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Abigail K Corona, Holly M Saulsbery, Angel F Corona Velazquez, William T Jackson
Enterovirus D68 (EV-D68) is a medically important respiratory plus-strand RNA virus of children that has been linked to acute flaccid myelitis. We have determined that EV-D68 induces autophagic signaling and membrane formation. Autophagy, a homeostatic degradative process that breaks down protein aggregates and damaged organelles, promotes replication of multiple plus-strand viruses. Induction of autophagic signals promotes EV-D68 replication, but the virus inhibits the downstream degradative steps of autophagy in multiple ways...
March 20, 2018: Cell Reports
Liansheng Liu, Jinqiu Lu, Xiaoling Li, Ailing Wu, Qingzhe Wu, Mujun Zhao, Nan Tang, Hai Song
Intracellular transport of membranous organelles and protein complexes to various destinations is fundamental to signaling transduction and cellular function. The cytoplasmic dynein motor and its regulatory proteins LIS1 and NDE1 are required for transporting a variety of cellular cargos along the microtubule network. In this study, we show that deletion of Lis1 in developing lung endoderm and limb mesenchymal cells causes agenesis of the lungs and limbs. In both mutants, there is increased cell death and decreased fibroblast growth factor (FGF) signaling activity...
March 20, 2018: Cell Reports
Wuxing Dong, Alison C Todd, Angelika Bröer, Sarah R Hulme, Stefan Bröer, Brian Billups
Astrocytes are glial cells that have an intimate physical and functional association with synapses in the brain. One of their main roles is to recycle the neurotransmitters glutamate and gamma-aminobutyric acid (GABA), as a component of the glutamate/GABA-glutamine cycle. They perform this function by sequestering neurotransmitters and releasing glutamine via the neutral amino acid transporter SNAT3. In this way, astrocytes regulate the availability of neurotransmitters and subsequently influence synaptic function...
March 21, 2018: International Journal of Molecular Sciences
Pradipta Ray, Andrew Torck, Lilyana Quigley, Andi Wangzhou, Matthew Neiman, Chandranshu Rao, Tiffany Lam, Ji-Young Kim, Tae Hoon Kim, Michael Q Zhang, Gregory Dussor, Theodore J Price
Molecular neurobiological insight into human nervous tissues is needed to generate next generation therapeutics for neurological disorders like chronic pain. We obtained human Dorsal Root Ganglia (DRG) samples from organ donors and performed RNA-sequencing (RNA-seq) to study the human DRG (hDRG) transcriptional landscape, systematically comparing it with publicly available data from a variety of human and orthologous mouse tissues, including mouse DRG (mDRG). We characterized the hDRG transcriptional profile in terms of tissue-restricted gene co-expression patterns and putative transcriptional regulators, and formulated an information-theoretic framework to quantify DRG enrichment...
March 20, 2018: Pain
Linlin Yang, Jun Zhao, Xinling Yu, Ruilong Zhang, Guangmei Han, Renyong Liu, Zhengjie Liu, Tingting Zhao, Ming-Yong Han, Zhongping Zhang
Hydrogen sulfide (H2S) is a key signaling molecule in the cytoprotection, vascular mediation and neurotransmission of living organisms. In-depth understanding of its production, trafficking, and transformation in cells is very important in the way H2S mediates cellular signal transductions and organism functions; it also motivates the development of H2S probes and imaging technologies. A fundamental challenge, however, is how to engineer probes with sensitivity and cellular penetrability that allow detection of spontaneous production of H2S in the entire cell space and live animals...
March 21, 2018: Analyst
Delphine Masschaele, Joris Wauman, Giel Vandemoortele, Delphine De Sutter, Leentje De Ceuninck, Sven Eyckerman, Jan Tavernier
Ring finger protein 41 (RNF41) is an E3 ubiquitin ligase involved in the ubiquitination and degradation of many proteins including ErbB3 receptors, BRUCE and parkin. Next to this, RNF41 regulates the intracellular trafficking of certain JAK2-associated cytokine receptors by ubiquitinating and suppressing USP8 which in turn destabilizes the ESCRT-0 complex. To further elucidate the function of RNF41 we used different orthogonal approaches to reveal the RNF41 protein complex: Affinity Purification-Mass Spectrometry, BioID and Virotrap...
March 21, 2018: Journal of Proteome Research
Andrea E Toth, Piotr Siupka, Thomas J P Augustine, Susanne T Venø, Louiza B Thomsen, Torben Moos, Hannes T Lohi, Peder Madsen, Karin Lykke-Hartmann, Morten S Nielsen
Receptor- and adsorptive-mediated transport through brain endothelial cells (BEC) of the blood-brain barrier (BBB) involves a complex array of subcellular vesicular structures, the endo-lysosomal system. It consists of several types of vesicles, such as early, recycling, and late endosomes, retromer-positive structures, and lysosomes. Since this system is important for receptor-mediated transcytosis of drugs across brain capillaries, our aim was to characterise the endo-lysosomal system in BEC with emphasis on their interactions with astrocytes...
March 20, 2018: Molecular Neurobiology
Robert D Guber, Alice B Schindler, Maher S Budron, Ke-Lian Chen, Yuebing Li, Kenneth H Fischbeck, Christopher Grunseich
Amyotrophic lateral sclerosis 8 (ALS8) is a rare progressive neurodegenerative disease resulting from mutation in the gene for vesicle-associated membrane protein-associated protein B. We evaluated a North American patient using exome sequencing, and identified a P56S mutation. The disease protein had similar subcellular localization and expression levels in the patient and control fibroblasts. Patient fibroblasts showed increased basal endoplasmic reticulum stress and dysfunction of nucleocytoplasmic transport as evidenced by impaired Ran trafficking...
March 2018: Annals of Clinical and Translational Neurology
Anish Sharda, Robert Flaumenhaft
Platelet granules are unique among secretory vesicles in both their content and their life cycle. Platelets contain three major granule types-dense granules, α-granules, and lysosomes-although other granule types have been reported. Dense granules and α-granules are the most well-studied and the most physiologically important. Platelet granules are formed in large, multilobulated cells, termed megakaryocytes, prior to transport into platelets. The biogenesis of dense granules and α-granules involves common but also distinct pathways...
2018: F1000Research
Afsar R Naqvi, Jennifer Shango, Alexandra Seal, Deepak Shukla, Salvador Nares
Prevalence of the members of herpesvirus family in oral inflammatory diseases is increasingly acknowledged suggesting their likely role as an etiological factor. However, the underlying mechanisms remain obscure. In our recent miRNA profiling of healthy and diseased human tooth pulps, elevated expression of human herpesvirus encoded viral microRNAs (v-miRs) were identified. Based on the fold induction and significance values, we selected three v-miRs namely miR-K12-3-3p [Kaposi sarcoma-associated virus (KSHV)], miR-H1 [herpes simplex virus 1 (HSV1)], and miR-UL-70-3p [human cytomegalovirus (HCMV)] to further examine their impact on host cellular functions...
2018: Frontiers in Immunology
Yunus E Demiray, Kati Rehberg, Stefanie Kliche, Oliver Stork
The serine/threonine kinase Ndr2 has been shown to control the inside-out activation of the β1 subunit of integrins and the formation of neurites in both primary neurons and neurally differentiated pheochromacytoma (PC12) cells. In this study, we demonstrate that Ndr2 kinase furthermore determines the substrate specificity of neurite extension in PC12 cells via expression of α1 β1 integrins. We show that stable overexpression of Ndr2 in PC12 cells increases neurite growth and extension on poly-D-lysine substrate, likely involving an increased expression of active β1 integrin in the growth tips of these cells...
2018: Frontiers in Molecular Neuroscience
Jude Masannat, Hamsa Thayele Purayil, Yushan Zhang, Michelle Russin, Iqbal Mahmud, Wanju Kim, Daiqing Liao, Yehia Daaka
Renal Cell Carcinoma (RCC) is one of the most lethal urological cancers worldwide. The disease does not present early clinical symptoms and is commonly diagnosed at an advanced stage. Limited molecular drivers have been identified for RCC, resulting in the lack of effective treatment for patients with progressive disease. Ubiquitous βArrestin2 (βArr2) is well established for its function in the desensitization and trafficking of G protein-coupled receptors. More recently, βArr2 has been implicated in the regulation of fundamental cellular functions, including proliferation and invasion...
March 20, 2018: Scientific Reports
Ralph Witzgall
Primary cilia represent small, yet distinct compartments of the plasma membrane. They are speculated to exercise chemo- and mechanosensory functions and to serve as signaling hubs for crucial pathways such as the Wnt and hedgehog cascades. It is therefore necessary that specific integral membrane proteins, in particular sensors and receptors, are sorted to the cilium and not to the surrounding somatic plasma membrane upon being synthesized at the rough endoplasmic reticulum. Apparently no singular "zip code" for the primary cilium exists but rather several ciliary targeting signals whose biochemical and cell biological implications are just about being unravelled...
March 17, 2018: Seminars in Cell & Developmental Biology
E K Hopper, L D Gonzalez
Human trafficking is a form of interpersonal trauma that has significant mental health impacts on survivors. This study examined psychological symptoms in 131 survivors of sex and labor trafficking, including people trafficked into or within the U.S. High rates of depression (71%) and PTSD (61%) were identified. Two thirds of survivors also met criteria for multiple categories of Complex PTSD (C-PTSD), including affect dysregulation and impulsivity; alterations in attention and consciousness; changes in interpersonal relationships; revictimization; somatic dysregulation; and alterations in self-perception...
March 20, 2018: Behavioral Medicine
Mekeila C Cook, Elizabeth Barnert, Roya Ijadi-Maghsoodi, Kayleen Ports, Eraka Bath
The study sought to: 1) describe the mental health and substance use profiles among participants of a specialty trafficking court program (the Succeed Though Achievement and Resilience Court); 2) describe youths' mental health and substance use treatment prior to participating in the program; and 3) examine whether abuse influences report of mental health problems and/or substance use. Retrospective case review of court files was performed on commercially sexually exploited youth who volunteered to participate in the court from 2012 to 2014 (N = 184)...
March 20, 2018: Behavioral Medicine
Helder Rocha, André F Maia, Reto Gassmann
Cytoplasmic dynein 1 (dynein) is the predominant microtubule minus end-directed motor in animals and participates in a wide range of cellular processes, including membrane trafficking, nuclear migration, and cell division. Dynein's functional diversity depends on co-factors that regulate its subcellular localization, interaction with cargo, and motor activity. The ubiquitous co-factor nuclear distribution gene E (NudE) is implicated in many of dynein's functions, and mutations in NudE cause the brain developmental disease microcephaly...
March 20, 2018: Scientific Data
Bram Verstockt, Marc Ferrante, Séverine Vermeire, Gert Van Assche
The advent of anti-TNF agents has dramatically changed the treatment algorithms for IBD in the last 15 years, but primarily and more importantly secondary loss of response is often observed. Fortunately , new treatment options have been actively explored and some have already entered our clinical practice. In the class of anti-cytokine agents, the anti-IL12/IL23 monoclonal antibodies (mAbs) have entered clinical practice with the anti-p40 mAb ustekinumab in Crohn's disease (CD). Also, more selective anti-IL23 agents (anti-p19) have shown efficacy and are being further developed, in contrast to agents inhibiting IL-17 downstream which have failed in clinical trials despite their clear efficacy in psoriasis (Verstockt et al...
March 19, 2018: Journal of Gastroenterology
Ludovic Ménard, Nicolas Floc'h, Matthew J Martin, Darren Ae Cross
Tyrosine kinase inhibitors (TKIs) targeting mutant-EGFR in NSCLC have been successful to control cancer growth, but acquired resistance inevitably occurs, including mutations directly on EGFR e.g. T790M and C797S. Strategies to prevent such acquired mutations by reducing mutant-EGFR expression have met limited success. Here we propose a new model of mutant-EGFR trafficking and demonstrate that clathrin inhibition induces rapid degradation across a large panel of endogenous mutant-EGFR (Ex19del, L858R, Ex20Ins)...
March 19, 2018: Cancer Research
Daniel Mattle, Bernd Kuhn, Johannes Aebi, Marc Bedoucha, Demet Kekilli, Nathalie Grozinger, Andre Alker, Markus G Rudolph, Georg Schmid, Gebhard F X Schertler, Michael Hennig, Jörg Standfuss, Roger J P Dawson
In the degenerative eye disease retinitis pigmentosa (RP), protein misfolding leads to fatal consequences for cell metabolism and rod and cone cell survival. To stop disease progression, a therapeutic approach focuses on stabilizing inherited protein mutants of the G protein-coupled receptor (GPCR) rhodopsin using pharmacological chaperones (PC) that improve receptor folding and trafficking. In this study, we discovered stabilizing nonretinal small molecules by virtual and thermofluor screening and determined the crystal structure of pharmacologically stabilized opsin at 2...
March 19, 2018: Proceedings of the National Academy of Sciences of the United States of America
Carlos G P Voogdt, Jaap A Wagenaar, Jos P M van Putten
Toll-like receptor 5 (TLR5) of mammals, birds, and reptiles detects bacterial flagellin and signals as a homodimeric complex. Structural studies using truncated TLR5b of zebrafish confirm the homodimeric TLR5-flagellin interaction. Here we provide evidence that zebrafish ( Danio rerio ) TLR5 unexpectedly signals as a heterodimer composed of the duplicated gene products drTLR5b and drTLR5a. Flagellin-induced signaling by the zebrafish TLR5 heterodimer increased in the presence of the TLR trafficking chaperone UNC93B1...
March 19, 2018: Proceedings of the National Academy of Sciences of the United States of America
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