 Feb 23 PMID: 20213889
Authors: Williams, N.
Journal: Curr Biol

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High life.

Publication Date: 2010 Feb 23 PMID: 20213888
Authors: Gross, M.
Journal: Curr Biol

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Biofuel boom.

Publication Date: 2010 Feb 23 PMID: 20213887
Authors: Martin, C.
Journal: Curr Biol

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Climate change attack.

Publication Date: 2010 Feb 23 PMID: 20213886
Authors: Williams, N.
Journal: Curr Biol

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Crowding Changes Appearance.

Publication Date: 2010 Mar 3 PMID: 20206527
Authors: Greenwood, J. A. - Bex, P. J. - Dakin, S. C.
Journal: Curr Biol

Crowding is the breakdown in object recognition that occurs in cluttered visual environments [1-4] and the fundamental limit on peripheral vision, affecting identification within many visual modalities [5-9] and across large spatial regions [10]. Though frequently characterized as a disruptive process through which object representations are suppressed [11, 12] or lost altogether [13-15], we demonstrate that crowding systematically changes the appearance of objects. In particular, target patches of visual noise that are surrounded ("crowded") by oriented Gabor flankers become perceptually oriented, matching the flankers. This was established with a change-detection paradigm: under crowded conditions, target changes from noise to Gabor went unnoticed when the Gabor orientation matched the flankers (and the illusory target percept), despite being easily detected when they differed. Rotation of the flankers (leaving target noise unaltered) also induced illusory target rotations. Blank targets led to similar results, demonstrating that crowding can induce apparent structure where none exists. Finally, adaptation to these stimuli induced a tilt aftereffect at the target location, consistent with signals from the flankers "spreading" across space. These results confirm predictions from change-based models of crowding, such as averaging [16], and establish crowding as a regularization process that simplifies the peripheral field by promoting consistent appearance among adjacent objects.

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Functional Diversity of Robo Receptor Immunoglobulin Domains Promotes Distinct Axon Guidance Decisions.

Publication Date: 2010 Mar 3 PMID: 20206526
Authors: Evans, T. A. - Bashaw, G. J.
Journal: Curr Biol

Recognition molecules of the immunoglobulin (Ig) superfamily control axon guidance in the developing nervous system. Ig-like domains are among the most widely represented protein domains in the human genome, and the number of Ig superfamily proteins is strongly correlated with cellular complexity [1]. In Drosophila, three Roundabout (Robo) Ig superfamily receptors respond to their common Slit ligand to regulate axon guidance at the midline: Robo and Robo2 mediate midline repulsion, Robo2 and Robo3 control longitudinal pathway selection, and Robo2 can promote midline crossing [2-5]. How these closely related receptors mediate distinct guidance functions is not understood. We report that the differential functions of Robo2 and Robo3 are specified by their ectodomains and do not reflect differences in cytoplasmic signaling. Functional modularity of Robo2's ectodomain facilitates multiple guidance decisions: Ig1 and Ig3 of Robo2 confer lateral positioning activity, whereas Ig2 confers promidline crossing activity. Robo2's distinct functions are not dependent on greater Slit affinity but are instead due in part to differences in multimerization and receptor-ligand stoichiometry conferred by Robo2's Ig domains. Together, our findings suggest that diverse responses to the Slit guidance cue are imparted by intrinsic structural differences encoded in the extracellular Ig domains of the Robo receptors.

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Complexity Increases Working Memory for Mating Signals.

Publication Date: 2010 Mar 3 PMID: 20206525
Authors: Akre, K. L. - Ryan, M. J.
Journal: Curr Biol

Females often prefer to mate with males who produce complex signals [1-3]. It is not clear why they do so. Females might prefer complexity if it predicts mate quality [4-6], or signals might evolve complexity to exploit females' sensory or cognitive biases [6-9]. We tested whether complexity increases active time, the period over which a signal influences a receiver's response to that signal. Mating signals are often ephemeral, yet their active time has largely been ignored. Here we demonstrate that signal complexity influences active time in tungara frogs. Male advertisement calls consist of frequency sweeps (whines) followed by 0-7 high-frequency bursts (chucks). Females preferentially approach complex (whines with chucks) over simple (whines alone) calls but do not consistently prefer greater complexity [10], so the function of multiple chucks has been uncertain. We found that females remember which speaker previously broadcast complex calls when choosing between simple calls broadcast after a delay. This effect occurred for calls with multiple chucks, but not with single chucks. Neither motivation nor orientation behavior differed with chuck number, suggesting that results are due to differential memory. Thus, female memory could favor the evolution of increasing signal complexity through sexual selection.

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Tubulin Glutamylation Regulates Ciliary Motility by Altering Inner Dynein Arm Activity.

Publication Date: 2010 Feb 25 PMID: 20189389
Authors: Suryavanshi, S. - Edde, B. - Fox, L. A. - Guerrero, S. - Hard, R. - Hennessey, T. - Kabi, A. - Malison, D. - Pennock, D. - Sale, W. S. - Wloga, D. - Gaertig, J.
Journal: Curr Biol

How microtubule-associated motor proteins are regulated is not well understood. A potential mechanism for spatial regulation of motor proteins is provided by posttranslational modifications of tubulin subunits that form patterns on microtubules. Glutamylation is a conserved tubulin modification [1] that is enriched in axonemes. The enzymes responsible for this posttranslational modification, glutamic acid ligases (E-ligases), belong to a family of proteins with a tubulin tyrosine ligase (TTL) homology domain (TTL-like or TTLL proteins) [2]. We show that in cilia of Tetrahymena, TTLL6 E-ligases generate glutamylation mainly on the B-tubule of outer doublet microtubules, the site of force production by ciliary dynein. Deletion of two TTLL6 paralogs caused severe deficiency in ciliary motility associated with abnormal waveform and reduced beat frequency. In isolated axonemes with a normal dynein arm composition, TTLL6 deficiency did not affect the rate of ATP-induced doublet microtubule sliding. Unexpectedly, the same TTLL6 deficiency increased the velocity of microtubule sliding in axonemes that also lack outer dynein arms, in which forces are generated by inner dynein arms. We conclude that tubulin glutamylation on the B-tubule inhibits the net force imposed on sliding doublet microtubules by inner dynein arms.

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Retinoids Regulate a Developmental Checkpoint for Tissue Regeneration in Drosophila.

Publication Date: 2010 Feb 25 PMID: 20189388
Authors: Halme, A. - Cheng, M. - Hariharan, I. K.
Journal: Curr Biol

Damage to Drosophila imaginal discs elicits a robust regenerative response from the surviving tissue [1-4]. However, as in other organisms, developmental progression and differentiation can restrict the regenerative capacity of Drosophila tissues. Experiments in Drosophila and other holometabolous insects have demonstrated that either damage to imaginal tissues [5, 6] or transplantation of a damaged imaginal disc [7, 8] delays the onset of metamorphosis. Therefore, in Drosophila there appears to be a mechanism that senses tissue damage and extends the larval phase to coordinate tissue regeneration with the overall developmental program of the organism. However, how such a pathway functions remains unknown. Here we demonstrate that a developmental checkpoint extends larval growth after imaginal disc damage by inhibiting the transcription of the gene encoding PTTH, a neuropeptide that promotes the release of the steroid hormone ecdysone. Using a genetic screen, we identify a previously unsuspected role for retinoid biosynthesis in regulating PTTH expression and delaying development in response to tissue damage. Retinoid signaling plays an important but poorly defined role in several vertebrate regeneration models [9-11]. Our findings demonstrate that retinoid biosynthesis in Drosophila is important for the maintenance of a condition that is permissive for regenerative growth.

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A "Primer"-Based Mechanism Underlies Branched Actin Filament Network Formation and Motility.

Publication Date: 2010 Feb 24 PMID: 20188562
Authors: Achard, V. - Martiel, J. L. - Michelot, A. - Guerin, C. - Reymann, A. C. - Blanchoin, L. - Boujemaa-Paterski, R.
Journal: Curr Biol

Cells use actin assembly to generate forces for membrane protrusions during movement [1] or, in the case of pathogens, to propel themselves in the host cells, in crude extracts [2], or in mixtures of actin and other purified proteins [3]. Significant progress has been made in understanding the mechanism of actin-based motility at a macroscopic level by using biomimetic systems in vitro [4-6]. Here, we combined such a system with evanescent wave microscopy to visualize Arp2/3-mediated actin network formation at single-actin-filament resolution. We found that actin filaments that we call "primers" determine the origin of the autocatalytic and propagative formation of the actin network. In the presence of capping protein, multiple "primers" generate independent networks that merge around the object to form an outer "shell" made of entangled and capped filaments. Simultaneously, newly created filaments on the surface of the particle initiate mechanical stress, which develops until symmetry breaking. Our results and extensive modeling support that the stress, which releases into propulsive forces [7], is controlled not by any specific orientation of actin filaments toward the nucleation sites but only by new monomers added near the load surface.

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Polyandry Prevents Extinction.

Publication Date: 2010 Feb 24 PMID: 20188561
Authors: Price, T. A. - Hurst, G. D. - Wedell, N.
Journal: Curr Biol

Females of most animal species are polyandrous, with individual females usually mating with more than one male [1, 2]. However, the ubiquity of polyandry remains enigmatic [3, 4] because of the potentially high costs to females of multiple mating [5, 6]. Current theory to account for the high prevalence of polyandry largely focuses on its benefits to individual females [7, 8]. There are also higher-level explanations for the high incidence of polyandry-polyandrous clades may speciate more rapidly [6]. Here we test the hypothesis that polyandry may also reduce population extinction risk. We demonstrate that mating with multiple males protects populations of the fruit fly Drosophila pseudoobscura against extinction caused by a "selfish" sex-ratio-distorting element. Thus, the frequency of female multiple mating in nature may be associated not only with individual benefits to females of this behavior but also with increased persistence over time of polyandrous species and populations. Furthermore, we show that female remating behavior can determine the frequency of sex-ratio distorters in populations. This may also be true for many other selfish genetic elements in natural populations.

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Tubulin Polyglutamylation Regulates Axonemal Motility by Modulating Activities of Inner-Arm Dyneins.

Publication Date: 2010 Feb 24 PMID: 20188560
Authors: Kubo, T. - Yanagisawa, H. A. - Yagi, T. - Hirono, M. - Kamiya, R.
Journal: Curr Biol

Tubulin polyglutamylation is a modification that adds multiple glutamates to the gamma-carboxyl group of a glutamate residue in the C-terminal tails of alpha- and beta-tubulin [1, 2]. This modification has been implicated in the regulation of axonal transport and ciliary motility. However, its molecular function in cilia remains unknown. Here, using a novel Chlamydomonas reinhardtii mutant (tpg1) that lacks a homolog of human TTLL9, a glutamic acid ligase enzyme [3], we found that the lack of a long polyglutamate side chain in alpha-tubulin moderately weakens flagellar motility without noticeably impairing the axonemal structure. Furthermore, the double mutant of tpg1 with oda2, a mutation that leads to loss of outer-arm dynein, completely lacks motility. More surprisingly, when treated with protease and ATP, the axoneme of this paralyzed double mutant displayed faster microtubule sliding than the motile oda2 axoneme. These and other results suggest that polyglutamylation directly regulates microtubule-dynein interaction mainly by modulating the function of inner-arm dyneins.

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KLUH/CYP78A5-Dependent Growth Signaling Coordinates Floral Organ Growth in Arabidopsis.

Publication Date: 2010 Feb 24 PMID: 20188559
Authors: Eriksson, S. - Stransfeld, L. - Adamski, N. M. - Breuninger, H. - Lenhard, M.
Journal: Curr Biol

Growth control in animals and plants involves mobile signals [1, 2]. Depending on their range of action, these signals coordinate the growth of cells within an organ or the growth of different organs in a larger, functionally integrated structure [3-7]. In plants, flowers are such integrated structures, yet it remains poorly understood how growth of the constituent organs is coordinated to ensure their correct relative sizes. The cytochrome P450 KLUH/CYP78A5 and its homolog CYP78A7 promote organ growth via a non-cell-autonomous signal [8-10]; however, the range of this signal and thus its developmental function are unknown. Here we use a system for the predictable generation of chimeric plants to determine the range of the KLUH-dependent signal. In contrast with the largely autonomous behavior of another tested growth-control gene, we find that KLUH activity extends beyond individual organs and flowers. Its overall activity is integrated across an inflorescence to determine final organ size, which is largely independent of the genotype of the individual organs. Thus, the KLUH-dependent signal appears to move beyond individual organs in a flower, providing a mechanism for coordinating their growth and ensuring floral symmetry as an important determinant of a plant's attractiveness to pollinators [11].

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Prioritization of Competing Damage and Developmental Signals by Migrating Macrophages in the Drosophila Embryo.

Publication Date: 2010 Feb 24 PMID: 20188558
Authors: Moreira, S. - Stramer, B. - Evans, I. - Wood, W. - Martin, P.
Journal: Curr Biol

The function of immune cells is critically dependent on their capacity to respond to a complex series of navigational cues that enable them to home to various organ sites in the body or to respond to inflammatory cues such as those released at sites of tissue damage. From early embryonic stages, immune cells are faced with a barrage of signals that will not all be directing the cell to do the same thing. Here we use the Drosophila embryo to investigate how hemocytes (Drosophila macrophages), are able to prioritize key guidance signals and ignore others so that they are not pulled every which way. We identify the immediate wound attractant signal as H(2)O(2) and investigate how Drosophila macrophages respond to competing guidance cues-those emanating from a wound-versus standard developmental guidance cues, as well as those signals drawing cells toward neighboring dying cells. We reveal a hierarchy of responsiveness to attractant cues that varies over time and we identify why there is a wound refractile period early in embryonic development when macrophages cannot be distracted from their developmental migratory pathway to a site of tissue damage.

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A Species of Reef Fish that Uses Ultraviolet Patterns for Covert Face Recognition.

Publication Date: 2010 Feb 24 PMID: 20188557
Authors: Siebeck, U. E. - Parker, A. N. - Sprenger, D. - Mathger, L. M. - Wallis, G.
Journal: Curr Biol

The evolutionary and behavioral significance of an animal's color patterns remains poorly understood [1-4], not least, patterns that reflect ultraviolet (UV) light [5]. The current belief is that UV signals must be broad and bold to be detected because (1) they are prone to scattering in air and water, (2) when present, UV-sensitive cones are generally found in low numbers, and (3) long-wavelength-sensitive cones predominate in form vision in those species tested to date [6]. We report a study of two species of damselfish whose appearance differs only in the fine detail of UV-reflective facial patterns. We show that, contrary to expectations, the Ambon damselfish (Pomacentrus amboinensis) is able to use these patterns for species discrimination. We also reveal that the essential features of the patterns are contained in their shape rather than color. The results provide support for the hypothesis that UV is used by some fish as a high-fidelity "secret communication channel" hidden from predators [7, 8]. In more general terms, the findings help unravel the details of a language of color and pattern long since lost to our primate forebears, but which has been part of the world of many seeing organisms for millions of years.

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Methylation of H3K4 Is Required for Inheritance of Active Transcriptional States.

Publication Date: 2010 Feb 24 PMID: 20188556
Authors: Muramoto, T. - Muller, I. - Thomas, G. - Melvin, A. - Chubb, J. R.
Journal: Curr Biol

BACKGROUND: Maintenance of differentiation programs requires stability, when appropriate, of transcriptional states. However, the extent to which inheritance of active transcriptional states occurs from mother to daughter cells has not been directly addressed in unperturbed cell populations. RESULTS: By live imaging of single-gene transcriptional events in individual cells, we have directly recorded the potential for mitotic inheritance of transcriptional states down cell lineages. Our data showed strong similarity in frequency of transcriptional firing between mother and daughter cells. This memory persisted for complete cell cycles. Both transcriptional pulse length and pulsing rate contributed to overall inheritance, and memory was determined by lineage, not cell environment. Analysis of transcription in chromatin mutants demonstrated that the histone H3K4 methylase Set1 and Ash2, a component of the methylase complex, are required for memory. The effects of Set1 methylation may be mediated directly by chromatin, because loss of memory also occurred when endogenous H3K4 was replaced by alanine. Although methylated H3K4 is usually associated with active transcriptional units, the modification was not required for gene activity but stabilized transcriptional frequency between generations. CONCLUSIONS: Our data indicate that methylated H3K4 can act as a chromatin mark reflecting the original meaning of "epigenetic."

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Repo-Man Controls a Protein Phosphatase 1-Dependent Threshold for DNA Damage Checkpoint Activation.

Publication Date: 2010 Feb 24 PMID: 20188555
Authors: Peng, A. - Lewellyn, A. L. - Schiemann, W. P. - Maller, J. L.
Journal: Curr Biol

BACKGROUND: In response to DNA damage, cells activate checkpoints to halt cell-cycle progression and prevent genomic instability. Checkpoint activation induced by DNA double-strand breaks (DSB) is dependent on the ATM kinase, a master regulator of the DNA damage response (DDR) that is activated through autophosphorylation and monomerization. RESULTS: Here we show that either protein phosphatase 1 or 2A is sufficient to suppress activation of the DDR and that simultaneous inhibition of both phosphatases fully activates the response. PP1-dependent DDR regulation is mediated by its chromatin-targeting subunit, Repo-Man. Studies in Xenopus egg extracts demonstrate that Repo-Man interacts with ATM and PP1 through distinct domains, leading to PP1-dependent regulation of ATM phosphorylation and activation. Consequently, the level of Repo-Man determines the activation threshold of the DNA damage checkpoint. Repo-Man interacts and extensively colocalizes with ATM in human cells. Expression of wild-type, but not PP1 binding-deficient, Repo-Man attenuates DNA damage-induced ATM activation. Moreover, Repo-Man dissociates from active ATM at DNA damage sites, suggesting that activation of the DDR involves removal of inhibitory regulators. Analysis of primary tumor tissues and cell lines demonstrates that Repo-Man is frequently upregulated in many types of cancers. Elevated Repo-Man expression blunts DDR activation in precancerous cells, whereas knockdown of Repo-Man in malignant cancer cells resensitizes the DDR and restrains growth in soft agar. CONCLUSIONS: We report essential DDR regulation mediated by Repo-Man-PP1 and further delineate underlying mechanisms. Moreover, our evidence suggests that elevated Repo-Man contributes to cancer progression.

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The genetics of human adaptation: hard sweeps, soft sweeps, and polygenic adaptation.

Publication Date: 2010 Feb 23 PMID: 20178769
Authors: Pritchard, J. K. - Pickrell, J. K. - Coop, G.
Journal: Curr Biol

There has long been interest in understanding the genetic basis of human adaptation. To what extent are phenotypic differences among human populations driven by natural selection? With the recent arrival of large genome-wide data sets on human variation, there is now unprecedented opportunity for progress on this type of question. Several lines of evidence argue for an important role of positive selection in shaping human variation and differences among populations. These include studies of comparative morphology and physiology, as well as population genetic studies of candidate loci and genome-wide data. However, the data also suggest that it is unusual for strong selection to drive new mutations rapidly to fixation in particular populations (the 'hard sweep' model). We argue, instead, for alternatives to the hard sweep model: in particular, polygenic adaptation could allow rapid adaptation while not producing classical signatures of selective sweeps. We close by discussing some of the likely opportunities for progress in the field.

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The human genetic history of the Americas: the final frontier.

Publication Date: 2010 Feb 23 PMID: 20178768
Authors: O'Rourke, D. H. - Raff, J. A.
Journal: Curr Biol

The Americas, the last continents to be entered by modern humans, were colonized during the late Pleistocene via a land bridge across what is now the Bering strait. However, the timing and nature of the initial colonization events remain contentious. The Asian origin of the earliest Americans has been amply established by numerous classical marker studies of the mid-twentieth century. More recently, mtDNA sequences, Y-chromosome and autosomal marker studies have provided a higher level of resolution in confirming the Asian origin of indigenous Americans and provided more precise time estimates for the emergence of Native Americans. But these data raise many additional questions regarding source populations, number and size of colonizing groups and the points of entry to the Americas. Rapidly accumulating molecular data from populations throughout the Americas, increased use of demographic models to test alternative colonization scenarios, and evaluation of the concordance of archaeological, paleoenvironmental and genetic data provide optimism for a fuller understanding of the initial colonization of the Americas.

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The human genetic history of Oceania: near and remote views of dispersal.

Publication Date: 2010 Feb 23 PMID: 20178767
Authors: Kayser, M.
Journal: Curr Biol

The human history of Oceania is unique in the way that it encompasses both the first out-of-Africa expansion of modern humans to New Guinea and Australia as well as the last regional human occupation of Polynesia. Other anthropological peculiarities of Oceania include features like the extraordinarily rich linguistic diversity especially of New Guinea with about 1,000 often very distinct languages, the independent and early development of agriculture in the highlands of New Guinea about 10,000 years ago, or the long-term isolation of the entire region from the outside world, which lasted as long as until the 1930s for most of the interior of New Guinea. This review will provide an overview on the genetic aspects of human population history of Oceania and how some of the anthropological peculiarities are reflected in human genetic data. Due to current data availability it will mostly focus on insights from sex-specifically inherited mitochondrial DNA and Y-chromosomal DNA, whereas more genome-wide autosomal DNA data are soon expected to add additional details or may correct views obtained from these two, albeit highly complex, genetic loci.

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The human genetic history of East Asia: weaving a complex tapestry.

Publication Date: 2010 Feb 23 PMID: 20178766
Authors: Stoneking, M. - Delfin, F.
Journal: Curr Biol

East Asia encompasses a wide variety of environments, peoples, cultures and languages. Although this review focuses on East Asia, no geographic region can be considered in isolation in terms of human population history, and migrations to and from East Asia have had a major impact. Here, we review the following topics: the initial colonization of East Asia, the direction of migrations between southeast Asia and northern Asia, the genetic relationships of East Asian hunter-gatherers and the genetic impact of various social practices on East Asian populations. By necessity we focus on insights derived from mitochondrial DNA and/or Y-chromosome data; ongoing and future studies of genome-wide SNP or multi-locus re-sequencing data, combined with the use of simulation, model-based methods to infer demographic parameters, will undoubtedly provide additional insights into the population history of East Asia.

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The human genetic history of South Asia.

Publication Date: 2010 Feb 23 PMID: 20178765
Authors: Majumder, P. P.
Journal: Curr Biol

South Asia--comprising India, Pakistan, countries in the sub-Himalayan region and Myanmar--was one of the first geographical regions to have been peopled by modern humans. This region has served as a major route of dispersal to other geographical regions, including southeast Asia. The Indian society comprises tribal, ranked caste, and other populations that are largely endogamous. As a result of evolutionary antiquity and endogamy, populations of India show high genetic differentiation and extensive structuring. Linguistic differences of populations provide the best explanation of genetic differences observed in this region of the world. Within India, consistent with social history, extant populations inhabiting northern regions show closer affinities with Indo-European speaking populations of central Asia that those inhabiting southern regions. Extant southern Indian populations may have been derived from early colonizers arriving from Africa along the southern exit route. The higher-ranked caste populations, who were the torch-bearers of Hindu rituals, show closer affinities with central Asian, Indo-European speaking, populations.

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The archaeogenetics of Europe.

Publication Date: 2010 Feb 23 PMID: 20178764
Authors: Soares, P. - Achilli, A. - Semino, O. - Davies, W. - Macaulay, V. - Bandelt, H. J. - Torroni, A. - Richards, M. B.
Journal: Curr Biol

A new timescale has recently been established for human mitochondrial DNA (mtDNA) lineages, making mtDNA at present the most informative genetic marker system for studying European prehistory. Here, we review the new chronology and compare mtDNA with Y-chromosome patterns, in order to summarize what we have learnt from archaeogenetics concerning five episodes over the past 50,000 years which significantly contributed to the settlement history of Europe: the pioneer colonisation of the Upper Palaeolithic, the Late Glacial re-colonisation of the continent from southern refugia after the Last Glacial Maximum, the postglacial re-colonization of deserted areas after the Younger Dryas cold snap, the arrival of Near Easterners with an incipient Neolithic package, and the small-scale migrations along continent-wide economic exchange networks beginning with the Copper Age. The available data from uniparental genetic systems have already transformed our view of the prehistory of Europe, but our knowledge of these processes remains limited. Nevertheless, their legacy remains as sedimentary layers in the gene pool of modern Europeans, and our understanding of them will improve substantially when more mtDNAs are completely sequenced, the Y chromosome more thoroughly analysed, and haplotype blocks of the autosomal genome become amenable to phylogeographic studies.

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The evolution of human genetic and phenotypic variation in Africa.

Publication Date: 2010 Feb 23 PMID: 20178763
Authors: Campbell, M. C. - Tishkoff, S. A.
Journal: Curr Biol

Africa is the birthplace of modern humans, and is the source of the geographic expansion of ancestral populations into other regions of the world. Indigenous Africans are characterized by high levels of genetic diversity within and between populations. The pattern of genetic variation in these populations has been shaped by demographic events occurring over the last 200,000 years. The dramatic variation in climate, diet, and exposure to infectious disease across the continent has also resulted in novel genetic and phenotypic adaptations in extant Africans. This review summarizes some recent advances in our understanding of the demographic history and selective pressures that have influenced levels and patterns of diversity in African populations.

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Archaeogenetics--towards a 'new synthesis'?

Publication Date: 2010 Feb 23 PMID: 20178762
Authors: Renfrew, C.
Journal: Curr Biol

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Behavioral neurobiology: how larval fish orient towards the light.

Publication Date: 2010 Feb 23 PMID: 20178761
Authors: Mueller, K. P. - Neuhauss, S. C.
Journal: Curr Biol

Orientation of animals towards or away from light is a simple behavior commonly found in the animal kingdom. A recent study using zebrafish larvae has revealed the underlying neural logic of this primal choice behavior, by differential use of the retinal ON- and OFF-pathways.

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Dendritic spines: the stuff that memories are made of?

Publication Date: 2010 Feb 23 PMID: 20178760
Authors: Hofer, S. B. - Bonhoeffer, T.
Journal: Curr Biol

Two new studies explore structural changes of nerve cells as a potential mechanism for memory formation by studying synaptic reorganization associated with motor learning.

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Lipid kinases: charging PtdIns(4,5)P2 synthesis.

Publication Date: 2010 Feb 23 PMID: 20178759
Authors: Divecha, N.
Journal: Curr Biol

Phosphatidylinositol (4,5) bisphosphate is a lipid second messenger that controls diverse cellular processes. Phosphatidylinositolphosphate-5-kinases synthesise this lipid at the plasma membrane, although it is not clear how the localisation of these kinases is controlled. A recent study suggests that the intrinsic surface charge of the plasma membrane may be an important factor.

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Convergent evolution: pick your poison carefully.

Publication Date: 2010 Feb 23 PMID: 20178758
Authors: Brodie, E. D. 3rd
Journal: Curr Biol

Genomic and biochemical analyses reveal that two independently evolved serine protease venoms in mammals and lizards have converged on nearly identical protein structures. Likewise, in two groups of frog, an identical toxin, caerulein, has arisen repeatedly from unique genes in those lineages.

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Phototransduction: keep an eye out for acid-labile TRPs.

Publication Date: 2010 Feb 23 PMID: 20178757
Authors: Gudermann, T. - Mederos y Schnitzler, M.
Journal: Curr Biol

Our mechanistic understanding of phototransduction in the Drosophila eye is still rudimentary. Recent work demonstrates that a combination of phosphoinositide depletion and microvillar acidification is sufficient to activate light-sensitive TRPC channels.

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Biological rhythms: the taste-time continuum.

Publication Date: 2010 Feb 23 PMID: 20178756
Authors: Krupp, J. J. - Levine, J. D.
Journal: Curr Biol

The gustatory system allows the fly to assess food quality, eliciting either acceptance or avoidance behaviors. A new study demonstrates that circadian clocks in gustatory receptor neurons regulate rhythms in taste sensitivity, drive rhythms in appetitive behavior and influence feeding.

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DNA repair: how MutM finds the needle in a haystack.

Publication Date: 2010 Feb 23 PMID: 20178755
Authors: Jiricny, J.
Journal: Curr Biol

High-resolution crystal structures of DNA complexes with the bacterial MutM protein show how the enzyme feels its way around the double helix in search of an oxidized guanine before flipping it out into its active site and excising it.

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Touch disambiguates rivalrous perception at early stages of visual analysis.

Publication Date: 2010 Feb 23 PMID: 20178754
Authors: Lunghi, C. - Binda, P. - Morrone, M. C.
Journal: Curr Biol

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Nitric oxide synthase is not essential for Drosophila development.

Publication Date: 2010 Feb 23 PMID: 20178753
Authors: Yakubovich, N. - Silva, E. A. - O'Farrell, P. H.
Journal: Curr Biol

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Working memory.

Publication Date: 2010 Feb 23 PMID: 20178752
Authors: Baddeley, A.
Journal: Curr Biol

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Anillin.

Publication Date: 2010 Feb 23 PMID: 20178751
Authors: Zhang, L. - Maddox, A. S.
Journal: Curr Biol

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Pickpocket Is a DEG/ENaC Protein Required for Mechanical Nociception in Drosophila Larvae.

Publication Date: 2010 Feb 17 PMID: 20171104
Authors: Zhong, L. - Hwang, R. Y. - Tracey, W. D.
Journal: Curr Biol

Highly branched class IV multidendritic sensory neurons of the Drosophila larva function as polymodal nociceptors that are necessary for behavioral responses to noxious heat (>39 degrees C) or noxious mechanical (>30 mN) stimuli. However, the molecular mechanisms that allow these cells to detect both heat and force are unknown. Here, we report that the pickpocket (ppk) gene, which encodes a Degenerin/Epithelial Sodium Channel (DEG/ENaC) subunit, is required for mechanical nociception but not thermal nociception in these sensory cells. Larvae mutant for pickpocket show greatly reduced nociception behaviors in response to harsh mechanical stimuli. However, pickpocket mutants display normal behavioral responses to gentle touch. Tissue-specific knockdown of pickpocket in nociceptors phenocopies the mechanical nociception impairment without causing defects in thermal nociception behavior. Finally, optogenetically triggered nociception behavior is unaffected by pickpocket RNAi, which indicates that ppk is not generally required for the excitability of the nociceptors. Interestingly, DEG/ENaCs are known to play a critical role in detecting gentle touch stimuli in Caenorhabditis elegans and have also been implicated in some aspects of harsh touch sensation in mammals. Our results suggest that neurons that detect harsh touch in Drosophila utilize similar mechanosensory molecules.

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MST1 Limits the Kinase Activity of Aurora B to Promote Stable Kinetochore-Microtubule Attachment.

Publication Date: 2010 Feb 17 PMID: 20171103
Authors: Oh, H. J. - Kim, M. J. - Song, S. J. - Kim, T. - Lee, D. - Kwon, S. H. - Choi, E. J. - Lim, D. S.
Journal: Curr Biol

The establishment and maintenance of proper attachment of kinetochores to microtubules are required to prevent chromosome missegregation and consequent chromosomal instability and tumorigenesis. Although MST1 (mammalian sterile 20-like kinase 1) has been implicated in many aspects of cell cycle regulation and tumor suppression [1], its precise mechanism of action has remained largely unknown. We now show that MST1 promotes accurate kinetochore-microtubule attachment by modulating the kinase activity of Aurora B. HeLa cells depleted of MST1 failed to develop stable end-on kinetochore-microtubule attachment, giving rise to unaligned mitotic chromosomes. The misaligned chromosomes activated the Mad2- and BubR1-dependent spindle checkpoint response, resulting in a delay in anaphase onset. The kinase activity of Aurora B, which promotes destabilization of kinetochore-microtubule attachment [2-4], was increased in cells depleted of MST1 or NDR1, a downstream kinase of MST1. MST1 and NDR1 associated with Aurora B. Moreover, MST1 directly phosphorylated Aurora B and inhibited its kinase activity in vitro. Depletion of Aurora B restored the stability of kinetochore-microtubule attachment in cells depleted of MST1 or NDR1. MST1 is thus a key regulator of Aurora B activity that ensures mitotic chromosome congression and accurate chromosome segregation.

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SCHIZORIZA Encodes a Nuclear Factor Regulating Asymmetry of Stem Cell Divisions in the Arabidopsis Root.

Publication Date: 2010 Feb 17 PMID: 20171102
Authors: Ten Hove, C. A. - Willemsen, V. - de Vries, W. J. - van Dijken, A. - Scheres, B. - Heidstra, R.
Journal: Curr Biol

Cell divisions generating daughter cells different in size, shape, identity, and function are indispensable for many developmental processes including fate specification, tissue patterning, and self-renewal. In animals and yeast, perturbations in factors required for well-described asymmetric cell divisions generally yield cells of equal fate. Here we report on SCHIZORIZA (SCZ), a single nuclear factor with homology to heat-shock transcription factors that controls the separation of cell fate in a set of stem cells generating different root tissues: root cap, epidermis, cortex, and endodermis. Loss-of-function, expression, and reconstitution experiments indicate that SCZ acts mainly from within its cortical expression domain in the stem cell niche, exerting both autonomous and nonautonomous effects to specify cortex identity and control the separation of cell fates in surrounding layers. Thus, SCZ defines a novel pathway for asymmetric cell division in plants.

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Reorganization of Global Form and Motion Processing during Human Visual Development.

Publication Date: 2010 Feb 17 PMID: 20171101
Authors: Wattam-Bell, J. - Birtles, D. - Nystrom, P. - von Hofsten, C. - Rosander, K. - Anker, S. - Atkinson, J. - Braddick, O.
Journal: Curr Biol

The functional selectivity of human primary visual cortex (V1) for orientation and motion direction is established by around 3 months of age [1-3], but there have been few studies of the development of extrastriate visual areas that integrate outputs from V1 [4-8]. We investigated sensitivity and topographical organization for global form and motion with high-density visual event-related potentials (VERPs) in 4- to 5-month-old infants and adults. Responses were measured to transitions between concentrically organized elements (short arc segments for form, dot trajectories for motion) and random arrangements. Adults showed topographically separate responses, with midline motion and more lateral form responses. Of 26 infants, 25 showed significant motion responses but only 13 showed form responses, suggesting more advanced development for extrastriate motion areas than form. Infants' form and motion responses were topographically distinct but contrasted with the corresponding adult topographies, with infants' motion responses more lateral than form responses. These results imply distinct neural sources at both ages and raise the possibility of substantial reorganization of extrastriate networks between infancy and adulthood. We speculate that global motion responses arise from area V5 in infants but are dominated by more medial areas such as V3/V3A and V6 in adults.

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MAPK Substrate Competition Integrates Patterning Signals in the Drosophila Embryo.

Publication Date: 2010 Feb 17 PMID: 20171100
Authors: Kim, Y. - Coppey, M. - Grossman, R. - Ajuria, L. - Jimenez, G. - Paroush, Z. - Shvartsman, S. Y.
Journal: Curr Biol

Terminal regions of the Drosophila embryo are patterned by the localized activation of the mitogen-activated protein kinase (MAPK) pathway [1]. This depends on the MAPK-mediated downregulation of Capicua (Cic), a repressor of the terminal gap genes [2, 3]. We establish that downregulation of Cic is antagonized by the anterior patterning morphogen Bicoid (Bcd). We demonstrate that this effect does not depend on transcriptional activity of Bcd and provide evidence suggesting that Bcd, a direct substrate of MAPK, decreases the availability of MAPK for its other substrates, such as Cic. Based on the quantitative analysis of MAPK signaling in multiple mutants, we propose that MAPK substrate competition coordinates the actions of the anterior and terminal patterning systems. In addition, we identify Hunchback as a novel target of MAPK phosphorylation that can account for the previously described genetic interaction between the posterior and terminal systems [4]. Thus, a common enzyme-substrate competition mechanism can integrate the actions of the anterior, posterior, and terminal patterning signals. Substrate competition can be a general signal integration strategy in networks where enzymes, such as MAPK, interact with their multiple regulators and targets [5-10].

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Drosophila timeless2 is required for chromosome stability and circadian photoreception.

Publication Date: 2010 Feb 23 PMID: 20153199
Authors: Benna, C. - Bonaccorsi, S. - Wulbeck, C. - Helfrich-Forster, C. - Gatti, M. - Kyriacou, C. P. - Costa, R. - Sandrelli, F.
Journal: Curr Biol

In Drosophila, there are two timeless paralogs, timeless1 (tim1) and timeless2 (tim2, or timeout). Phylogenetic analyses suggest that tim1 originated as a duplication of tim2 around the time of the Cambrian explosion. The function of tim1 as a canonical circadian component is well established, but the role of tim2 in the fly is poorly understood. Many organisms possess a single tim2-like gene that has been implicated in DNA synthesis and, in the case of mammals, somewhat controversially, in circadian rhythmicity. Here we analyze the structure and the functional role of fly tim2. tim2 is a large locus (approximately 75 kb) that harbors several transcribed intronic sequences. Using insertional mutations and tissue-specific RNA interference-mediated downregulation, we find that tim2 is an essential gene required for normal DNA metabolism and chromosome integrity. Moreover, tim2 is involved in light entrainment of the adult circadian clock, via its expression in the T1 basket cells of the optic lobes. tim2's residual role in light entrainment thus provides an evolutionary link that may explain why its derived paralog, tim1, came to play such a major role in both circadian photosensitivity and core clock function.

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CRT-1/calreticulin and the E3 ligase EEL-1/HUWE1 control hemidesmosome maturation in C. elegans development.

Publication Date: 2010 Feb 23 PMID: 20153198
Authors: Zahreddine, H. - Zhang, H. - Diogon, M. - Nagamatsu, Y. - Labouesse, M.
Journal: Curr Biol

Hemidesmosomes connect the extracellular matrix (ECM) to intermediate filaments through ECM receptors and plakins (plectin and BPAG1e). They affect tissue integrity, wound healing, and carcinoma invasion. Although biochemical and time-lapse studies indicate that alpha6beta4-integrin (ECM receptor) and plectin play a central role in modulating hemidesmosome disassembly, the mechanisms controlling hemidesmosome biogenesis in vivo remain poorly understood. The nematode C. elegans provides a powerful genetic model to address this issue. We performed a genome-wide RNA interference screen in C. elegans, searching for genes that decrease the viability of a weak VAB-10A/plakin mutant. We identified 14 genes that have human homologs with predicted roles in different cellular processes. We further characterized two genes encoding the chaperone CRT-1/calreticulin and the HECT domain E3 ubiquitin ligase EEL-1/HUWE1. CRT-1 controls by as little as 2-fold the abundance of UNC-52/perlecan, an essential hemidesmosome ECM ligand. Likewise, EEL-1 fine tunes by 2-fold the abundance of myotactin, the putative hemidesmosome ECM receptor. CRT-1 and EEL-1 activities, and by extension other genes identified in our screen, are essential during embryonic development to enable hemidesmosomes exposed to mechanical tension to mature into a tension-resistant form. Our findings should help understand how hemidesmosome dynamics are regulated in vertebrate systems.

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A negative feedback signal that is triggered by peril curbs honey bee recruitment.

Publication Date: 2010 Feb 23 PMID: 20153197
Authors: Nieh, J. C.
Journal: Curr Biol

Decision making in superorganisms such as honey bee colonies often uses self-organizing behaviors, feedback loops that allow the colony to gather information from multiple individuals and achieve reliable and agile solutions. Honey bees use positive feedback from the waggle dance to allocate colony foraging effort. However, the use of negative feedback signals by superorganisms is poorly understood. I show that conspecific attacks at a food source lead to the production of stop signals, communication that was known to reduce waggle dancing and recruitment but lacked a clear natural trigger. Signalers preferentially targeted nestmates visiting the same food source, on the basis of its odor. During aggressive food competition, attack victims increased signal production by 43 fold. Foragers that attacked competitors or experienced no aggression did not alter signal production. Biting ambush predators also attack foragers at flowers. Simulated biting of foragers or exposure to bee alarm pheromone also elicited signaling (88-fold and 14-fold increases, respectively). This provides the first clear evidence of a negative feedback signal elicited by foraging peril to counteract the positive feedback of the waggle dance. As in intra- and intercellular communication, negative feedback may play an important, though currently underappreciated, role in self-organizing behaviors within superorganisms.

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The kinesin-8 Kif18A dampens microtubule plus-end dynamics.

Publication Date: 2010 Feb 23 PMID: 20153196
Authors: Du, Y. - English, C. A. - Ohi, R.
Journal: Curr Biol

Motility is a fundamentally important property of most members of the kinesin superfamily, but a rare subset of kinesins are also able to alter microtubule dynamics. At kinetochore-microtubule plus ends, the kinesin-8 family member Kif18A is essential to align mitotic chromosomes at the spindle equator during cell division, but how it accomplishes this function is unclear. We report here that Kif18A is a plus-end-directed motor that inhibits the polymerization dynamics of microtubule plus ends without destabilizing them, distinguishing Kif18A from the budding yeast ortholog Kip3. In interphase cells, Kif18A uses this activity to reduce the overall dynamicity of microtubule plus ends and effectively constrains the distance over which plus ends grow and shrink. Our findings suggest that kinesin-8 family members have developed biochemically distinct activities throughout evolution and have implications for how Kif18A affects kinetochore-microtubule plus-end dynamics during mitosis in animal cells.

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Circadian clock gene Bmal1 is not essential; functional replacement with its paralog, Bmal2.

Publication Date: 2010 Feb 23 PMID: 20153195
Authors: Shi, S. - Hida, A. - McGuinness, O. P. - Wasserman, D. H. - Yamazaki, S. - Johnson, C. H.
Journal: Curr Biol

Most of the central circadian clock genes in the mouse exist as paralog pairs (Per1 and Per2, Cry1 and Cry2, Clock and Npas2) in which each gene of the pair must be knocked out to confer arrhythmicity. The only exception to this pattern is Bmal1 (also known as Mop3), the single knockout of which confers arrhythmicity, despite the presence of its paralog, Bmal2 (also known as Mop9). The knockout of Bmal1 also has significant effects on longevity, metabolism, etc. These results have led to the conclusion that Bmal1 is a singularly essential clock gene and that Bmal2 has a minimal role in the clock system. In contrast, we find that expression of Bmal2 from a constitutively expressed promoter can rescue the clock and metabolic phenotypes of Bmal1-knockout mice, including rhythmic locomotor activity, rhythmic metabolism, low body weight, and enhanced fat deposition. Combined with the data of Bunger and colleagues, who reported that knockout of Bmal1 downregulates Bmal2, we conclude that Bmal1 and Bmal2 form a circadian paralog pair that is functionally redundant and that, in the mouse, Bmal2 is regulated by Bmal1 such that knockout of Bmal1 alone results in a functionally double Bmal1 and Bmal2 knockout. Therefore, the role(s) of Bmal2 may be more important than has been appreciated heretofore.

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Distinct retinal pathways drive spatial orientation behaviors in zebrafish navigation.

Publication Date: 2010 Feb 23 PMID: 20153194
Authors: Burgess, H. A. - Schoch, H. - Granato, M.
Journal: Curr Biol

Navigation requires animals to adjust ongoing movements in response to pertinent features of the environment and select between competing target cues. The neurobiological basis of navigational behavior in vertebrates is hard to analyze, partly because underlying neural circuits are experience dependent. Phototaxis in zebrafish is a hardwired navigational behavior, performed at a stage when larvae swim by using a small repertoire of stereotyped movements. We established conditions to elicit robust phototaxis behavior and found that zebrafish larvae deploy directional orienting maneuvers and regulate forward swimming speed to navigate toward a target light. Using genetic analysis and targeted laser ablations, we show that retinal ON and OFF pathways play distinct roles during phototaxis. The retinal OFF pathway controls turn movements via retinotectal projections and establishes correct orientation by causing larvae to turn away from nontarget areas. In contrast, the retinal ON pathway activates the serotonergic system to trigger rapid forward swimming toward the target. Computational simulation of phototaxis with an OFF-turn, ON-approach algorithm verifies that our model accounts for key features of phototaxis and provides a simple and robust mechanism for behavioral choice between competing targets.

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Both interaction surfaces within cohesin's hinge domain are essential for its stable chromosomal association.

Publication Date: 2010 Feb 23 PMID: 20153193
Authors: Mishra, A. - Hu, B. - Kurze, A. - Beckouet, F. - Farcas, A. M. - Dixon, S. E. - Katou, Y. - Khalid, S. - Shirahige, K. - Nasmyth, K.
Journal: Curr Biol

BACKGROUND: The cohesin complex that mediates sister chromatid cohesion contains three core subunits: Smc1, Smc3, and Scc1. Heterotypic interactions between Smc1 and Smc3 dimerization domains create stable V-shaped Smc1/Smc3 heterodimers with a hinge at the center and nucleotide-binding domains (NBDs) at the ends of each arm. Interconnection of each NBD through their association with the N- and C-terminal domains of Scc1 creates a tripartite ring, within which sister DNAs are thought to be entrapped (the ring model). Crystal structures show that the Smc1/Smc3 hinge has a toroidal shape, with independent "north" and "south" interaction surfaces on an axis of pseudosymmetry. The ring model predicts that sister chromatid cohesion would be lost by transient hinge opening. RESULTS: We find that mutations within either interface weaken heterodimerization of isolated half hinges in vitro but do not greatly compromise formation of cohesin rings in vivo. They do, however, reduce the residence time of cohesin on chromosomes and cause lethal defects in sister chromatid cohesion. This demonstrates that mere formation of rings is insufficient for cohesin function. Stable cohesion requires cohesin rings that cannot easily open. CONCLUSIONS: Either the north or south hinge interaction surface is sufficient for the assembly of V-shaped Smc1/Smc3 heterodimers in vivo. Any tendency of Smc proteins with weakened hinges to dissociate will be suppressed by interconnection of their NBDs by Scc1. We suggest that transient hinge dissociation caused by the mutations described here is incompatible with stable sister chromatid cohesion because it permits chromatin fibers to escape from cohesin rings.

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Regulation of gustatory physiology and appetitive behavior by the Drosophila circadian clock.

Publication Date: 2010 Feb 23 PMID: 20153192
Authors: Chatterjee, A. - Tanoue, S. - Houl, J. H. - Hardin, P. E.
Journal: Curr Biol

BACKGROUND: Circadian regulation of chemosensory processes is common in animals, but little is known about how circadian clocks control chemosensory systems or the consequences of rhythms in chemosensory system function. Taste is a major chemosensory gate used to decide whether or not an animal will eat, and the main taste organ in Drosophila, the proboscis, harbors autonomous circadian oscillators. Here we examine gustatory physiology, tastant-evoked appetitive behavior, and food ingestion to understand clock-dependent regulation of the Drosophila gustatory system. RESULTS: Here we report that single-unit responses from labellar gustatory receptor neurons (GRNs) to attractive and aversive tastants show diurnal and circadian rhythms in spike amplitude, frequency, and duration across different classes of gustatory sensilla. Rhythms in electrophysiological responses parallel behavioral rhythms in proboscis extension reflex. Molecular oscillators in GRNs are necessary and sufficient for rhythms in gustatory responses and drive rhythms in G protein-coupled receptor kinase 2 (GPRK2) expression that mediate rhythms in taste sensitivity. Eliminating clock function in certain GRNs increases feeding and locomotor activity, mimicking a starvation response. CONCLUSIONS: Circadian clocks in GRNs control neuronal output and drive behavioral rhythms in taste responses that peak at a time of day when feeding is maximal in flies. Our results argue that oscillations in GPRK2 levels drive rhythms in gustatory physiology and behavior and that GRN clocks repress feeding. The similarity in gustatory system organization and feeding behavior in flies and mammals, as well as diurnal changes in taste sensitivity in humans, suggest that our results are relevant to the situation in humans.

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The actin-bundling protein fascin stabilizes actin in invadopodia and potentiates protrusive invasion.

Publication Date: 2010 Feb 23 PMID: 20137952
Authors: Li, A. - Dawson, J. C. - Forero-Vargas, M. - Spence, H. J. - Yu, X. - Konig, I. - Anderson, K. - Machesky, L. M.
Journal: Curr Biol

Fascin is an actin-bundling protein involved in filopodia assembly and cancer invasion and metastasis of multiple epithelial cancer types. Fascin forms stable actin bundles with slow dissociation kinetics in vitro and is regulated by phosphorylation of serine 39 by protein kinase C (PKC). Cancer cells use invasive finger-like protrusions termed invadopodia to invade into and degrade extracellular matrix. Invadopodia have highly dynamic actin that is assembled by both Arp2/3 complex and formins; they also contain components of membrane trafficking machinery such as dynamin and cortactin and have been compared with focal adhesions and podosomes. We show that fascin is an integral component of invadopodia and that it is important for the stability of actin in invadopodia. The phosphorylation state of fascin at S39, a PKC site, contributes to its regulation at invadopodia. We further implicate fascin in invasive migration into collagen I-Matrigel gels and particularly in cell types that use an elongated mesenchymal type of motility in 3D. We provide a potential molecular mechanism for how fascin increases the invasiveness of cancer cells, and we compare invadopodia with invasive filopod-like structures in 3D.

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Centrosome size sets mitotic spindle length in Caenorhabditis elegans embryos.

Publication Date: 2010 Feb 23 PMID: 20137951
Authors: Greenan, G. - Brangwynne, C. P. - Jaensch, S. - Gharakhani, J. - Julicher, F. - Hyman, A. A.
Journal: Curr Biol

Just as the size of an organism is carefully controlled, the size of intracellular structures must also be regulated. The mitotic spindle is a supramolecular machine that generates the forces which separate sister chromatids during mitosis. Although spindles show little size variation between cells of the same type, spindle length can vary at least 10-fold between different species. Recent experiments on spindle length showed that in embryonic systems spindle length varied with blastomere size. Furthermore, a comparison between two Xenopus species showed that spindle length was dependent on some cytoplasmic factor. These data point toward mechanisms to scale spindle length with cell size. Centrosomes play an important role in organizing microtubules during spindle assembly. Here we use Caenorhabditis elegans to study the role of centrosomes in setting spindle length. We show that spindle length correlates with centrosome size through development and that a reduction of centrosome size by molecular perturbation reduces spindle length. By systematically analyzing centrosome proteins, we show that spindle length does not depend on microtubule density at centrosomes. Rather, our data suggest that centrosome size sets mitotic spindle length by controlling the length scale of a TPXL-1 gradient along spindle microtubules.

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Mixed microtubules steer dynein-driven cargo transport into dendrites.

Publication Date: 2010 Feb 23 PMID: 20137950
Authors: Kapitein, L. C. - Schlager, M. A. - Kuijpers, M. - Wulf, P. S. - van Spronsen, M. - MacKintosh, F. C. - Hoogenraad, C. C.
Journal: Curr Biol

BACKGROUND: To establish and maintain their polarized morphology, neurons employ active transport driven by molecular motors to sort cargo between axons and dendrites. However, the basic traffic rules governing polarized transport on neuronal microtubule arrays are unclear. RESULTS: Here we show that the microtubule minus-end-directed motor dynein is required for the polarized targeting of dendrite-specific cargo, such as AMPA receptors. To directly examine how dynein motors contribute to polarized dendritic transport, we established a trafficking assay in hippocampal neurons to selectively probe specific motor protein activity. This revealed that, unlike kinesins, dynein motors drive cargo selectively into dendrites, governed by their mixed microtubule array. Moreover, axon-specific cargos, such as presynaptic vesicle protein synaptophysin, are redirected to dendrites by coupling to dynein motors. Quantitative modeling demonstrated that bidirectional dynein-driven transport on mixed microtubules provides an efficient mechanism to establish a stable density of continuously renewing vesicles in dendrites. CONCLUSIONS: These results demonstrate a powerful approach to study specific motor protein activity inside living cells and imply a key role for dynein in dendritic transport. We propose that dynein establishes the initial sorting of dendritic cargo and additional motor proteins assist in subsequent delivery.

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Cell-nonautonomous regulation of C. elegans germ cell death by kri-1.

Publication Date: 2010 Feb 23 PMID: 20137949
Authors: Ito, S. - Greiss, S. - Gartner, A. - Derry, W. B.
Journal: Curr Biol

Programmed cell death (or apoptosis) is an evolutionarily conserved, genetically controlled suicide mechanism for cells that, when deregulated, can lead to developmental defects, cancers, and degenerative diseases. In C. elegans, DNA damage induces germ cell death by signaling through cep-1/p53, ultimately leading to the activation of CED-3/caspase. It has been hypothesized that the major regulatory events controlling cell death occur by cell-autonomous mechanisms, that is, within the dying cell. In support of this, genetic studies in C. elegans have shown that the core apoptosis pathway genes ced-4/APAF-1 and ced-3/caspase are required in cells fated to die. However, it is not known whether the upstream signals that activate apoptosis function in a cell-autonomous manner. Here we show that kri-1, an ortholog of KRIT1/CCM1, which is mutated in the human neurovascular disease cerebral cavernous malformation, is required to activate DNA damage-dependent cell death independently of cep-1/p53. Interestingly, we find that kri-1 regulates cell death in a cell-nonautonomous manner, revealing a novel regulatory role for nondying cells in eliciting cell death in response to DNA damage.

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In vivo coupling of cell elongation and lumen formation in a single cell.

Publication Date: 2010 Feb 23 PMID: 20137948
Authors: Gervais, L. - Casanova, J.
Journal: Curr Biol

Fine tubes form inside cells as they reach their target tissues in epithelial ducts and in angiogenesis. Although a very suggestive model of cell hollowing proposes that intracellular lumen could arise by coalescence of intracellular vacuoles, how those tubes form in vivo remains an open question. We addressed this issue by examining intracellular lumen formation in the Drosophila trachea. The main branches of the Drosophila tracheal system have an extracellular lumen because their cells fold to form a tube. However, terminal cells, specialized cells in some of the main branches, form unicellular branches by the generation of an intracellular lumen. Conversely to the above-mentioned model, we find that the intracellular lumen arises by growth of an apical membrane inwards the cell. In support, we detect an appropriate subcellular compartmentalization of different components of the intracellular trafficking machinery. We show that both cellular elongation and lumen formation depend on a mechanism based on asymmetric actin accumulation and microtubule network organization. Given the similarities in the formation of fine respiratory tubes and capillaries, we propose that an inward membrane growth model could account for lumen formation in both processes.

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Mad2 prolongs DNA damage checkpoint arrest caused by a double-strand break via a centromere-dependent mechanism.

Publication Date: 2010 Feb 23 PMID: 20096585
Authors: Dotiwala, F. - Harrison, J. C. - Jain, S. - Sugawara, N. - Haber, J. E.
Journal: Curr Biol

Eukaryotic cells employ a suite of replication and mitotic checkpoints to ensure the accurate transmission of their DNA. In budding yeast, both the DNA damage checkpoint and the spindle assembly checkpoint (SAC) block cells prior to anaphase. The presence of a single unrepaired double-strand break (DSB) activates ATR and ATM protein kinase homologs Mec1 and Tel1, which then activate downstream effectors to trigger G2/M arrest and also phosphorylate histone H2A (creating gamma-H2AX) in chromatin surrounding the DSB. The SAC monitors proper attachment of spindle microtubules to the kinetochore formed at each centromere and the biorientation of sister centromeres toward opposite spindle pole bodies. Although these two checkpoints sense quite different perturbations, recent evidence has demonstrated both synergistic interactions and cross-talk between them. Here we report that Mad2 and other SAC proteins play an unexpected role in prolonging G2/M arrest after induction of a single DSB. This function of the SAC depends not only on Mec1 and other components of the DNA damage checkpoint but also on the presence of the centromere located > or = 90 kb from the DNA damage. DNA damage induces epigenetic changes at the centromere, including the gamma-H2AX modification, that appear to alter kinetochore function, thus triggering the canonical SAC. Thus, a single DSB triggers a response by both checkpoints to prevent the segregation of a damaged chromosome.

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Many families of C. elegans microRNAs are not essential for development or viability.

Publication Date: 2010 Feb 23 PMID: 20096582
Authors: Alvarez-Saavedra, E. - Horvitz, H. R.
Journal: Curr Biol

MicroRNAs (miRNAs) are approximately 23 nt regulatory RNAs that posttranscriptionally inhibit the functions of protein-coding mRNAs. We previously found that most C. elegans miRNAs are individually not essential for development or viability and proposed that paralogous miRNAs might often function redundantly. To test this hypothesis, we generated mutant C. elegans strains that each lack multiple or all members of one of 15 miRNA families. Mutants for 12 of these families did not display strong synthetic abnormalities, suggesting that these miRNA families have subtle roles during development. By contrast, mutants deleted for all members of the mir-35 or mir-51 families died as embryos or early larvae, and mutants deleted for four members of the mir-58 family showed defects in locomotion, body size, and egg laying and an inability to form dauer larvae. Our findings indicate that the regulatory functions of most individual miRNAs and most individual families of miRNAs related in sequence are not critical for development or viability. Conversely, because in some cases miRNA family members act redundantly, our findings emphasize the importance of determining miRNA function in the absence of miRNAs related in sequence.

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