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Paulo Wagner Pires, Scott Earley
Hypoxia and ischemia are linked to oxidative stress, which can activate the oxidant-sensitive transient receptor potential ankyrin 1 (TRPA1) channel in cerebral artery endothelial cells, leading to vasodilation. We hypothesized that TRPA1 channels in endothelial cells are activated by hypoxia-derived reactive oxygen species, leading to cerebral artery dilation and reduced ischemic damage. Using isolated cerebral arteries expressing a Ca2+ biosensor in endothelial cells, we show that 4-hydroxynonenal and hypoxia increased TRPA1 activity, detected as TRPA1 sparklets...
September 21, 2018: ELife
Katherine A Smith, Stephan Löser, Fumi Varyani, Yvonne Harcus, Henry J McSorley, Andrew Nj McKenzie, Rick M Maizels
Interleukin 25 (IL-25) is a major 'alarmin' cytokine, capable of initiating and amplifying the type 2 immune response to helminth parasites. However its role in the later effector phase of clearing chronic infection remains unclear. The helminth Heligmosomoides polygyrus establishes long-term infections in susceptible C57BL/6 mice, but is slowly expelled in BALB/c mice from day 14 onwards. We noted that IL-25R ( Il17rb )-deficient BALB/c mice were unable to expel parasites despite type 2 immune activation comparable to the wild-type...
September 21, 2018: ELife
Christopher M Kim, Carson C Chow
Spiking activity of neurons engaged in learning and performing a task show complex spatiotemporal dynamics. While the output of recurrent network models can learn to perform various tasks, the possible range of recurrent dynamics that emerge after learning remains unknown. Here we show that modifying the recurrent connectivity with a recursive least squares algorithm provides sufficient flexibility for synaptic and spiking rate dynamics of spiking networks to produce a wide range of spatiotemporal activity...
September 20, 2018: ELife
Gang Lu, Stephanie Weng, Mary Matyskiela, Xinde Zheng, Wei Fang, Scott Wood, Christine Surka, Reina Mizukoshi, Chin-Chun Lu, Derek Mendy, In Sock Jang, Kai Wang, Mathieu Marella, Suzana Couto, Brian Cathers, James Carmichael, Philip Chamberlain, Mark Rolfe
The cereblon modulating agents (CMs) including lenalidomide, pomalidomide and CC-220 repurpose the Cul4-RBX1-DDB1-CRBN (CRL4CRBN ) E3 ubiquitin ligase complex to induce the degradation of specific neomorphic substrates via polyubiquitination in conjunction with E2 ubiquitin-conjugating enzymes, which have until now remained elusive. Here we show that the ubiquitin-conjugating enzymes UBE2G1 and UBE2D3 cooperatively promote the K48-linked polyubiquitination of CRL4CRBN neomorphic substrates via a sequential ubiquitination mechanism...
September 20, 2018: ELife
Neus Martínez-Abadías, Roger Mateu Estivill, Jaume Sastre Tomas, Susan Motch Perrine, Melissa Yoon, Alex Robert-Moreno, Jim Swoger, Lucia Russo, Kazuhiko Kawasaki, Joan Richtsmeier, James Sharpe
The earliest developmental origins of dysmorphologies are poorly understood in many congenital diseases. They often remain elusive because the first signs of genetic misregulation may initiate as subtle changes in gene expression, which are hard to detect and can be obscured later in development by secondary effects. Here, we develop a method to trace the origins of phenotypic abnormalities by accurately quantifying the 3D spatial distribution of gene expression domains in developing organs. By applying geometric morphometrics to 3D gene expression data obtained by Optical Projection Tomography, we determined that our approach is sensitive enough to find regulatory abnormalities that have never been detected previously...
September 20, 2018: ELife
Jimmie M Gmaz, James E Carmichael, Matthijs Aa van der Meer
The nucleus accumbens (NAc) is important for learning from feedback, and for biasing and invigorating behavior in response to cues that predict motivationally relevant outcomes. NAc encodes outcome-related cue features such as the magnitude and identity of reward. However, little is known about how features of cues themselves are encoded. We designed a decision making task where rats learned multiple sets of outcome-predictive cues, and recorded single-unit activity in the NAc during performance. We found that coding of cue identity and location occurred alongside coding of expected outcome...
September 20, 2018: ELife
Feng-Ching Tsai, Aurelie Bertin, Hugo Bousquet, John Manzi, Yosuke Senju, Meng-Chen Tsai, Laura Picas, Stephanie Miserey-Lenkei, Pekka Lappalainen, Emmanuel Lemichez, Evelyne Coudrier, Patricia Bassereau
One challenge in cell biology is to decipher the biophysical mechanisms governing protein enrichment on curved membranes and the resulting membrane deformation. The ERM protein ezrin is abundant and associated with cellular membranes that are flat, positively or negatively curved. Using in vitro and cell biology approaches, we assess mechanisms of ezrin's enrichment on curved membranes. We evidence that wild-type ezrin (ezrinWT) and its phosphomimetic mutant T567D (ezrinTD) do not deform membranes but self-assemble anti-parallelly, zipping adjacent membranes...
September 20, 2018: ELife
Clémence Hocquet, Xavier Robellet, Laurent Modolo, Xi-Ming Sun, Claire Burny, Sara Cuylen-Haering, Esther Toselli, Sandra Clauder-Münster, Lars Steinmetz, Christian H Haering, Samuel Marguerat, Pascal Bernard
Condensins are genome organisers that shape chromosomes and promote their accurate transmission. Several studies have also implicated condensins in gene expression, although any mechanisms have remained enigmatic. Here, we report on the role of condensin in gene expression in fission and budding yeasts. In contrast to previous studies, we provide compelling evidence that condensin plays no direct role in the maintenance of the transcriptome, neither during interphase nor during mitosis. We further show that the changes in gene expression in post-mitotic fission yeast cells that result from condensin inactivation are largely a consequence of chromosome missegregation during anaphase, which notably depletes the RNA-exosome from daughter cells...
September 19, 2018: ELife
Jennifer S Sun, Nikki K Larter, J Sebastian Chahda, Douglas Rioux, Ankita Gumaste, John R Carlson
Hygrosensation is an essential sensory modality that is used to find sources of moisture. Hygroreception allows animals to avoid desiccation, an existential threat that is increasing with climate change. Humidity response, however, remains poorly understood. Here we find that humidity-detecting sensilla in the Drosophila antenna express and rely on a small protein, Obp59a. Mutants lacking this protein are defective in three hygrosensory behaviors, one operating over seconds, one over minutes, and one over hours...
September 19, 2018: ELife
Garron T Dodd, Natalie J Michael, Robert S Lee-Young, Salvatore P Mangiafico, Jack T Pryor, Astrid C Munder, Stephanie E Simonds, Jens Claus Brüning, Zhong-Yin Zhang, Michael A Cowley, Sofianos Andrikopoulos, Tamas L Horvath, David Spanswick, Tony Tiganis
Hypothalamic neurons respond to nutritional cues by altering gene expression and neuronal excitability. The mechanisms that control such adaptive processes remain unclear. Here we define populations of POMC neurons in mice that are activated or inhibited by insulin and thereby repress or inhibit hepatic glucose production (HGP). The proportion of POMC neurons activated by insulin was dependent on the regulation of insulin receptor signaling by the phosphatase TCPTP, which is increased by fasting, degraded after feeding and elevated in diet-induced obesity...
September 19, 2018: ELife
Aleksandra Badura, Jessica L Verpeut, Julia W Metzger, Talmo D Pereira, Thomas J Pisano, Ben Deverett, Dariya E Bakshinskaya, Samuel S-H Wang
Cognitive and social capacities require postnatal experience, yet the pathways by which experience guides development are unknown. Here we show that the normal development of motor and nonmotor capacities requires cerebellar activity. Using chemogenetic perturbation of molecular layer interneurons to attenuate cerebellar output in mice, we found that activity of posterior regions in juvenile life modulates adult expression of eyeblink conditioning (paravermal lobule VI, crus I), reversal learning (lobule VI), persistive behavior and novelty-seeking (lobule VII), and social preference (crus I/II)...
September 18, 2018: ELife
Niko Välimäki, Heli Kuisma, Annukka Pasanen, Oskari Heikinheimo, Jari Sjöberg, Ralf Bützow, Nanna Sarvilinna, Hanna-Riikka Heinonen, Jaana Tolvanen, Simona Bramante, Tomas Tanskanen, Juha Auvinen, Terhi Piltonen, Amjad Alkodsi, Rainer Lehtonen, Eevi Kaasinen, Kimmo Palin, Lauri A Aaltonen
Uterine leiomyomas (ULs) are benign tumors that are a major burden to women's health. A genome-wide association study on 15,453 UL cases and 392,628 controls was performed, followed by replication of the genomic risk in six cohorts. Effects of the risk alleles were evaluated in view of molecular and clinical characteristics. 22 loci displayed a genome-wide significant association. The likely predisposition genes could be grouped to two biological processes. Genes involved in genome stability were represented by TERT, TERC, OBFC1 - highlighting the role of telomere maintenance - TP53 and ATM ...
September 18, 2018: ELife
Nagayasu Nakanishi, Mark Q Martindale
Neuropeptides are evolutionarily ancient peptide hormones of the nervous and neuroendocrine systems, and are thought to have regulated metamorphosis in early animal ancestors. In particular, the deeply conserved Wamide family of neuropeptides-shared across Bilateria (e.g. insects and worms) and its sister group Cnidaria (e.g. jellyfishes and corals)-has been implicated in mediating life-cycle transitions, yet their endogenous roles remain poorly understood. By using CRISPR-Cas9-mediated reverse genetics, we show that cnidarian Wamide-referred to as GLWamide-regulates the timing of life cycle transition in the sea anemone cnidarian Nematostella vectensis ...
September 18, 2018: ELife
Olga Kornienko, Patrick Latuske, Mathis Bassler, Laura Kohler, Kevin Allen
Computational models postulate that head-direction (HD) cells are part of an attractor network integrating head turns. This network requires inputs from visual landmarks to anchor the HD signal to the external world. We investigated whether information about HD and visual landmarks is integrated in the medial entorhinal cortex and parasubiculum, resulting in neurons expressing a conjunctive code for HD and visual landmarks. We found that parahippocampal HD cells could be divided into two classes based on their theta-rhythmic activity: non-rhythmic and theta-rhythmic HD cells...
September 17, 2018: ELife
Judith Gunzelmann, Diana Rüthnick, Tien-Chen Lin, Wanlu Zhang, Annett Neuner, Ursula Jäkle, Elmar Schiebel
Stu2/XMAP215/ZYG-9/Dis1/Alp14/Msps/ch-TOG family members nucleate microtubules together with γ-tubulin complexes. However, we know little about the interplay of these nucleation factors. Here, we show that the budding yeast Stu2 in complex with the γ-tubulin receptor Spc72 nucleates microtubules in vitro without the small γ-tubulin complex (γ-TuSC). Upon γ-TuSC addition, Stu2 facilitates Spc72-γ-TuSC interaction by binding to Spc72 and γ-TuSC. Stu2 together with Spc72-γ-TuSC increases microtubule nucleation depended on the TOG domains of Stu2...
September 17, 2018: ELife
Jochen Triesch, Anh Duong Vo, Anne-Sophie Hafner
Changes in the efficacies of synapses are thought to be the neurobiological basis of learning and memory. The efficacy of a synapse depends on its current number of neurotransmitter receptors. Recent experiments have shown that these receptors are highly dynamic, moving back and forth between synapses on time scales of seconds and minutes. This suggests spontaneous fluctuations in synaptic efficacies and a competition of nearby synapses for available receptors. Here we propose a mathematical model of this competition of synapses for neurotransmitter receptors from a local dendritic pool...
September 17, 2018: ELife
Daiane Santana Alves, Justin M Westerfield, Xiaojun Shi, Vanessa P Nguyen, Katherine M Stefanski, Kristen R Booth, Soyeon Kim, Jennifer Morrell-Falvey, Bing-Cheng Wang, Steven M Abel, Adam W Smith, Francisco N Barrera
Misregulation of the signaling axis formed by the receptor tyrosine kinase (RTK) EphA2 and its ligand, ephrinA1, causes aberrant cell-cell contacts that contribute to metastasis. Solid tumors are characterized by an acidic extracellular medium. We intend to take advantage of this tumor feature to design new molecules that specifically target tumors. We created a novel pH-dependent transmembrane peptide, TYPE7, by altering the sequence of the transmembrane domain of EphA2. TYPE7 is highly soluble and interacts with the surface of lipid membranes at neutral pH, while acidity triggers transmembrane insertion...
September 17, 2018: ELife
Harry Nunns, Lea Goentoro
One challenge in biology is to make sense of the complexity of biological networks. A good system to approach this is signaling pathways, whose well-characterized molecular details allow us to relate the internal processes of each pathway to their input-output behavior. In this study, we analyzed mathematical models of three metazoan signaling pathways: the canonical Wnt, ERK, and Tgfβ pathways. We find an unexpected convergence: the three pathways behave in some physiological contexts as linear signal transmitters...
September 17, 2018: ELife
Manon Morin, Emily C Pierce, Rachel J Dutton
Microbial community structure and function rely on complex interactions whose underlying molecular mechanisms are poorly understood. To investigate these interactions in a simple microbiome, we introduced E. coli into an experimental community based on a cheese rind and identified the differences in E. coli's genetic requirements for growth in interactive and non-interactive contexts using Random Barcode Transposon Sequencing (RB-TnSeq) and RNASeq. E. coli's genetic requirements varied among pairwise growth conditions and between pairwise and community conditions...
September 13, 2018: ELife
Ying Wang, Wei Wu, Xiangbing Wu, Yan Sun, Yi P Zhang, Ling-Xiao Deng, Melissa Jane Walker, Wenrui Qu, Chen Chen, Nai-Kui Liu, Qi Han, Heqiao Dai, Lisa Be Shields, Christopher B Shields, Dale R Sengelaub, Kathryn J Jones, George M Smith, Xiao-Ming Xu
Retrogradely-transported neurotrophin signaling plays an important role in regulating neural circuit specificity. Here we investigated whether targeted delivery of neurotrophin-3 (NT-3) to lumbar motoneurons (MNs) caudal to a thoracic (T10) contusive spinal cord injury (SCI) could modulate dendritic patterning and synapse formation of the lumbar MNs. In vitro , Adeno-associated virus serotype 2 overexpressing NT-3 (AAV-NT-3) induced NT-3 expression and neurite outgrowth in cultured spinal cord neurons. In vivo , targeted delivery of AAV-NT-3 into transiently demyelinated adult mouse sciatic nerves led to the retrograde transportation of NT-3 to the lumbar MNs, significantly attenuating SCI-induced lumbar MN dendritic atrophy...
September 12, 2018: ELife
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