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1.  Organelle biogenesis and interorganellar connections 
Membrane contact sites (MCSs) allow the exchange of molecules and information between organelles, even when their membranes cannot fuse directly. In recent years, a number of functions have been attributed to these contacts, highlighting their critical role in cell homeostasis. Although inter-organellar connections typically involve the endoplasmic reticulum (ER), we recently reported the presence of a novel MCSs between melanosomes and mitochondria. Melanosome-mitochondrion contacts appear mediated by fibrillar bridges resembling the protein tethers linking mitochondria and the ER, both for their ultrastructural features and the involvement of Mitofusin 2. The frequency of these connections correlates spatially and timely with melanosome biogenesis, suggesting a functional link between the 2 processes and in general that organelle biogenesis in the secretory pathway requires interorganellar crosstalks at multiple steps. Here, we summarize the different functions attributed to MCSs, and discuss their possible relevance for the newly identified melanosome-mitochondrion liaison.
PMCID: PMC4203768  PMID: 25346798
lysosome-related organelles; lipid transfer; calcium signaling; protein-protein interactions; organelle dynamics; ATP supply; cytosolic microdomains
2.  A “mix-and-match” approach to designing Ca2+ microdomains at membrane-contact sites 
Ca2+ microdomains are critical for regulating cellular activity and often form at membrane contact sites. Such sites between lysosomes and the ER potentially provide a platform for signaling by the Ca2+ mobilizing messenger NAADP. However, at present we know little of how Ca2+ release events are coordinated at these experimentally intractable junctions. We therefore developed a computational model of lysosome-ER microdomains, which suggested that small leaks of Ca2+ from the lysosome couple to Ca2+-sensitive Ins(1,4,5)P3 receptors on the ER to generate global, microdomain-dependent Ca2+ signals. Here we discuss how the “mix-and-match” arrangement of different Ca2+ signaling proteins on the “source” and “target” membranes might generate functionally heterogeneous Ca2+ microdomains.
PMCID: PMC4114918  PMID: 25077010
Ca2+; Membrane Contact Sites; Microdomains; NAADP; 2-Pore Channel; Lysosomes; computational modeling; SERCA; Endoplasmic Reticulum
3.  Analysis of the Retromer complex-WASH complex interaction illuminates new avenues to explore in Parkinson disease 
The retromer complex mediates endosomal protein sorting by concentrating membrane proteins (cargo) into nascent tubules formed through the action of sorting nexin (SNX) proteins. The WASH complex is recruited to endosomes by binding to the VPS35 subunit of retromer and facilitates cargo protein sorting by promoting formation of endosomally-localized F-actin. The VPS35 protein is mutated in Parkinson disease (PD) and a recent report has revealed that the PD-causing mutation impairs the association of retromer with the WASH complex leading to perturbed endosomal protein sorting. Another important player in endosomal protein sorting is the DNAJC13/RME-8 protein, which associates with SNX1 and has also recently been linked to PD. An additional recent report has now shown that RME-8 also interacts with the WASH complex thus establishing retromer and WASH complex-mediated endosomal protein sorting as a key pathway linked to the pathology of PD and providing new avenues to explore in the search for insights into the disease mechanism.
PMCID: PMC4106150  PMID: 25067992
retromer; WASH complex; RME-8; Parkinson disease; endosomal protein sorting; tubule
4.  Catching synaptic vesicles in action 
The synaptic vesicle (SV) cycle was initially discovered at the neuromuscular junction using electron microscopy (EM) analysis.1 With the introduction of fluorescent probes that are able to monitor real-time cellular events in live cells, EM analysis was pushed to the side lines because it could not provide meaningful kinetic analyses of the various steps in the synaptic vesicle cycle.
PMCID: PMC4138221  PMID: 25143799
synaptic vesicle retrieval; endocytosis; electron microscopy; fast fixation; endosome; kiss and run; clathrin
5.  Rectifying rectifier channels in Huntington disease 
Neuronal abnormalities in neurodegenerative disorders such as Huntington disease, Alzheimer disease or Parkinson disease have been the primary focus of decades of research. However, increasing evidences indicate that glial cells and more specifically astrocytes could be as important players as their big brother. It is now particularly evident in Huntington disease where astrocytal potassium channels have emerged as a likely key factor in the pathogenesis of the disease.
PMCID: PMC4153761  PMID: 25191533
Huntington disease; Huntingtin; HTT; channel; potassium; Kir4.1; glutamate; NMDA receptor; neuron; excitability
6.  Lung cell-specific modulation of LPS-induced TLR4 receptor and adaptor localization 
Lung infection by Gram-negative bacteria is a major cause of morbidity and mortality in humans. Lipopolysaccharide (LPS), located in the outer membrane of the Gram-negative bacterial cell wall, is a highly potent stimulus of immune and structural cells via the TLR4/MD2 complex whose function is sequentially regulated by defined subsets of adaptor proteins. Regulatory mechanisms of lung-specific defense pathways point at the crucial role of resident alveolar macrophages, alveolar epithelial cells, the TLR4 receptor pathway, and lung surfactant in shaping the innate immune response to Gram-negative bacteria and LPS. During the past decade intracellular spatiotemporal localization of TLR4 emerged as a key feature of TLR4 function. Here, we briefly review lung cell type- and compartment-specific mechanisms of LPS-induced TLR4 regulation with a focus on primary resident hematopoietic and structural cells as well as modifying microenvironmental factors involved.
PMCID: PMC4134348  PMID: 25136402
lung innate immunity; Gram-negative pneumonia; Surfactant; Surfactant proteins; alveolar macrophages; alveolar epithelial cells; Toll-like receptor 4; TLR receptor localization/trafficking; LPS
7.  Asymmetry in olfactory generalization and the inclusion criterion in ants 
Animals constantly face the challenge of extracting important information out of their environment, and for many animals much of this information is chemical in nature. The ability to discriminate and generalize between chemical stimuli is extremely important and is commonly thought to depend mostly on the structural similarity between the different stimuli. However, we previously provided evidence that in the carpenter ant Camponotus aethiops, generalization not only depends on structural similarity, but also on the animal’s previous training experience. When individual ants were conditioned to substance A, they generalized toward a mixture of A and B. However, when trained to substance B, they did not generalize toward this mixture, resulting in asymmetrical generalization. This asymmetry followed an inclusion criterion, where the ants consistently generalized from a molecule with a long carbon chain to molecules with a shorter chain, but not the other way around. Here I will review the evidence for the inclusion criterion, describe possible proximate mechanisms underlying this phenomenon as well as discuss its potential adaptive significance.
PMCID: PMC4203582  PMID: 25346797
Conditioning; asymmetrical generalization; discrimination; inclusion criterion; ants; perception; action component
8.  The colorful language of Australian flowers 
The enormous increase in phylogenetic information in recent years has allowed many old questions to be reexamined from a macroevolutionary perspective. We have recently considered evolutionary convergence in floral colors within pollination syndromes, using bird-pollinated species in Australia. We combined quantitative measurements of floral reflectance spectra, models of avian color vision, and a phylogenetic tree of 234 Australian species to show that bird-pollinated flowers as a group do not have colors that are significantly different from the colors of insect-pollinated flowers. However, about half the bird-pollinated flowers have convergently evolved a narrow range of colors with dominant long-wavelength reflection far more often than would be expected by chance. These convergent colors would be seen as distinctly different from other floral colors in our sample when viewed by honeyeaters (family Meliphagidae), birds with a phylogenetically ancestral type of color vision and the dominant avian pollinators in Australia. Our analysis shows how qualitative ideas in natural history, like the concept of pollination syndromes, can be given more precise definition and rigorous statistical testing that takes into account phylogenetic information.
PMCID: PMC4203498  PMID: 25346795
bird pollination; convergent evolution; floral color; pollination syndrome; reflectance spectra
9.  Exploring vortex enhancement and manipulation mechanisms in jellyfish that contributes to energetically efficient propulsion 
The ability of animals to propel themselves efficiently through a fluid medium is ecologically advantageous. Flexible components that influence vortex interactions are widespread among animal propulsors. However the mechanisms by which vortices are enhanced and appropriately positioned for thrust generation are still poorly understood. Here, we describe how kinematic propulsor movements of a jellyfish can enhance and reposition a vortex ring that allows the recapture of wake energy for secondary thrust generation and efficient locomotion. We use high-speed video and digital particle image velocimetry (DPIV) to resolve kinematics simultaneously with fluid structures. These results provide new insight into how animals can manipulate fluid structures to reduce metabolic energy demands of swimming muscles and may have implications in bio-inspired design.
PMCID: PMC4203578  PMID: 25346796
energetics; fluid dynamics; kinematics; swimming efficiency; vortex
10.  Summertime blues 
A successful honey bee forager tells her nestmates the location of good nectar and pollen with the waggle dance, a symbolic language that communicates a distance and direction. Because bees are adept at scouting out profitable forage and are very sensitive to energetic reward, we can use the distance that bees communicate via waggle dances as a proxy for forage availability, where the further the bees fly, the less forage can be found locally. Previously we demonstrated that bees fly furthest in the summer compared with spring or autumn to bring back forage that is not necessarily of better quality. Here we show that August is also the month when significantly more foragers return with empty crops (P = 7.63e-06). This provides additional support that summer may represent a seasonal foraging challenge for honey bees.
PMCID: PMC4203501  PMID: 25346794
Apis mellifera; forage availability; foraging dearth; foraging ecology; waggle dance
11.  Tissue guidance without filopodia 
Filopodia are highly dynamic, rod-like protrusions that are found in abundance at the leading edge of migrating cells such as endothelial tip cells and at axonal growth cones of developing neurons. One proposed function of filopodia is that of an environmental probe, which serves to sense guidance cues during neuronal pathfinding and blood vessel patterning. However, recent studies show that tissue guidance occurs unhindered in the absence of filopodia, suggesting a dispensability of filopodia in this process. Here, we discuss evidence that support as well as dispute the role of filopodia in guiding the formation of stereotypic neuronal and blood vessel patterns.
PMCID: PMC4203535  PMID: 25346793
cell guidance; cell migration; endothelial tip cell; filopodia; neuronal pathfinding; vascular patterning
12.  Routing of Physarum polycephalum “signals” using simple chemicals 
In previous work the chemotaxis toward simple organic chemicals was assessed. We utilize the knowledge gained from these chemotactic assays to route Physarum polycephalum “signals” at a series of junctions. By applying chemical inputs at a simple T-junction we were able to reproducibly control the path taken by the plasmodium of P. Polycephalum. Where the chemoattractant farnesene was used at one input a routed signal could be reproducibly generated i.e., P. Polycephalum moves toward the source of chemoattractant. Where the chemoattractant was applied at both inputs the signal was reproducibly split i.e., at the junction the plasmodium splits and moves toward both sources of chemoattractant. If a chemorepellent was used then the signal was reproducibly suppressed i.e., P. Polycephalum did not reach either output and was confined to the input channel. This was regardless of whether a chemoattractant was used in combination with the chemorepellent showing a hierarchy of inhibition over attraction. If no chemical input was used in the simple circuit then a random signal was generated, whereby P. Polycephalum would move toward one output at the junction, but the direction was randomly selected.
PMCID: PMC4201598  PMID: 25346788
Physarum polycephalum; chemotaxis; signal-routing; computing-circuits
13.  Vps11, a subunit of the tethering complexes HOPS and CORVET, is involved in regulation of glycolipid degradation and retrograde toxin transport 
We recently reported that ERM (ezrin, radixin, moesin) proteins are involved in intracellular sorting of Shiga toxin (Stx) and its receptor globotriaosylceramide (Gb3), and that depletion of ezrin and moesin reduced retrograde Golgi transport of Stx. In the same study, we found that knockdown of Vps11, a core subunit of both the homotypic fusion and protein sorting (HOPS) complex and the class C core vacuole/endosome tethering factor (CORVET), increased retrograde transport of Stx and could counteract the inhibiting effect of moesin and ezrin knockdown. In this study we demonstrate that Vps11 knockdown also leads to increased Stx toxicity as well as increased retrograde transport and toxicity of ricin. Additionally, we show that knockdown of Vps11 restores the reduced Gb3 level observed after moesin depletion.
PMCID: PMC3995726  PMID: 24778763
HOPS; CORVET; Vps11; moesin; ERM proteins; Shiga toxin; ricin; Gb3; retrograde transport
14.  The role of F-actin in modulating Clathrin-mediated endocytosis: Lessons from neurons in health and neuropsychiatric disorder 
Clathrin-mediated endocytosis is one of several mechanisms for retrieving transmembrane proteins from the cell surface. This key mechanism is highly conserved in evolution and is found in any eukaryotic cell from yeast to mammals. Studies from several model organisms have revealed that filamentous actin (F-actin) plays multiple distinct roles in shaping Clathrin-mediated endocytosis. Yet, despite the identification of numerous molecules at the interface between endocytic machinery and the cytoskeleton, our mechanistic understanding of how F-actin regulates endocytosis remains limited. Key insights come from neurons where vesicular release and internalization are critical to pre- and postsynaptic function. Recent evidence from human genetics puts postsynaptic organization, glutamate receptor trafficking, and F-actin remodeling in the spotlight as candidate mechanisms underlying neuropsychiatric disorders. Here I review recent findings that connect the F-actin cytoskeleton mechanistically to Clathrin-mediated endocytosis in the central nervous system, and discuss their potential involvement in conferring risk for neuropsychiatric disorder.
PMCID: PMC4091099  PMID: 25053985
Clathrin-mediated endocytosis; F-actin; cytoskeleton; CPG2; SYNE1; schizophrenia; synaptic plasticity; internalization; AMPA receptor; bipolar disorder; synapse
15.  Salicylic acid-dependent gene expression is activated by locomotion mucus of different molluscan herbivores 
Slugs and snails specifically secrete mucus to aid their locomotion. This mucus is the contact material between molluscan herbivores and plants. We have recently shown that the locomotion mucus of the slug Deroceras reticulatum contains salicylic acid (SA).1 When applied to wounded leaves of Arabidopsis thaliana this mucus induces the activity of the SA-responsive pathogenesis related 1 (PR1) promotor1. Here we analyzed PR1 promotor activity in response to treatments with locomotion mucus of eight slugs and snails. Although none of the mucus contained SA, their application still elicited PR1 promotor activity. These data provide further insights into the complex interactions between molluscan herbivores and plants.
PMCID: PMC4203486  PMID: 25346792
plant; mollusk; slug; snail; PR1; salicylic acid
16.  On the origin of giant cells in Hodgkin lymphoma 
Multinucleated giant tumor cells are frequently observed in tissue sections of lymphoma patients. In Hodgkin lymphoma (HL), these cells are pathognomonic for the disease and named Reed-Sternberg (RS) cells. Despite the well-described disease-promoting functions of RS cells, their development has remained obscure. We addressed this open question by continuous live cell imaging to observe the generation of RS cells. Single-cell tracking of HL cell lines revealed that RS cells develop from mononucleated progenitors that divide and subsequently re-fuse, before they grow and become multinucleated giant cells. Thus, RS cell generation is neither due to cell fusion of unrelated Hodgkin cells nor to endomitosis, as previously suggested. In the majority of cases, re-fusion of daughter cells was preceded by an incomplete cytokinesis, visualized by a persistent microtubule bridge connecting the cells. This surprising finding describes a novel mechanism for the formation of multinuclear giant cells with potential relevance beyond HL.
PMCID: PMC4203491  PMID: 25346790
Hodgkin lymphoma; Reed-Sternberg cells; giant cells; re-fusion; cell fusion; endomitosis; acytokinetic mitosis; incomplete cytokinesis; single-cell tracking; time-lapse microscopy
17.  Pigeon homing from unfamiliar areas 
The conclusion that pigeons and other birds can find their way home from unfamiliar areas by means of olfactory signals is well based on a variety of experiments and supporting investigations of the chemical atmosphere. Here I argue that alternative concepts proposing other sources of geopositional information are disproved by experimental findings or, at least, are not experimentally supported and hardly realistic.
PMCID: PMC4203629  PMID: 25346789
avian navigation; homing pigeon; olfaction; atmospheric trace gases; geomagnetism; gravity; infrasound
18.  Sunbathing 
Solar radiation is an important risk factor for skin cancer, the incidence of which is increasing, especially in the fair-skinned populations of the world. While the ultraviolet (UV)B component has direct DNA damaging ability, UVA-induced effects are currently mainly attributed to the production of reactive oxygen species. In our recent study, we compared the effects of UVA and UVB radiation on human keratinocytes and found that UVA-induced plasma membrane damage was rapidly repaired by lysosomal exocytosis, which was detected based on the expression of lysosomal membrane associated protein-1 (LAMP-1) on the plasma membrane of non-permeabilized cells. Later, the keratinocytes died through caspase-8 mediated apoptosis. In contrast, the plasma membranes of keratinocytes exposed to UVB showed no LAMP-1 expression, and, although the cells died by apoptosis, no initial caspase-8 activity was detected. We have also demonstrated the occurrence of UVA-induced lysosomal exocytosis in reconstructed skin and shown the relocation of lysosomes from the center of cells to the vicinity of the plasma membrane. Thus, we suggest that lysosomal exocytosis also occurs in keratinocytes covered by the stratum corneum following exposure to UVA. Our findings provide new insight into the mechanism of UVA-induced skin damage.
PMCID: PMC4201597  PMID: 25346791
UV irradiation; keratinocytes; lysosomes; exocytosis; plasma membrane repair; lysosomal associated membrane protein
19.  A function for the midbody remnant in embryonic patterning 
Asymmetric cell divisions combine cell division with fate specification and one general model of how this is achieved was proposed already decades ago1,2: During interphase, the cell polarity axis is specified, followed by orientation of the spindle along the polarity axis and segregation of fate determinants along the polarity axis during mitosis. In most cells, the polarity axis and the spindle will usually align with the long axis that the cell had before division, also called Hertwig’s rule3–6. In the C. elegans embryo, the first polarity axis also forms along the long axis of the embryo by enrichment of myosin in the anterior7 and formation of mutually exclusive anterior and posterior cortical polarity domains, mediated through directional cortical contractile flow8–10. The directionality of this flow is determined by an extrinsic cue, the entry of the sperm, which inhibits Rho-dependent myosin activation at the future posterior pole by bringing with it the Rho GTPase activating protein CYK-411,12. Moreover, since there is no previous division ‘history’ before the first cleavage, mechanisms have to ensure that the nucleus-centrosome complex undergoes a 90 degree rotation so that the spindle can subsequently elongate along the long axis13–15. Additional mechanisms ensure that the site of cleavage is perpendicular to the long axis16,17. Hence, tight coupling of an extrinsic cue to intrinsic polarity formation and spindle elongation enables alignment of the division orientation with the long axis of the organism and successful segregation of fate determinants.
PMCID: PMC4203541  PMID: 25346787
midbody; asymmetry; axis formation; patterning; development; C. elegans; cytokinesis
20.  Chromatin-mediated microtubule nucleation in Drosophila syncytial embryos 
Upon entry into mitosis, many microtubules are nucleated that coordinately integrate into a stable, yet dynamic, mitotic spindle apparatus. In a recent publication, we examined microtubule-generating pathways within a single model system, the Drosophila syncytial embryo. We found that, following depolymerisation of metaphase spindle microtubules by cold treatment, spindles regenerate predominantly from microtubules nucleated within the vicinity of chromatin. We also showed this chromatin-mediated microtubule nucleation is mediated by the Drosophila homolog of a vertebrate spindle assembly factor (SAF), HURP and is dependent on the conserved microtubule amplifying protein complex, Augmin. Here, we expand our investigation into Drosophila SAFs, providing evidence that, in vitro, both D-HURP and D-TPX2 are able to bind to and stabilize microtubules. We show that GFP-D-HURP purified from embryos interacts with Importin-β and Augmin and, consistent with this, demonstrate that the underlying basis of chromatin-mediated microtubule nucleation in Drosophila syncytial embryos is dependent on Ran-GTP.
PMCID: PMC4091100  PMID: 25053984
microtubule; mitosis; Drosophila; Ran; HURP; Augmin
21.  Apm4, the mu subunit of yeast AP-2 interacts with Pkc1, and mutation of the Pkc1 consensus phosphorylation site Thr176 inhibits AP-2 recruitment to endocytic sites 
The AP-2 endocytic adaptor has been extensively characterized in mammalian cells and is considered to play a role both in cargo binding and in formation of endocytic sites. However, despite our detailed knowledge of mechanistic aspects of endocytic complex assembly and disassembly in the model organism Saccharomyces cerevisiae, no function of AP-2 had been described in wild-type yeast under normal growth conditions. A recent study however revealed that disruption of the complex caused by deletion of the gene encoding its mu subunit (APM4) caused defects in cell polarity such that responses to pheromone, nutritional status and cell wall damage were affected. Furthermore, a homozygous deletion of the mu subunit gene in Candida albicans affected its ability to grow hyphae. Direct binding to the yeast cell wall stress sensor Mid2 was detected, and in an apm4 deletion strain Mid2 showed reduced re-localization to the mother bud neck region following cell wall damage with calcofluor or to the mating projection tip. Here we demonstrate an interaction between Apm4 and the yeast cell wall integrity pathway component Pkc1 and show that mutation of the predicted Pkc1 site in the Apm4 hinge region affects recruitment of the AP-2 complex to endocytic sites.
PMCID: PMC4203630  PMID: 25346786
protein kinase C; endocytosis; Saccharomyces cerevisiae; adaptor proteins; phosphorylation
22.  On the computational ability of the RNA polymerase II carboxy terminal domain 
The RNA polymerase II carboxy terminal domain has long been known to play an important role in the control of eukaryotic transcription. This role is mediated, at least in part, through complex post-translational modifications that take place on specific residues within the heptad repeats of the domain. In this addendum, a speculative, but formal mathematical conceptualization of this biological phenomenon (in the form of a semi-Thue string rewriting system) is presented. Since the semi-Thue formalism is known to be Turing complete, this raises the possibility that the CTD – in association with the regulatory pathways controlling its post-translational modification – functions as a biological incarnation of a universal computing machine.
PMCID: PMC4217226  PMID: 25371772
Semi-Thue string rewriting system; RNA polymerase II; Carboxy terminal domain; Transcription; Turing completeness; Computation; Universal Turing machine
23.  Discovering electrophysiology in photobiology 
The mini-review gives special attention to holistic approach and mechanisms of processes. The physical and chemical frames and background for visual perception and signaling are discussed. Perception of photons by retinal rod cells is described in more detail starting from photon absorption and culminating in ion currents. Dark noise and temperature-dependence of photocurrents in photoreceptor cells are analyzed. Perception of polarized light, its effects and informational importance are discussed based on underlying mechanisms and specialized morphological structures of biological organisms. Role of statistics of photons in photoreception is questioned. The review also pinpoints new and developing directions and raises questions for future research.
PMCID: PMC4183612  PMID: 25328636
Photobiology; electrophysiology; polarized light; rod cells; dark noise; statistics of photons; optogenetics; quantum dots
24.  Does cycad aulacaspis scale (Aulacaspis yasumatsui, Hemiptera: Diaspididae) play a direct role in causing soil phytotoxicity? 
Cycad aulacaspis scale (CAS, Aulacaspis yasumatsui, Hemiptera: Diaspididae) was accidentally introduced to Guam in 2003, and has caused acute mortality of the dominant, endemic forest tree Cycas micronesica. A phytotoxic legacy in the soils beneath cycad trees killed by CAS over a period of about three years has been demonstrated. The origin of the toxicity may be large quantities of CAS-encrusted cycad leaf litter. We explore the possibility that a major contribution to this toxic legacy may come from the scale insects, not just from the plant material.
PMCID: PMC4094193  PMID: 25083170
cycads; Cycas micronesica; Guam; invasive species; scale cover
25.  Differential leaflet mortality may influence biogeochemical cycling following tropical cyclones 
Intensity of tropical cyclones is expected to increase in the coming century, and an improved understanding of their influence on biogeochemical cycles would benefit ecologists and conservationists. We studied the November 2013 Typhoon Haiyan damage to observe that numerous examples of partial leaf necrosis on intact leaves of trees in the Cycadaceae and Arecaceae families resulted, leaving behind a copious amount of arboreal dead leaf material attached to live leaves. The decay process of this form of arboreal litter has not been previously studied. When compared with decay of ground litter or detached litter suspended in the canopy, we predict the decay process of this form of arboreal litter will include increased photooxidation, leaching, and comminution by detritivorous insects and mites; but decreased catabolism of organic molecules by saprophytic organisms.
PMCID: PMC4094194  PMID: 25083171
arboreal litter; Arecaceae; Cycadaceae; cyclones; hurricanes; Philippines; typhoons

Results 1-25 (930)