December 2014

Research articles

1. 1. Structural Biology and Molecular Biophysics

   Recognition of the small regulatory RNA RydC by the bacterial Hfq protein

   Daniela Dimastrogiovanni, Kathrin S Fröhlich ... Ben F Luisi

   The regulatory RNA RydC binds to Hfq to make an effector complex for the recognition of targeted mRNA in the regulation of genetic information.
2. 1. Microbiology and Infectious Disease

   A mutant Escherichia coli that attaches peptidoglycan to lipopolysaccharide and displays cell wall on its surface

   Marcin Grabowicz, Dorothee Andres ... Thomas J Silhavy

   A single mutation in Escherichia coli connects two essential cell envelope assembly pathways and confers vancomycin resistance by displaying molecular decoys at the cell surface.
3. 1. Cell Biology
   2. Cancer Biology

   A kinase-independent function of AKT promotes cancer cell survival

   Igor Vivanco, Zhi C Chen ... Ingo K Mellinghoff

   The oncogenic potential of the serine threonine kinase AKT is not exclusively dependent on catalytic activity, but also involves the non-catalytic function of the pleckstrin homology domain.
4. 1. Biochemistry and Chemical Biology
   2. Cell Biology

   Specificity in endoplasmic reticulum-stress signaling in yeast entails a step-wise engagement of HAC1 mRNA to clusters of the stress sensor Ire1

   Eelco van Anken, David Pincus ... Peter Walter

   Selective docking of HAC1 mRNA on Ire1 clusters at a site separate from the Ire1 RNase domain is key for endoplasmic reticulum stress signaling.
5. 1. Developmental Biology
   2. Neuroscience

   Genetic transformation of structural and functional circuitry rewires the Drosophila brain

   Sonia Sen, Deshou Cao ... K VijayRaghavan

   Large-scale changes in the brain's functional circuitry can be brought about by simple changes in gene expression in neural stem cells during development.
6. 1. Neuroscience

   A highly tunable dopaminergic oscillator generates ultradian rhythms of behavioral arousal

   Ian D Blum, Lei Zhu ... Kai-Florian Storch

   An internal clock based on brain levels of dopamine works with the circadian clock to maintain daily patterns of alertness and activity, and may be implicated in the altered behavioral patterns seen in schizophrenia and bipolar disorder.
7. 1. Immunology and Inflammation

   Epigenetic modification of the PD-1 (Pdcd1) promoter in effector CD4⁺ T cells tolerized by peptide immunotherapy

   Rhoanne C McPherson, Joanne E Konkel ... Stephen M Anderton

   Peptide immunotherapy in mice depends upon sustained expression of co-inhibitory protein PD-1 in T cells.
8. 1. Structural Biology and Molecular Biophysics
   2. Chromosomes and Gene Expression

   3D imaging of Sox2 enhancer clusters in embryonic stem cells

   Zhe Liu, Wesley R Legant ... Robert Tjian

   Lattice light-sheet single-molecule imaging shows 3D Sox2 enhancer clusters in live embryonic stem cells and reveals a model linking 3D spatial distribution of cis-elements, differential target search features and localized gene regulation.
9. 1. Cell Biology
   2. Developmental Biology

   Regulation of RNA granule dynamics by phosphorylation of serine-rich, intrinsically disordered proteins in C. elegans

   Jennifer T Wang, Jarrett Smith ... Geraldine Seydoux

   The MEG (maternal-effect germline defective) proteins, MEG-1, 2, 3 and 4, regulate RNA granule dynamics in vivo.
10. 1. Immunology and Inflammation
    2. Microbiology and Infectious Disease

    Competition between antagonistic complement factors for a single protein on N. meningitidis rules disease susceptibility

    Joseph JE Caesar, Hayley Lavender ... Susan M Lea

    Genetic susceptibility to an infectious disease is linked to competition for binding a molecule on the bacterial surface by two host proteins with opposing roles in host immunity.
11. 1. Cell Biology
    2. Neuroscience

    Developmental mechanism of the periodic membrane skeleton in axons

    Guisheng Zhong, Jiang He ... Xiaowei Zhuang

    Super-resolution imaging reveals how the skeleton that supports the outer membrane of axons is assembled during development, and provides an explanation for why this structure preferentially forms in axons but rarely in dendrites.
12. 1. Developmental Biology
    2. Chromosomes and Gene Expression

    Gap junctions composed of connexins 41.8 and 39.4 are essential for colour pattern formation in zebrafish

    Uwe Irion, Hans Georg Frohnhöfer ... Christiane Nüsslein-Volhard

    Melanophores and xanthophores interact via heteromeric gap junctions composed of Connexin 41.8 and Connexin 39.4 to establish the adult pigment pattern in zebrafish.
13. 1. Neuroscience

    Corticothalamic phase synchrony and cross-frequency coupling predict human memory formation

    Catherine M Sweeney-Reed, Tino Zaehle ... Alan Richardson-Klavehn

    Direct electrophysiological evidence demonstrates a role for the anterior thalamic nucleus in human memory formation.
14. 1. Developmental Biology

    Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1

    Edward Kim, Yuan Wang ... Yuan Zhu

    Nf1 is required during early, but not late, cerebellar development to facilitate neuronal lamination, providing a potential therapeutic prevention strategy for NF1-associated developmental abnormalities.
15. 1. Neuroscience

    Mushroom body output neurons encode valence and guide memory-based action selection in Drosophila

    Yoshinori Aso, Divya Sitaraman ... Gerald M Rubin

    Output neurons in the mushroom body of the fruit fly brain encode the positive or negative survival value of stimuli, enabling insects to choose adaptive approach and avoidance behaviors through associative learning.
16. 1. Neuroscience

    The neuronal architecture of the mushroom body provides a logic for associative learning

    Yoshinori Aso, Daisuke Hattori ... Gerald M Rubin

    A map of the entire array of cell types and potential projections in the mushroom body of the fruit fly brain provides insights into the circuitry that supports learning of stimulus-reward and stimulus–punishment associations.
17. 1. Biochemistry and Chemical Biology
    2. Cell Biology

    Identification of PLXDC1 and PLXDC2 as the transmembrane receptors for the multifunctional factor PEDF

    Guo Cheng, Ming Zhong ... Hui Sun

    Two membrane proteins that belong to a new type of cell-surface receptor mediate the transmembrane signaling for a secreted factor that has broad therapeutic value.
18. 1. Structural Biology and Molecular Biophysics

    Domain–domain interactions determine the gating, permeation, pharmacology, and subunit modulation of the IKs ion channel

    Mark A Zaydman, Marina A Kasimova ... Jianmin Cui

    Contrary to a generally accepted principle, the pore properties of KCNQ1 channels depend on the states of voltage-sensing domains activation; KCNE1 alters the voltage-sensing domains-pore coupling to modulate KCNQ1 channel properties.
19. 1. Biochemistry and Chemical Biology
    2. Cancer Biology

    Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy

    Alexander A Warkentin, Michael S Lopez ... Kevan M Shokat

    Anti-targets are proteins that cause problems when inhibited along with an intended target and our novel chemical strategy affords unprecedented selectivity in the context of FLT3 vs. KIT inhibition for treatment of a devastating blood cancer.
20. 1. Neuroscience

    Spatial cue reliability drives frequency tuning in the barn Owl's midbrain

    Fanny Cazettes, Brian J Fischer, Jose L Pena

    Space-specific neurons in the owl's auditory midbrain are selective for the frequencies that yield the most reliable sound localization cues.
21. 1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics

    A novel N-terminal extension in mitochondrial TRAP1 serves as a thermal regulator of chaperone activity

    James R Partridge, Laura A Lavery ... David A Agard

    Cytosolic and organellar Hsp90s from higher eukaryotes have evolved a variable, and environmentally responsive N-terminal extension to regulate their activity.
22. 1. Neuroscience

    Transcriptional profiling at whole population and single cell levels reveals somatosensory neuron molecular diversity

    Isaac M Chiu, Lee B Barrett ... Clifford J Woolf

    Molecular analysis paints a detailed picture of the distinctiveness and complexities of peripheral somatosensory neurons.
23. 1. Neuroscience

    A genuine layer 4 in motor cortex with prototypical synaptic circuit connectivity

    Naoki Yamawaki, Katharine Borges ... Gordon M G Shepherd

    New evidence challenges the long-held view that motor cortex lacks a fourth layer, and reveals that its circuitry resembles that of other cortical regions more than previously thought.
24. 1. Neuroscience

    Differential effects of light and feeding on circadian organization of peripheral clocks in a forebrain Bmal1 mutant

    Mariko Izumo, Martina Pejchal ... Joseph S Takahashi

    Conditional deletion of Bmal1 in the forebrain/SCN reveals an essential role of a functional master clock in maintaining synchronized and high amplitude rhythms of peripheral clocks.
25. 1. Physics of Living Systems
    2. Cell Biology

    Mechanical design principles of a mitotic spindle

    Jonathan J Ward, Hélio Roque ... François Nédélec

    Precise control of microtubule architecture greatly increases the force that the spindle can exert on chromosomes.
26. 1. Physics of Living Systems

    Active torque generation by the actomyosin cell cortex drives left–right symmetry breaking

    Sundar Ram Naganathan, Sebastian Fürthauer ... Stephan W Grill

    The actomyosin cytoskeleton generates active chiral torques that lead to left-right asymmetry in C. elegans embryos.
27. 1. Microbiology and Infectious Disease

    Quantitative microscopy of functional HIV post-entry complexes reveals association of replication with the viral capsid

    Ke Peng, Walter Muranyi ... Hans-Georg Kräusslich

    A robust method to quantitatively visualize HIV-1 replication complexes in infected cells shows that these complexes remain associated with the viral capsid beyond nuclear import in primary macrophages.
28. 1. Chromosomes and Gene Expression
    2. Genetics and Genomics

    Metagenomic chromosome conformation capture (meta3C) unveils the diversity of chromosome organization in microorganisms

    Martial Marbouty, Axel Cournac ... Romain Koszul

    A technique called meta3C provides an elegant and integrated approach to metagenomic analysis by allowing the de novo assembly, scaffolding and 3D characterization of unknown genomes from a complex mix of species
29. 1. Cell Biology
    2. Neuroscience

    Astrocytes refine cortical connectivity at dendritic spines

    W Christopher Risher, Sagar Patel ... Cagla Eroglu

    Spines with multiple excitatory contacts are potential sites for competition between thalamic and cortical axons, which is regulated by the astrocytes through the secreted synaptogenic protein hevin.
30. 1. Structural Biology and Molecular Biophysics
    2. Cell Biology

    An intracellular anion channel critical for pigmentation

    Nicholas W Bellono, Iliana E Escobar ... Elena Oancea

    Oculocutaneous albinism II (OCA2) contributes to a melanosome-specific anion channel that modulates organellar pH and is critical for melanin synthesis.
31. 1. Neuroscience

    Decoding odor quality and intensity in the Drosophila brain

    Antonia Strutz, Jan Soelter ... Silke Sachse

    The lateral horn can be classified into three functional odor response domains that decode opposing hedonic valences and odor intensity.
32. 1. Developmental Biology
    2. Neuroscience

    Foxc1 dependent mesenchymal signalling drives embryonic cerebellar growth

    Parthiv Haldipur, Gwendolyn S Gillies ... Kathleen J Millen

    The mesenchyme surrounding the developing brain plays a significant role in controlling the fundamental growth and patterning of the cerebellum, and misregulation of this signalling can lead to important neurodevelopmental disorders.
33. 1. Chromosomes and Gene Expression
    2. Genetics and Genomics

    Heterochromatin assembly and transcriptome repression by Set1 in coordination with a class II histone deacetylase

    David R Lorenz, Lauren F Meyer ... Hugh P Cam

    Set1 has roles in chromatin organization and transcriptome control that are largely independent of histone H3 lysine 4 methylation.
34. 1. Cell Biology

    Dynamic recruitment of the curvature-sensitive protein ArhGAP44 to nanoscale membrane deformations limits exploratory filopodia initiation in neurons

    Milos Galic, Feng-Chiao Tsai ... Tobias Meyer

    Local inward plasma membrane deformations caused by actomyosin-dependent contraction trigger the dynamic recruitment of a curvature-sensitive actin-regulatory protein, which represents a receptor-independent auto-regulatory mechanism to control local actin polymerization dynamics at the plasma membrane.
35. 1. Cell Biology
    2. Chromosomes and Gene Expression

    Enhanced homology-directed human genome engineering by controlled timing of CRISPR/Cas9 delivery

    Steven Lin, Brett T Staahl ... Jennifer A Doudna

    Building on previous work (Jinek et al., 2013), we report a simple and robust system to achieve high fidelity and high efficiency (30% of homologous recombination) genome engineering by homology-directed repair pathway in human cells using cell cycle synchronization and timed delivery of Cas9 ribonucleoprotein complexes.
36. 1. Neuroscience

    A neural circuit mechanism for regulating vocal variability during song learning in zebra finches

    Jonathan Garst-Orozco, Baktash Babadi, Bence P Ölveczky

    By demonstrating song learning-related synaptic strengthening and pruning in the vocal control circuits of songbirds, and showing how such changes can reduce the sensitivity of the circuit to ‘noisy’ inputs, a simple neural circuit mechanism for regulating motor variability during motor skill learning is identified.
37. 1. Structural Biology and Molecular Biophysics
    2. Microbiology and Infectious Disease

    Structural basis for ligand and innate immunity factor uptake by the trypanosome haptoglobin-haemoglobin receptor

    Harriet Lane-Serff, Paula MacGregor ... Matthew K Higgins

    The structure of the trypanosome haptoglobin-haemoglobin receptor bound to its ligand reveals the molecular basis for ligand recognition in innate immunity and identifies molecular determinants that aid efficient uptake.
38. 1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics

    Molecular insights into RNA and DNA helicase evolution from the determinants of specificity for a DEAD-box RNA helicase

    Anna L Mallam, David J Sidote, Alan M Lambowitz

    The core domains of an RNA helicase interact with a wide variety of NTPs and nucleic acids suggesting how related enzymes may have evolved to have diverse functions.
39. 1. Developmental Biology

    The transcription factor Pitx2 positions the embryonic axis and regulates twinning

    Angela Torlopp, Mohsin A F Khan ... Claudio D Stern

    In higher vertebrates, the position of the embryonic axis (the location at which gastrulation starts) is determined by the transcription factor Pitx2, which suggests that the mechanisms of this process, and hence those that regulate twinning, are related to those that set up the left–right axis.
40. 1. Evolutionary Biology
    2. Neuroscience

    Evolved differences in larval social behavior mediated by novel pheromones

    Joshua D Mast, Consuelo M De Moraes ... David L Stern

    A novel pheromone/receptor neuron pair mediates attraction between Drosophila larvae, and evolved differences in pheromone signaling underlie changes in social behavior between drosophilid species.
41. 1. Evolutionary Biology

    Tumor evolutionary directed graphs and the history of chronic lymphocytic leukemia

    Jiguang Wang, Hossein Khiabanian ... Raul Rabadan

    A general framework captures the evolutionary routes leading to the formation and progression of tumors.
42. 1. Microbiology and Infectious Disease

    Genome-wide regulatory dynamics of translation in the Plasmodium falciparum asexual blood stages

    Florence Caro, Vida Ahyong ... Joseph L DeRisi

    Ribosome profiling has bridged the knowledge gap between transcription and translation during malaria blood stage development and provided a comprehensive gene expression resource for this parasite.
43. 1. Structural Biology and Molecular Biophysics

    Architecture and dynamics of the autophagic phosphatidylinositol 3-kinase complex

    Sulochanadevi Baskaran, Lars-Anders Carlson ... James H Hurley

    The first three-dimensional structure of the PI3KC3 complex I, which is involved in autophagy, provides a framework for understanding the allosteric regulation of lipid kinase activity.
44. 1. Developmental Biology
    2. Immunology and Inflammation

    The extraembryonic serosa is a frontier epithelium providing the insect egg with a full-range innate immune response

    Chris G C Jacobs, Herman P Spaink, Maurijn van der Zee

    Contrary to the current perception, insect eggs are very capable of defending themselves against pathogens.
45. 1. Cell Biology

    Spatial quality control bypasses cell-based limitations on proteostasis to promote prion curing

    Courtney L Klaips, Megan L Hochstrasser ... Tricia R Serio

    Cell division imposes a limit on proteostasis capacity by reducing chaperone accumulation, but chaperone-substrate interactions reverse these events to allow clearance of even chronically misfolded protein amyloids.
46. 1. Neuroscience

    Nanodomain coupling explains Ca²⁺ independence of transmitter release time course at a fast central synapse

    Itaru Arai, Peter Jonas

    Ca²⁺ channels and release sensors at a fast central synapse are tightly coupled, which minimizes the effect of extracellular Ca²⁺ concentration on the timing of transmitter release.
47. 1. Neuroscience

    Maximally informative foraging by Caenorhabditis elegans

    Adam J Calhoun, Sreekanth H Chalasani, Tatyana O Sharpee

    C. elegans foraging efficiently approximate maximally informative search strategies that involve abrupt switching between different types of behaviors.
48. 1. Neuroscience

    A dedicated visual pathway for prey detection in larval zebrafish

    Julia L Semmelhack, Joseph C Donovan ... Herwig Baier

    A subset of retinal ganglion cells respond specifically to small moving objects and project to a visual area that plays a key role in prey capture behavior.
49. 1. Microbiology and Infectious Disease

    RNA virus attenuation by codon pair deoptimisation is an artefact of increases in CpG/UpA dinucleotide frequencies

    Fiona Tulloch, Nicky J Atkinson ... Peter Simmonds

    Attenuating candidate live virus vaccines by incorporating unfavoured codon pairs to reduce translation efficiency is actually mediated though changes in frequencies of CpG and UpA dinucleotides, which make viruses more visible to the innate immune system.
50. 1. Genetics and Genomics

    Genome-wide mapping in a house mouse hybrid zone reveals hybrid sterility loci and Dobzhansky-Muller interactions

    Leslie M Turner, Bettina Harr

    The genomic regions that cause male hybrids between house mouse subspecies to have low fertility have been identified.
51. 1. Cell Biology
    2. Microbiology and Infectious Disease

    Architecture of the ring formed by the tubulin homologue FtsZ in bacterial cell division

    Piotr Szwedziak, Qing Wang ... Jan Löwe

    The architecture of the bacterial cytokinetic ring in cells and in artificial liposome reconstitutions has been described using electron microscopy, leading to a mechanism of constriction.
52. 1. Ecology
    2. Neuroscience

    Dopamine drives Drosophila sechellia adaptation to its toxic host

    Sofía Lavista-Llanos, Aleš Svatoš ... Bill S Hansson

    The insect dopaminergic system serves an important function in the regulation of ontogenesis and early development, contributing to the evolutionary processes that limit the ecological niche of Drosophila sechellia.
53. 1. Structural Biology and Molecular Biophysics
    2. Microbiology and Infectious Disease

    The export receptor Crm1 forms a dimer to promote nuclear export of HIV RNA

    David S Booth, Yifan Cheng, Alan D Frankel

    The nuclear export receptor Crm1 cooperatively binds its HIV Rev-RRE cargo as a dimer using a species-specific interface that supports viral replication by enhancing nuclear export of HIV RNA.
54. 1. Cell Biology
    2. Developmental Biology

    Cis-interactions between Notch and its ligands block ligand-independent Notch activity

    William Hunt Palmer, Dongyu Jia, Wu-Min Deng

    Notch ligands expressed in the same cell as the Notch receptor are crucial to prevent accidental, ligand-independent Notch activity.
55. 1. Neuroscience

    Vocalization–whisking coordination and multisensory integration of social signals in rat auditory cortex

    Rajnish P Rao, Falk Mielke ... Michael Brecht

    Snout-to-snout contact modulates the response of rat auditory cortex to calls from other animals, indicating that the multisensory nature of social interaction is directly represented in the rat brain.
56. 1. Structural Biology and Molecular Biophysics

    Ambiguities in helical reconstruction

    Edward H Egelman

    While electron microscopic helical reconstruction is a powerful technique in structural biology, mistakes can be made in determining the helical symmetry, leading to structures that are artifactual.
57. 1. Biochemistry and Chemical Biology
    2. Microbiology and Infectious Disease

    RNA-directed remodeling of the HIV-1 protein Rev orchestrates assembly of the Rev–Rev response element complex

    Bhargavi Jayaraman, David C Crosby ... Alan D Frankel

    A pliable hydrophobic interface in the HIV-1 Rev protein enables assembly of diverse oligomeric structures, guided by the RRE scaffold present in HIV-1 mRNAs.
58. 1. Structural Biology and Molecular Biophysics

    Sequential conformational rearrangements in flavivirus membrane fusion

    Luke H Chao, Daryl E Klein ... Stephen C Harrison

    The West Nile Virus envelope protein catalyzes membrane fusion through low-pH induced conformational rearrangement, with a rate determined by the formation of two trimeric complexes at the contact zone between the virus and target membrane.
59. 1. Cell Biology

    Mapping the dynamics of force transduction at cell–cell junctions of epithelial clusters

    Mei Rosa Ng, Achim Besser ... Gaudenz Danuser

    The integrated quantification of spontaneous dynamic cell-cell force transmissions at both multi-cellular and subcellular scales enables spatiotemporal correlations of stress distribution with biomolecules in small cell clusters.
60. 1. Neuroscience

    Homeostasis in C. elegans sleep is characterized by two behaviorally and genetically distinct mechanisms

    Stanislav Nagy, Nora Tramm ... David Biron

    The sleep cycle of nematode worms adjusts to compensate for sleep disturbances, with neuropeptide Y involved in the response to minor disruptions, and the transcription factor DAF-16/FOXO in the response to major disruptions.
61. 1. Cell Biology
    2. Developmental Biology

    Early asymmetric cues triggering the dorsal/ventral gene regulatory network of the sea urchin embryo

    Vincenzo Cavalieri, Giovanni Spinelli

    During early embryogenesis of the sea urchin, asymmetrical positioning of the dorsal/ventral organizer relies upon the suppression of organizer activities in dorsal blastomeres by the Hbox12 homeodomain-containing repressor.
62. 1. Structural Biology and Molecular Biophysics

    Stepwise visualization of membrane pore formation by suilysin, a bacterial cholesterol-dependent cytolysin

    Carl Leung, Natalya V Dudkina ... Bart W Hoogenboom

    Electron and atomic force microscopy show how bacterial toxins bind to a host membrane and assemble into arcs and rings, before undergoing a dramatic, concerted conformational change to insert into the membrane.
63. 1. Cell Biology
    2. Immunology and Inflammation

    Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis

    Snehlata Kumari, Younes Redouane ... Fumiyo Ikeda

    The adaptor proteins FADD and TRADD play an important role in the Sharpin-dependent anti-apoptosis signaling pathway in keratinocytes and regulate skin homeostasis.
64. 1. Cell Biology
    2. Developmental Biology

    TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice

    James A Rickard, Holly Anderton ... John Silke

    Skin inflammation in Sharpin-deficient mice is primarily due to TNFR1-dependent apoptosis, but necroptosis appears to play a bigger role in inflammation of internal organs.
65. 1. Neuroscience

    Homeostatic reinforcement learning for integrating reward collection and physiological stability

    Mehdi Keramati, Boris Gutkin

    A mathematical model built around the assumption that the desire to maintain internal homeostasis drives the behavior of animals, by affecting their learning processes, can explain many real-world behaviors, including some that might otherwise appear irrational.
66. 1. Biochemistry and Chemical Biology

    Thermodynamic evidence for a dual transport mechanism in a POT peptide transporter

    Joanne L Parker, Joseph A Mindell, Simon Newstead

    Two thermodynamically distinct transport mechanisms operating within the same binding site explains the remarkable promiscuity of POT family transporters towards peptide and drug ligands.
67. 1. Cell Biology
    2. Developmental Biology

    LINKIN, a new transmembrane protein necessary for cell adhesion

    Mihoko Kato, Tsui-Fen Chou ... Paul W Sternberg

    LINKIN and three of its interactors-RUVBL1, RUVBL2, and α-tubulin-are required for cells to migrate together during organogenesis.
68. 1. Cell Biology
    2. Stem Cells and Regenerative Medicine

    EGFR signaling promotes self-renewal through the establishment of cell polarity in Drosophila follicle stem cells

    Angela Castanieto, Michael J Johnston, Todd G Nystul

    The specification of cell polarity is essential for self-renewal and the segregation of stem-cell and daughter-cell fates in an epithelial stem cell lineage.