Read by QxMD icon Read


Elaine Pirie, Shayoni Ray, Calvin Pan, Wuxia Fu, Andrew F Powers, Danielle Polikoff, Colton M Miller, Katrina M Kudrna, Edward N Harris, Aldons J Lusis, Rosanne M Crooke, Richard G Lee
Antisense oligonucleotides (ASOs) have demonstrated variation of efficacy in patient populations. This has prompted our investigation into the contribution of genetic architecture to ASO pharmacokinetics (PK) and pharmacodynamics (PD). Genome wide association (GWA) and transcriptomic analysis in a hybrid mouse diversity panel (HMDP) were used to identify and validate novel genes involved in the uptake and efficacy of a single dose of a Malat1 constrained ethyl (cEt) modified ASO. The GWA of the HMDP identified two significant associations on chromosomes 4 and 10 with hepatic Malat1 ASO concentrations...
October 2018: PLoS Genetics
Seng Zhu, Shaarvari Bhat, Sylvie Syan, Yoshihiko Kuchitsu, Mitsunori Fukuda, Chiara Zurzolo
Tunneling nanotubes (TNTs) are actin-enriched membranous channels enabling cells to communicate over long distances. TNT-like structures form between various cell types and mediate the exchange of different cargos, such as ions, vesicles, organelles and pathogens; thus, they may play a role in physiological conditions and diseases (e.g. cancer and infection). TNTs also allow the intercellular passage of protein aggregates related to neurodegenerative diseases, thus propagating protein misfolding. Understanding the mechanism of TNT formation is mandatory in order to reveal the mechanism of disease propagation and to uncover their physiological function...
October 5, 2018: Journal of Cell Science
Smita Joshi, Meenakshi Banerjee, Jinchao Zhang, Akhil Kesaraju, Irina D Pokrovskaya, Brian Storrie, Sidney W Whiteheart
We genetically manipulated the major platelet vesicle-associated membrane proteins (VAMP2, VAMP3, and VAMP8) to create mice with varying degrees of disrupted platelet secretion. As previously shown, loss of VAMP8 reduced granule secretion, and this defect was exacerbated by further deletion of VAMP2 and VAMP3. VAMP2Δ 3Δ 8-/- platelets also had reduced VAMP7. Loss of VAMP2 and VAMP3 (VAMP2Δ 3Δ ) had a minimal impact on secretion when VAMP7 and VAMP8 were present. Integrin αIIbβ3 activation and aggregation were not affected, although spreading was reduced in VAMP2Δ 3Δ 8-/- platelets...
September 11, 2018: Blood Advances
Nicoletta Caronni, Francesca Simoncello, Francesca Stafetta, Corrado Guarnaccia, Juan Sebastian Ruiz-Moreno, Bastian Opitz, Thierry Galli, Veronique Proux-Gillardeaux, Federica Benvenuti
Restoring antigen presentation for efficient and durable activation of tumor-specific CD8+ T-cell responses is pivotal to immunotherapy, yet the mechanisms that cause subversion of dendritic cell (DC) functions are not entirely understood, limiting the development of targeted approaches. In this study, we show that bona fide DCs resident in lung tumor tissues or DCs exposed to factors derived from whole lung tumors become refractory to endosomal and cytosolic sensor stimulation and fail to secrete IL12 and IFNI...
April 1, 2018: Cancer Research
Hui Zhang, Jia-Qiang Yu, Li-Li Yang, Luke M Kramer, Xin-Yang Zhang, Wei Na, James M Reecy, Hui Li
BACKGROUND: In addition to additive genetic effects, epistatic interactions can play key roles in the control of phenotypic variation of traits of interest. In the current study, 475 male birds from lean and fat chicken lines were utilized as a resource population to detect significant epistatic effects associated with growth and carcass traits. RESULTS: A total of 421 significant epistatic effects were associated with testis weight (TeW), from which 11 sub-networks (Sub-network1 to Sub-network11) were constructed...
November 21, 2017: BMC Genomics
Alexis Combes, Voahirana Camosseto, Prudence N'Guessan, Rafael J Argüello, Julie Mussard, Christophe Caux, Nathalie Bendriss-Vermare, Philippe Pierre, Evelina Gatti
Toll-like receptors (TLR) are essential components of the innate immune system. Several accessory proteins, such as UNC93B1, are required for transport and activation of nucleic acid sensing Toll-like receptors in endosomes. Here, we show that BAD-LAMP (LAMP5) controls TLR9 trafficking to LAMP1+ late endosomes in human plasmacytoid dendritic cells (pDC), leading to NF-κB activation and TNF production upon DNA detection. An inducible VAMP3+/ LAMP2+/ LAMP1- endolysosome compartment exists in pDCs from which TLR9 activation triggers type I interferon expression...
October 13, 2017: Nature Communications
Yvonne Schwarz, Na Zhao, Frank Kirchhoff, Dieter Bruns
Communication between glia cells and neurons is crucial for brain functions, but the molecular mechanisms and functional consequences of gliotransmission remain enigmatic. Here we report that astrocytes express synaptobrevin II and cellubrevin as functionally non-overlapping vesicular SNARE proteins on glutamatergic vesicles and neuropeptide Y-containing large dense-core vesicles, respectively. Using individual null-mutants for Vamp2 (synaptobrevin II) and Vamp3 (cellubrevin), as well as the corresponding compound null-mutant for genes encoding both v-SNARE proteins, we delineate previously unrecognized individual v-SNARE dependencies of astrocytic release processes and their functional impact on neuronal signaling...
November 2017: Nature Neuroscience
Hoan Van Ngo, Manmeet Bhalla, Da-Yuan Chen, Keith Ireton
The bacterial surface protein InlB mediates internalisation of Listeria monocytogenes into human cells through interaction with the host receptor tyrosine kinase, Met. InlB-mediated entry requires localised polymerisation of the host actin cytoskeleton. Apart from actin polymerisation, roles for other host processes in Listeria entry are unknown. Here, we demonstrate that exocytosis in the human cell promotes InlB-dependent internalisation. Using a probe consisting of VAMP3 with an exofacial green fluorescent protein tag, focal exocytosis was detected during InlB-mediated entry...
November 2017: Cellular Microbiology
Yukiko Yoshida, Sayaka Yasuda, Toshiharu Fujita, Maho Hamasaki, Arisa Murakami, Junko Kawawaki, Kazuhiro Iwai, Yasushi Saeki, Tamotsu Yoshimori, Noriyuki Matsuda, Keiji Tanaka
Ubiquitination functions as a signal to recruit autophagic machinery to damaged organelles and induce their clearance. Here, we report the characterization of FBXO27, a glycoprotein-specific F-box protein that is part of the SCF (SKP1/CUL1/F-box protein) ubiquitin ligase complex, and demonstrate that SCFFBXO27 ubiquitinates glycoproteins in damaged lysosomes to regulate autophagic machinery recruitment. Unlike F-box proteins in other SCF complexes, FBXO27 is subject to N-myristoylation, which localizes it to membranes, allowing it to accumulate rapidly around damaged lysosomes...
August 8, 2017: Proceedings of the National Academy of Sciences of the United States of America
Juan-Juan Zhu, Yue-Feng Liu, Yun-Peng Zhang, Chuan-Rong Zhao, Wei-Juan Yao, Yi-Shuan Li, Kuei-Chun Wang, Tse-Shun Huang, Wei Pang, Xi-Fu Wang, Xian Wang, Shu Chien, Jing Zhou
Vascular endothelial cells (ECs) at arterial branches and curvatures experience disturbed blood flow and induce a quiescent-to-activated phenotypic transition of the adjacent smooth muscle cells (SMCs) and a subsequent smooth muscle hyperplasia. However, the mechanism underlying the flow pattern-specific initiation of EC-to-SMC signaling remains elusive. Our previous study demonstrated that endothelial microRNA-126-3p (miR-126-3p) acts as a key intercellular molecule to increase turnover of the recipient SMCs, and that its release is reduced by atheroprotective laminar shear (12 dynes/cm2 ) to ECs...
August 1, 2017: Proceedings of the National Academy of Sciences of the United States of America
G Aarabi, T Zeller, H Seedorf, D R Reissmann, G Heydecke, A S Schaefer, U Seedorf
Periodontal disease (PD) and coronary artery disease (CAD) are common diseases characterized by an overaggressive inflammatory response to diverse stimuli. Whereas PD leads to destruction of the tooth-supporting structures, CAD is a chronic inflammatory condition ultimately causing myocardial infarction via narrowing and occluding of blood vessels. Classical twin studies led to the conclusion that both complex diseases have a similar degree of heritability and that a significant fraction of the genetic factors accounting for this heritability is shared...
June 2017: Journal of Dental Research
Daniëlle Rianne José Verboogen, Natalia González Mancha, Martin Ter Beest, Geert van den Bogaart
SNARE proteins play a crucial role in intracellular trafficking by catalyzing membrane fusion, but assigning SNAREs to specific intracellular transport routes is challenging with current techniques. We developed a novel Förster resonance energy transfer-fluorescence lifetime imaging microscopy (FRET-FLIM)-based technique allowing visualization of real-time local interactions of fluorescently tagged SNARE proteins in live cells. We used FRET-FLIM to delineate the trafficking steps underlying the release of the inflammatory cytokine interleukin-6 (IL-6) from human blood-derived dendritic cells...
May 19, 2017: ELife
David E Gordon, Joanne Chia, Kamburpola Jayawardena, Robin Antrobus, Frederic Bard, Andrew A Peden
The cellular machinery required for the fusion of constitutive secretory vesicles with the plasma membrane in metazoans remains poorly defined. To address this problem we have developed a powerful, quantitative assay for measuring secretion and used it in combination with combinatorial gene depletion studies in Drosophila cells. This has allowed us to identify at least three SNARE complexes mediating Golgi to PM transport (STX1, SNAP24/29 and Syb; STX1, SNAP24/29 and YKT6; STX4, SNAP24 and Syb). RNAi mediated depletion of YKT6 and VAMP3 in mammalian cells also blocks constitutive secretion suggesting that YKT6 has an evolutionarily conserved role in this process...
April 2017: PLoS Genetics
Nimi Vashi, Syed Bilal Ahmad Andrabi, Swapnil Ghanwat, Mrutyunjay Suar, Dhiraj Kumar
The role of Golgi apparatus during phagocytic uptake by macrophages has been ruled out in the past. Notably, all such reports were limited to Fcγ receptor-mediated phagocytosis. Here, we unravel a highly devolved mechanism for recruitment of Golgi-derived secretory vesicles during phagosome biogenesis, which was important for uptake of most cargos, except the IgG-coated ones. We report recruitment of mannosidase-II-positive Golgi-derived vesicles during uptake of diverse targets, including latex beads, Escherichia coli , Salmonella typhimurium , and Mycobacterium tuberculosis in human and mouse macrophages...
March 31, 2017: Journal of Biological Chemistry
Tomoya Takeuchi, Yuika Harada, Satomi Moriyama, Kazuyuki Furuta, Satoshi Tanaka, Takaaki Miyaji, Hiroshi Omote, Yoshinori Moriyama, Miki Hiasa
Mast cells are secretory cells that play an important role in host defense by discharging various intragranular contents, such as histamine and serotonin, upon stimulation of Fc receptors. The granules also contain spermine and spermidine, which can act as modulators of mast cell function, although the mechanism underlying vesicular storage remains unknown. Vesicular polyamine transporter (VPAT), the fourth member of the SLC18 transporter family, is an active transporter responsible for vesicular storage of spermine and spermidine in neurons...
March 3, 2017: Journal of Biological Chemistry
Juan Agustín Cueto, María Cristina Vanrell, Betiana Nebaí Salassa, Sébastien Nola, Thierry Galli, María Isabel Colombo, Patricia Silvia Romano
Trypanosoma cruzi, the etiologic agent of Chagas disease, is an obligate intracellular parasite that exploits different host vesicular pathways to invade the target cells. Vesicular and target soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are key proteins of the intracellular membrane fusion machinery. During the early times of T. cruzi infection, several vesicles are attracted to the parasite contact sites in the plasma membrane. Fusion of these vesicles promotes the formation of the parasitic vacuole and parasite entry...
June 2017: Cellular Microbiology
Stephanie N Hurwitz, Mark A Rider, Joseph L Bundy, Xia Liu, Rakesh K Singh, David G Meckes
Packed with biological information, extracellular vesicles (EVs) offer exciting promise for biomarker discovery and applications in therapeutics and non-invasive diagnostics. Currently, our understanding of EV contents is confined by the limited cells from which vesicles have been characterized utilizing the same enrichment method. Using sixty cell lines from the National Cancer Institute (NCI-60), here we provide the largest proteomic profile of EVs in a single study, identifying 6,071 proteins with 213 common to all isolates...
December 27, 2016: Oncotarget
Takashi Nozawa, Atsuko Minowa-Nozawa, Chihiro Aikawa, Ichiro Nakagawa
Macroautophagy/autophagy plays a critical role in immunity by directly degrading invading pathogens such as Group A Streptococcus (GAS), through a process that has been named xenophagy. We previously demonstrated that autophagic vacuoles directed against GAS, termed GAS-containing autophagosome-like vacuoles (GcAVs), use recycling endosomes (REs) as a membrane source. However, the precise molecular mechanism that facilitates the fusion between GcAVs and REs remains unclear. Here, we demonstrate that STX6 (syntaxin 6) is recruited to GcAVs and forms a complex with VTI1B and VAMP3 to regulate the GcAV-RE fusion that is required for xenophagy...
January 2, 2017: Autophagy
Paulo S Caceres, Mariela Mendez, Mohammed Z Haque, Pablo A Ortiz
Renal cells of the thick ascending limb (TAL) reabsorb NaCl via the apical Na(+)/K(+)/2Cl(-) co-transporter NKCC2. Trafficking of NKCC2 to the apical surface regulates NKCC2-mediated NaCl absorption and blood pressure. The molecular mechanisms by which NKCC2 reaches the apical surface and their role in renal function and maintenance of blood pressure are poorly characterized. Here we report that NKCC2 interacts with the vesicle fusion protein VAMP3, and they co-localize at the TAL apical surface. We observed that silencing VAMP3 in vivo blocks constitutive NKCC2 exocytic delivery, decreasing the amount of NKCC2 at the TAL apical surface...
October 14, 2016: Journal of Biological Chemistry
Huanjiao Jenny Zhou, Lingfeng Qin, Haifeng Zhang, Wenwen Tang, Weidong Ji, Yun He, Xiaoling Liang, Zongren Wang, Qianying Yuan, Alexander Vortmeyer, Derek Toomre, Germaine Fuh, Minghong Yan, Martin S Kluger, Dianqing Wu, Wang Min
Cerebral cavernous malformations (CCMs) are vascular malformations that affect the central nervous system and result in cerebral hemorrhage, seizure and stroke. CCMs arise from loss-of-function mutations in one of three genes: KRIT1 (also known as CCM1), CCM2 or PDCD10 (also known as CCM3). PDCD10 mutations in humans often result in a more severe form of the disease relative to mutations in the other two CCM genes, and PDCD10-knockout mice show severe defects, the mechanistic basis for which is unclear. We have recently reported that CCM3 regulates exocytosis mediated by the UNC13 family of exocytic regulatory proteins...
September 2016: Nature Medicine
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"