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| Open AccessEndocannabinoid-Goα signalling inhibits axon regeneration in Caenorhabditis elegans by antagonizing Gqα-PKC-JNK signalling
Axon regeneration inC. elegansis positively regulated by the JNK/MAP kinase pathway. Pastuhov and colleagues identify the endocannabinoid anandamide as a negative regulator of this pathway and show that anandamide inhibits axon regeneration in mature neurons after axotomy.
- Strahil Iv. Pastuhov
- , Kota Fujiki
- & Naoki Hisamoto
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Article
| Open AccessA multi-omic map of the lipid-producing yeast Rhodosporidium toruloides
The ability of oleaginous fungi to produce lipids for biofuels remains untapped, in part due to a lack of genetic information required to engineer industrial strains. Zhuet al. present the genome of R. toruloides, and identify transcriptomic and proteomic changes associated with lipid production.
- Zhiwei Zhu
- , Sufang Zhang
- & Zongbao K. Zhao
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Article
| Open AccessStructural and molecular insights into the mechanism of action of human angiogenin-ALS variants in neurons
Mutations in human angiogenin are implicated in the progression of amyotrophic lateral sclerosis. Thiyagarajan and colleagues show that structural differences between angiogenin variants affect neuronal survival, and the ability to induce stress granules in neuronal cell lines.
- Nethaji Thiyagarajan
- , Ross Ferguson
- & K. Ravi Acharya
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Article
| Open AccessStructure of a bacterial voltage-gated sodium channel pore reveals mechanisms of opening and closing
Sodium-gated ion channels open and close in response to the flow of ions. Here, McCusker et al.report the open structure of a sodium-gated ion channel pore from a bacterial homologue, and show, by comparison with the closed structure, that the movement of a C-terminal helix is sufficient to open the channel.
- Emily C. McCusker
- , Claire Bagnéris
- & B.A. Wallace
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Robust photoregulation of GABAA receptors by allosteric modulation with a propofol analogue
The design of chemical photoswitches could potentially lead to the development of novel therapeutics that regulates neurotransmission. In this study, a light-sensitive modified derivative of propofol is shown to activate GABAA receptors in Xenopusoocytes, rat ganglion cells and mouse cerebellar slices.
- Lan Yue
- , Michal Pawlowski
- & David R. Pepperberg
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Article
| Open AccessThyroid hormone determines the start of the sensitive period of imprinting and primes later learning
Filial imprinting allows precocial birds to form social attachment to other animals or objects soon after hatching. Yamaguchi and colleagues investigate the mechanisms responsible for this, and find that thyroid hormones circulating in the plasma regulate the sensitive period during which imprinting occurs.
- Shinji Yamaguchi
- , Naoya Aoki
- & Koichi J. Homma
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Article
| Open AccessEnhanced HSP70 lysine methylation promotes proliferation of cancer cells through activation of Aurora kinase B
HSP70 is a molecular chaperone that aids protein folding. In this study, HSP70 is shown to be methylated and this post-translationally modified protein is elevated in expression in human cancers and promotes the activity of Aurora kinase B.
- Hyun-Soo Cho
- , Tadahiro Shimazu
- & Ryuji Hamamoto
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Article
| Open AccessGreatwall kinase and cyclin B-Cdk1 are both critical constituents of M-phase-promoting factor
Cyclin B–Cdk1 is thought to be synonymous with the promoting factor that drives entry into M-phase of the cell cycle. Here, Greatwall kinase is shown to be required for the breakdown of the nuclear envelope and the assembly of the spindle on entry into M-phase, suggesting that it too is a part of the M-phase-promoting factor.
- Masatoshi Hara
- , Yusuke Abe
- & Takeo Kishimoto
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TGFβ induces the formation of tumour-initiating cells in claudinlow breast cancer
TGF-β signalling suppresses tumorigenesis in breast cancer cells but its effects on breast cancer initiating cells have not been reported. Using cells in culture, Brunaet al. show that TGF-β increases breast cancer initiating cell numbers in cells that have low levels of the tight junction protein claudin.
- Alejandra Bruna
- , Wendy Greenwood
- & Carlos Caldas
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Discovery of acetylene hydratase activity of the iron–sulphur protein IspH
The iron–sulphur enzyme IspH catalyses the final step of the methylerythritol phosphate isoprenoid biosynthesis pathway. Spanet al. report that IspH can hydrate acetylenes to aldehydes and ketones, in addition to its role as a 2H+/2e−reductase.
- Ingrid Span
- , Ke Wang
- & Michael Groll
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Article
| Open AccessEfficacy of the β2-adrenergic receptor is determined by conformational equilibrium in the transmembrane region
Many drugs exist that target the β-adrenergic receptor, but they have different efficacies. Kofukuet al. use NMR to show that methionine 82 in the transmembrane domain undergoes conformational changes depending on whether agonists or inverse agonists are bound, explaining the differential drug efficacy.
- Yutaka Kofuku
- , Takumi Ueda
- & Ichio Shimada
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Lysine methylation of VCP by a member of a novel human protein methyltransferase family
Methyltransferases modify cellular proteins in addition to DNA and histones. These authors identify a new family of lysine-specific methyltransferases and show that a member of this family, which is associated with tumour metastasis, methylates the ATP-dependent protein chaperone VCP/p97.
- Stefan Kernstock
- , Erna Davydova
- & Pål Ø. Falnes
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Article
| Open AccessThe allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling
Class A seven transmembrane helical receptors harbour vestibules at the entrance to the ligand-binding domain. Here, Bocket al. use probes to monitor the conformation of the M2 muscarinic receptor and show that the vestibule alters the extent of receptor movement.
- Andreas Bock
- , Nicole Merten
- & Klaus Mohr
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Identification of the functional binding pocket for compounds targeting small-conductance Ca2+-activated potassium channels
Small- and intermediate-conductance K+channels are activated by calcium-bound calmodulin and modulated by small molecules. In this study, a functional binding pocket for the 1-EBIO class of modulators is described and is located at the calmodulin-channel interface.
- Miao Zhang
- , John M. Pascal
- & Ji-Fang Zhang
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Macrophage VLDL receptor promotes PAFAH secretion in mother's milk and suppresses systemic inflammation in nursing neonates
Mother's milk contains a number of protective factors, such as the anti-inflammatory enzyme PAFAH. Here, Duet al. show that the VLDL receptor protects nursing newborns from systemic inflammation by maintaining secretion of PAFAH from maternal macrophages into mother's milk.
- Yang Du
- , Marie Yang
- & Yihong Wan
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Protein sliding and DNA denaturation are essential for DNA organization by human mitochondrial transcription factor A
The mitochondrial transcription factor A (TFAM) mediates both mitochondrial transcription and DNA compaction, but how it achieves these two functions is unknown. In this study, TFAM is shown to slide along DNA and cause local melting, suggesting a mechanism for how TFAM modulates both transcription and compaction.
- Géraldine Farge
- , Niels Laurens
- & Gijs J.L. Wuite
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Structures of Pup ligase PafA and depupylase Dop from the prokaryotic ubiquitin-like modification pathway
Pupylation is a bacterial posttranslational modification pathway with functional analogies to ubiquitination. Here, Özceliket al.report the structures of the Pup Ligase, PafA and the Depupylase, Dop. Mutational analysis revealed residues required for catalysis and for the interaction with Pup.
- Dennis Özcelik
- , Jonas Barandun
- & Eilika Weber-Ban
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Aβ alters the connectivity of olfactory neurons in the absence of amyloid plaques in vivo
The amyloid beta peptide can aggregate into insoluble plaques, which may indicate the onset of Alzheimer's disease. In a mouse model of Alzheimer's disease, Cao and colleagues report a phenotype of altered connectivity in the olfactory neuronal circuit that precedes amyloid plaque deposition.
- Luxiang Cao
- , Benjamin R. Schrank
- & Mark W. Albers
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Organellar mechanosensitive channels in fission yeast regulate the hypo-osmotic shock response
Mechanosensitive channels are required to sense cell swelling in response to osmotic shock. Nakayamaet al.report that Msy1 and Msy2 are the fission yeast homologues of the bacterial mechanosensitive channel MscS, and are required for regulating intracellular calcium in response to cell swelling.
- Yoshitaka Nakayama
- , Kenjiro Yoshimura
- & Hidetoshi Iida
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Mechanism of resilin elasticity
Resilin is a polymeric elastic protein that is important for the flight and jumping of insects. Here, the structure-function relationships ofDrosophilaresilin are investigated, and a mechanical model is proposed to account for its elasticity.
- Guokui Qin
- , Xiao Hu
- & David L. Kaplan
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Controlled delivery of bioactive molecules into live cells using the bacterial mechanosensitive channel MscL
The bacterial channel protein MscL opens in response to mechanical forces and could be exploited for vesicular-based drug delivery. Doerneret al. show that functional MscL can be expressed in mammalian cells and facilitate the controlled cellular uptake of relatively large, membrane-impermeable bioactive molecules.
- Julia F. Doerner
- , Sebastien Febvay
- & David E. Clapham
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Article
| Open AccessDistinct loops in arrestin differentially regulate ligand binding within the GPCR opsin
Following retinalcis/trans isomerisation, the active form of the G-protein-coupled receptor rhodopsin decays to opsin and all-trans-retinal. In this study, arrestin, a regulator of G-protein-coupled receptor activity, is shown to facilitate the concurrent sequestering of toxic all-trans-retinal and regeneration of 11-cis-retinal within the opsin population.
- Martha E. Sommer
- , Klaus Peter Hofmann
- & Martin Heck
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Article
| Open AccessProteomic screen reveals Fbw7 as a modulator of the NF-κB pathway
Fbw7 is a ubiquitin-ligase, which targets several oncoproteins for proteolysis, and is therefore important for the control and prevention of tumorigenesis. In this study, Arabi and colleagues carry out a proteomic screen of the targets of Fbw7, and identify Nuclear Factor of κ-B2 as a substrate.
- Azadeh Arabi
- , Karim Ullah
- & Olle Sangfelt
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Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis
Fas-associated protein with death domain (FADD) is part of a signalling complex that controls some forms of programmed cell death. Lee and colleagues demonstrate that FADD ubiquitination by the E3 ubiquitin ligase MKRN1 regulates FADD protein stability and thereby cell death.
- Eun-Woo Lee
- , Jung-Hoon Kim
- & Jaewhan Song
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Comprehensive interrogation of natural TALE DNA-binding modules and transcriptional repressor domains
The peptide sequence of transcription activator-like effectors (TALEs) can be customized to tailor the binding of TALEs to specific DNA sequences. Conget al. improve TALE specificity for guanine binding and use a genetic construct based on TALEs to efficiently repress expression of a target gene.
- Le Cong
- , Ruhong Zhou
- & Feng Zhang
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Gating of cyclic nucleotide-gated channels is voltage dependent
Cyclic nucleotide-gated channels are apparently voltage insensitive despite having the S4-type voltage sensor. Marchesiet al.show that the gating of wild-type CNGA1 and native CNG channels is voltage-independent in the presence of Li+, Na+ and K+, but that it is voltage-dependent in the presence of Rb+, Cs+ and organic cations.
- Arin Marchesi
- , Monica Mazzolini
- & Vincent Torre
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Article
| Open AccessUnfolded protein response, activated by OASIS family transcription factors, promotes astrocyte differentiation
The protein OASIS belongs to the CREB/ATF transcription factor family and is involved in endoplasmic reticulum stress responses. Saito and colleagues show that these stress responses temporally activate OASIS in neural precursor cells, resulting in their differentiation into astrocytes.
- Atsushi Saito
- , Soshi Kanemoto
- & Kazunori Imaizumi
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The yeast regulator of transcription protein Rtr1 lacks an active site and phosphatase activity
Regulator of transcription 1, Rtr1, has been proposed to function as an RNA polymerase II phosphatase. Here, the lack of phosphatase activity in purified Rtr1 and the absence of an active site in the structure of the yeast protein suggest that Rtr1 does not dephosphorylate RNA polymerase II.
- Kehui Xiang
- , James L. Manley
- & Liang Tong
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Article
| Open AccessStructure of the Acid-sensing ion channel 1 in complex with the gating modifier Psalmotoxin 1
The activity of the Acid sensing ion channel 1, ASIC1, can be modulated by the gating modifier Psalmotoxin 1 but the molecular mechanism is unclear. Dawsonet al. report the structure of chicken ASIC1 bound to Psalmotoxin 1 and find that the toxin locks two regulatory regions of the channel into a desensitized conformation.
- Roger J.P. Dawson
- , Jörg Benz
- & Armin Ruf
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Article
| Open AccessABCA4 is an N-retinylidene-phosphatidylethanolamine and phosphatidylethanolamine importer
In mammalian cells, ABC transporter proteins were thought to exclusively export a range of substrates out of cells. Quazi and colleagues show that, in retinal photoreceptor cells, ABCA4 is acting as an importer of phospholipids and that mutations known to cause Stargardt disease decrease its activity.
- Faraz Quazi
- , Stepan Lenevich
- & Robert S. Molday
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Article
| Open AccessProtein L-isoaspartyl methyltransferase regulates p53 activity
Protein L-isoaspartyl methyltransferase (PIMT) is a carboxyl methyltransferase, but its role in regulating the tumour suppressor p53 is unclear. Here, PIMT is shown to methylate p53, obstructing the tumour suppressor function of p53 through reduced protein levels and stability.
- Jae-Cheol Lee
- , Sung-Ung Kang
- & Jeung-Whan Han
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Article |
Transmembrane anion transport mediated by halogen-bond donors
The transport of anions across bilayer membranes is achieved by ion channel proteins, but some small molecules are also able to mediate transmembrane movement of anions. In this study, the halogen bonding of small perfluorinated molecules is shown to allow the transmembrane movement of anions.
- Andreas Vargas Jentzsch
- , Daniel Emery
- & Stefan Matile
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Visualizing specific protein glycoforms by transmembrane fluorescence resonance energy transfer
A common post-translational modification is the attachment of sugars, but proteins with different sugar chains, known as glycoforms, are hard to distinguish. Here, the authors use transmembrane fluorescence resonance energy transfer to visualize specific glycoforms of the membrane protein GLUT4 in living cells.
- Yoshimi Haga
- , Kumiko Ishii
- & Tadashi Suzuki
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Crystal structure of a plectonemic RNA supercoil
Nucleic acid superstructures are required to package genomes into the nucleus of cells. In this study, the superstructure of an RNA supercoil species is reported and is shown to be dependent on an RNA-binding protein that induces a higher level of organization compared with DNA superstructures.
- Jason R. Stagno
- , Buyong Ma
- & Xinhua Ji
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Structure and mechanism of a canonical poly(ADP-ribose) glycohydrolase
Poly(ADP-ribose) glycohydrolase catabolises poly(ADP-ribose), which is covalently attached to proteins following post-translational modification. In this study, the structure of poly(ADP-ribose) glycohydrolase fromTetrahymena thermophilais reported in complex with the small molecule inhibitor RBPI-3.
- Mark S. Dunstan
- , Eva Barkauskaite
- & Ivan Ahel
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Article
| Open AccessQuantitative maps of protein phosphorylation sites across 14 different rat organs and tissues
The function of proteins is often regulated by their phosphorylation at specific amino-acid residues. The authors of this article have catalogued phosphoproteins and their phosphorylation sites in 14 rat organs and tissues, and provide these data as a resource for researchers.
- Alicia Lundby
- , Anna Secher
- & Jesper V. Olsen
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Prediction of variable translation rate effects on cotranslational protein folding
Proteins can undergo folding while being translated by the ribosome, and the extent of this folding is influenced by the rate at which amino acids are added to the nascent chain. This study provides a framework for predicting domain folding probabilities as a function of the kinetics of amino-acid addition.
- Edward P. O'Brien
- , Michele Vendruscolo
- & Christopher M. Dobson
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Assembly kinetics determine the architecture of α-actinin crosslinked F-actin networks
Processes that regulate the mechanical and dynamic properties of actin cytoskeleton are important for multiple eukaryotic cell functions. In this study, using reconstituted crosslinked actin networks, organization is found to be determined by the competing kinetics of actin gelation and bundle formation.
- Tobias T. Falzone
- , Martin Lenz
- & Margaret L. Gardel
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Article
| Open AccessSerine-7 but not serine-5 phosphorylation primes RNA polymerase II CTD for P-TEFb recognition
Phosphorylation of the carboxy-terminal domain of RNA polymerase II is important for controlling gene transcription. In this study, the transcription elongation factor Tefb is shown to phosphorylate serine-5 and its activity is enhanced when the polymerase is already phosphorylated on serine-7.
- Nadine Czudnochowski
- , Christian A. Bösken
- & Matthias Geyer
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Article
| Open AccessThe cytoplasmic coiled-coil mediates cooperative gating temperature sensitivity in the voltage-gated H+ channel Hv1
In the dimeric voltage-gated H+channel, Hv1/VSOP, the gating of each subunit is coupled, but the molecular basis of dimer formation and intersubunit coupling is unclear. This study shows that channel assembly and cooperative gating are mediated by the cytoplasmic domain.
- Yuichiro Fujiwara
- , Tatsuki Kurokawa
- & Yasushi Okamura
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Article |
Involvement of urinary bladder Connexin43 and the circadian clock in coordination of diurnal micturition rhythm
Humans and rodents normally store more urine in the bladder when fast asleep than when awake. In this study, the production of the gap junction protein connexin43, a regulator of bladder capacity, is shown to oscillate in mouse urinary bladder muscle in synchrony with the circadian clock.
- Hiromitsu Negoro
- , Akihiro Kanematsu
- & Osamu Ogawa
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Article
| Open AccessThe C-terminal helical bundle of the tetrameric prokaryotic sodium channel accelerates the inactivation rate
Many channels have cytosolic domains which regulate channel function. Irieet al. show that the cytosolic C-terminal region of NavSulP, a prokaryotic voltage-gated sodium channel, forms a four-helix bundle which stabilises the tetrameric channel and accelerates channel inactivation.
- Katsumasa Irie
- , Takushi Shimomura
- & Yoshinori Fujiyoshi
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Article
| Open AccessDistinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons
Sodium channel Nav1.7 is essential for acute human pain but its role in chronic neuropathic pain is unclear. Minett and colleagues show that Nav1.7 expression specifically in sympathetic neurons, rather than sensory neurons, is required for the development of chronic neuropathic pain after injury.
- Michael S. Minett
- , Mohammed A. Nassar
- & John N. Wood
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The structure of the FANCM–MHF complex reveals physical features for functional assembly
Fanconi's anaemia is characterized by an inability to repair DNA damage and is associated with mutations in the Fanconi anaemia nuclear complex, which includes the protein FANCM. This study reports the crystal structures of a fragment of FANCM bound to the histone-fold-containing protein complex, MHF1–MHF2.
- Yuyong Tao
- , Changjiang Jin
- & Maikun Teng
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Nanodomain Ca2+ of Ca2+ channels detected by a tethered genetically encoded Ca2+ sensor
Calcium nanodomains arise from the cytoplasmic mouth of calcium channels but have not been directly visualized. In this study, the nanodomain of the CaV2.2 calcium channel is imaged using total internal reflection fluorescence microscopy and a genetically encoded calcium sensor attached to the carboxy terminus.
- Lai Hock Tay
- , Ivy E. Dick
- & David T. Yue
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Casein kinase 2 reverses tail-independent inactivation of kinesin-1
Kinesin-1 is a motor protein that transports cargo along microtubules and defects in this process can result in neurodegeneration. In this study, a role for casein kinase 2 in regulating the activity of Kinesin-1 is reported, suggesting that signalling molecules can modulate this transport process.
- Jing Xu
- , Babu J. N. Reddy
- & Steven P. Gross
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FAT10 and NUB1L bind to the VWA domain of Rpn10 and Rpn1 to enable proteasome-mediated proteolysis
FAT-10 targets proteins for degradation in a ubiquitin-independent manner and NUB1L accelerates this process. In this study, both FAT-10 and NUB1L are shown to interact with the VWA domain of the Rpn10 subunit of the 26S proteasome, suggesting that this is a receptor site for ubiquitin-like modifiers.
- Neha Rani
- , Annette Aichem
- & Marcus Groettrup
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Transient activation of specific neurons in mice by selective expression of the capsaicin receptor
The ability to spatially and temporally control excitation of neuronsin vivo is an invaluable tool. By expressing the TRPV1 receptor in specific neuronal populations, Güler et al. have developed a rapid and noninvasive method to stimulate neuronal activity by the simple administration of capsaicin.
- Ali D. Güler
- , Aundrea Rainwater
- & Richard D. Palmiter
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Article
| Open AccessActivation of canonical Wnt signalling is required for TGF-β-mediated fibrosis
Aberrant activation of the TGF-β pathway leads to fibrotic disease. Distler and colleagues show that TGF-β-mediated fibrosis requires the decrease of Dickkopf-1, an antagonist of canonical Wnt signalling, suggesting that the two pathways interact for the manifestation of this disease.
- Alfiya Akhmetshina
- , Katrin Palumbo
- & Jörg H.W. Distler
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