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Helen L May-Simera, Jessica D Gumerson, Chun Gao, Maria Campos, Stephanie M Cologna, Tina Beyer, Karsten Boldt, Koray D Kaya, Nisha Patel, Friedrich Kretschmer, Matthew W Kelley, Ronald S Petralia, Megan G Davey, Tiansen Li
Microtubule actin crosslinking factor 1 (MACF1) plays a role in the coordination of microtubules and actin in multiple cellular processes. Here, we show that MACF1 is also critical for ciliogenesis in multiple cell types. Ablation of Macf1 in the developing retina abolishes ciliogenesis, and basal bodies fail to dock to ciliary vesicles or migrate apically. Photoreceptor polarity is randomized, while inner retinal cells laminate correctly, suggesting that photoreceptor maturation is guided by polarity cues provided by cilia...
October 25, 2016: Cell Reports
Jose Gonçalo Pais Estrela da Silveira Zúquete, Edinilsa Ramos de Souza, Suely Ferreira Deslandes
This study focuses on concepts involved in women trafficking for sexual exploitation according to representatives of government and nongovernmental institutions working with policies to confront and prevent trafficking and assist victims in Brazil and Portugal. An exploratory qualitative study was performed to identify the institutional discourses on women trafficking using thematic analysis. Interviewees displayed conceptual imprecision concerning women trafficking, sometimes ignoring the rights of sex workers to migrate and work in other countries...
October 20, 2016: Cadernos de Saúde Pública
Alireza Mashaghi, Sergey Bezrukavnikov, David P Minde, Anne S Wentink, Roman Kityk, Beate Zachmann-Brand, Matthias P Mayer, Günter Kramer, Bernd Bukau, Sander J Tans
The Hsp70 system is a central hub of chaperone activity in all domains of life. Hsp70 performs a plethora of tasks, including folding assistance, protection against aggregation, protein trafficking, and enzyme activity regulation, and interacts with non-folded chains, as well as near-native, misfolded, and aggregated proteins. Hsp70 is thought to achieve its many physiological roles by binding peptide segments that extend from these different protein conformers within a groove that can be covered by an ATP-driven helical lid...
October 26, 2016: Nature
Ivan Kadurin, Laurent Ferron, Simon W Rothwell, James O Meyer, Leon R Douglas, Claudia S Bauer, Beatrice Lana, Wojciech Margas, Orpheas Alexopoulos, Manuela Nieto-Rostro, Wendy S Pratt, Annette C Dolphin
The auxiliary α2δ subunits of voltage-gated calcium channels are extracellular membrane-associated proteins, which are post-translationally cleaved into disulfide-linked polypeptides α2 and δ. We now show, using α2δ constructs containing artificial cleavage sites, that this processing is an essential step permitting voltage-dependent activation of plasma membrane N-type (CaV2.2) calcium channels. Indeed, uncleaved α2δ inhibits native calcium currents in mammalian neurons. By inducing acute cell-surface proteolytic cleavage of α2δ, voltage-dependent activation of channels is promoted, independent from the trafficking role of α2δ...
October 26, 2016: ELife
Yunfei Li, Brock Humphries, Zhishan Wang, Shuyao Lang, Xuefei Huang, Hua Xiao, Yiguo Jiang, Chengfeng Yang
Many polycation-based gene delivery vehicles have limited in vivo transfection efficiency because of their excessive exterior positive charges and/or PEGylation, both of which could result in premature dissociation and poor cellular uptake and trafficking. Here we reported a novel hybrid PEGylated nanoparticles (HNPs) that are composed of (a) poly(ethylene glycol)-b-poly(aspartate)-adamantane (PEG-P(asp)-Ad) constituting the outer PEG layer to provide colloidal stability; (b) poly(ethylenimine)10K (PEI10K) forming complex coacervate with P(asp) as the cross-linked cage preventing premature dissociation; and (c) cyclodextrin-decorated PEI10K (PEI10K-CD) forming the core with reporter plasmid DNA (pDNA)...
October 26, 2016: ACS Applied Materials & Interfaces
Corinne Schwarz, Erik Unruh, Katie Cronin, Sarah Evans-Simpson, Hannah Britton, Megha Ramaswamy
The medical sector presents a unique opportunity for identification and service to victims of human trafficking. In this article, we describe local and site-specific efforts to develop an intervention tool to be used in an urban hospital's emergency department in the midwestern United States. In the development of our tool, we focused on both identification and intervention to assist trafficked persons, through a largely collaborative process in which we engaged local stakeholders for developing site-specific points of intervention...
June 2016: Health and Human Rights
Frank Loganzo, Matthew Sung, Hans-Peter Gerber
Drug resistance limits the effectiveness of cancer therapies. Despite attempts to develop curative anticancer treatments, tumors evolve evasive mechanisms limiting durable responses. Hence, diverse therapies are used to attack cancer, including cytotoxic and targeted agents. Antibody-drug conjugates (ADC) are biotherapeutics designed to deliver potent cytotoxins to cancer cells via tumor-specific antigens. Little is known about the clinical manifestations of drug resistance to this class of therapy; however, recent preclinical studies reveal potential mechanisms of resistance...
October 25, 2016: Molecular Cancer Therapeutics
Madis Jaagura, Kati Taal, Indrek Koppel, Jürgen Tuvikene, Tõnis Timmusk, Richard Tamme
Neuralized, an E3 ubiquitin ligase, interacts with and positively modulates the Notch pathway by promoting ubiquitination and subsequent endocytosis of its ligands. NEURL1 mRNA is dendritically localised in the dentate gyrus of adult rat brain, implying that it may be locally translated, but its transport mechanisms remain unstudied. Here, we report the presence of a previously unknown, shorter splice-variant of rat NEURL1 3'UTR (1477bp in length), and identify it as a potential target of nonsense-mediated decay...
October 22, 2016: Neuroscience Letters
Meng Wang, Ying Li, Mingyi HuangFu, Yi Xiao, Tianyuan Zhang, Min Han, Donghang Xu, Fangyuan Li, Daishun Ling, Yi Jin, Jianqing Gao
AIM: To design pluronic F68 (PF68)-conjugated polyamidoamine (PAMAM) dendrimer conjugates for doxorubicin (DOX) delivery for overcoming multidrug resistance, and clarify the reversal mechanism. MATERIALS & METHODS: A series of PAMAM-PF68 conjugates were designed. The antitumor activity of the DOX-loaded conjugates was evaluated against MCF-7/ADR cells, tumor spheroids and tumors. Several bioinformatics were detected to characterize the reversal mechanism. RESULTS: Increased antitumor activity of the DOX-loaded conjugates was achieved in vitro and in vivo...
October 26, 2016: Nanomedicine
Chiara Tersigni, Fiorella Di Nicuolo, Giuseppe Maulucci, Alessandro Rolfo, Domenica Giuffrida, Manuela Veglia, Marco De Spirito, Giovanni Scambia, Tullia Todros, Nicoletta Di Simone
BACKGROUND: Pre-eclampsia (PE) is a major cause of maternal and perinatal morbidity and mortality worldwide. It is defined by new onset of hypertension and proteinuria after the 20th week of gestation and characterized by systemic exaggerated inflammatory response. D6 is a chemokines scavenger receptor that binds with high affinity CC chemokines, internalizes and targets the ligands for degradation. It is expressed in trophoblast-derived tissues and prevents excessive placenta leukocyte infiltration...
2016: PloS One
Cheng-Feng Chiang, Mike Flint, Jin-Mann S Lin, Christina F Spiropoulou
Andes virus (ANDV) is the major cause of hantavirus pulmonary syndrome (HPS) in South America. Despite a high fatality rate (up to 40%), no vaccines or antiviral therapies are approved to treat ANDV infection. To understand the role of endocytic pathways in ANDV infection, we used 3 complementary approaches to identify cellular factors required for ANDV entry into human lung microvascular endothelial cells. We screened an siRNA library targeting 140 genes involved in membrane trafficking, and identified 55 genes required for ANDV infection...
2016: PloS One
Sanchaita Das, David G Lambright
Long-range tethering is a ubiquitous recognition event preceding membrane fusion. A new study shows that Rab GTPase binding causes 'entropic collapse' of the coiled-coil endosome tether EEA1, driving membrane apposition and facilitating short-range interactions required for fusion.
October 24, 2016: Current Biology: CB
Catherine L Jackson, Laurence Walch, Jean-Marc Verbavatz
An evolutionarily conserved feature of cellular organelles is the distinct phospholipid composition of their bounding membranes, which is essential to their identity and function. Within eukaryotic cells, two major lipid territories can be discerned, one centered on the endoplasmic reticulum and characterized by membranes with lipid packing defects, the other comprising plasma-membrane-derived organelles and characterized by membrane charge. We discuss how this cellular lipid organization is maintained, how lipid flux is regulated, and how perturbations in cellular lipid homeostasis can lead to disease...
October 24, 2016: Developmental Cell
Jeffery S Babischkin, Graham W Aberdeen, Gerald J Pepe, Eugene D Albrecht
We have shown that fetal adrenal fetal zone (FZ) volume and serum dehydroepiandrosterone sulfate (DHAS) levels were increased, whereas definitive and transitional zone (DZ/TZ) volume was unaltered, in baboons in which estrogen levels were suppressed by administration of the aromatase inhibitor letrozole. The interaction of the melanocortin 2 receptor (MC2R) with its accessory protein (MRAP) is essential for trafficking MC2R to the adrenal cell surface for binding to ACTH. The present study determined whether the estrogen-dependent regulation of fetal adrenocortical development is mediated by ACTH and/or expression/interaction of MC2R and MRAP...
October 25, 2016: Endocrinology
Zheng Zhang, Hannah A Ledford, Seojin Park, Wenying Wang, Sassan Rafizadeh, Hyo Jeong Kim, Wilson Xu, Ling Lu, Victor C Lau, Anne A Knowlton, Xiao-Dong Zhang, Ebenezer N Yamoah, Nipavan Chiamvimonvat
The normal function of ion channels depends critically on the precise subcellular localization and the number of channel proteins on the cell surface membrane. Small-conductance, Ca(2+) -activated K(+) channels (SK, KCa 2) are expressed in human atrial myocytes and responsible for shaping atrial action potentials. Understanding the mechanisms of SK channel trafficking may provide new insights into the regulation controlling the repolarization of atrial myocytes. We have previously demonstrated that the C and N termini of SK2 channels interact with actin-binding proteins, α-actinin2 and filamin A, respectively...
October 25, 2016: Journal of Physiology
Bing Yang, Xin Ming, Hajer Abdelkafi, Valerie Pons, Aurelien Michau, Daniel Gillet, Jean-Christophe Cintrat, Julien Barbier, Rudy Juliano
Retro-1 is a small molecule that displays two important biological activities: First, it blocks the actions of certain toxins by altering their intracellular trafficking. Second, it enhances the activity of oligonucleotides by releasing them from entrapment in endosomes. This raises the question of whether the two actions involve the same cellular target. Herein we report the effects of several Retro-1 analogues on both toxins and oligonucleotides. We found analogues that affect toxins but not oligonucleotides and vice-versa, while Retro-1 is the only compound that affects both...
October 25, 2016: ChemMedChem
Katinka Karenberg, Hannes Hudalla, David Frommhold
Impaired cellular innate immune defense accounts for susceptibility to sepsis and its high morbidity and mortality in preterm infants. Leukocyte recruitment is an integral part of the cellular immune response and follows a well-defined cascade of events from rolling of leukocytes along the endothelium to firm adhesion and finally transmigration which is concerted by a variety of adhesion molecules. Recent analytical advances such as fetal intravital microscopy have granted new insights into ontogenetic regulation and maturation of fetal immune cell recruitment...
December 2016: Molecular and Cellular Pediatrics
Nasrin Dehghan-Nayeri, Mostafa Rezaei-Tavirani, Mir Davood Omrani, Ahmad Gharehbaghian, Kourosh Goudarzi Pour, Peyman Eshghi
Response to dexamethasone (DEXA), as a hallmark drug in the treatment of childhood acute lymphoblastic leukemia (ALL), is one of the pivotal prognostic factors in the prediction of outcome in ALL. Identification of predictive markers of chemoresistance is beneficial to selecting of the best therapeutic protocol with the lowest effect adverse. Hence, we aimed to find drug targets using the 2DE/MS proteomics study of a DEXA-resistant cell line (REH) as a model for poor DEXA responding patients before and after drug treatment...
October 24, 2016: Journal of Cell Communication and Signaling
Toshifumi Fujiwara, Shiqiao Ye, Thiago Castro-Gomes, Caylin G Winchell, Norma W Andrews, Daniel E Voth, Kottayil I Varughese, Samuel G Mackintosh, Yunfeng Feng, Nathan Pavlos, Takashi Nakamura, Stavros C Manolagas, Haibo Zhao
Mutations of the Plekhm1 gene in humans and rats cause osteopetrosis, an inherited bone disease characterized by diminished bone resorption by osteoclasts. PLEKHM1 binds to RAB7 and is critical for lysosome trafficking. However, the molecular mechanisms by which PLEKHM1 regulates lysosomal pathways remain unknown. Here, we generated germline and conditional Plekhm1-deficient mice. These mice displayed no overt abnormalities in major organs, except for an increase in trabecular bone mass. Furthermore, loss of PLEKHM1 abrogated the peripheral distribution of lysosomes and bone resorption in osteoclasts...
October 20, 2016: JCI Insight
Brie Sorrenson, Emmanuelle Cognard, Kathryn L Lee, Waruni C Dissanayake, Yanyun Fu, Weiping Han, William E Hughes, Peter R Shepherd
The processes regulating glucose-stimulated insulin secretion (GSIS) and its modulation by incretins in pancreatic β-cells are only partly understood. Here we investigate the involvement of β-catenin in these processes. Reducing β-catenin levels using siRNA knockdown attenuated GSIS in a range of β-cell models and blocked the ability of GLP-1 agonists and the depolarizing agent KCl to potentiate this. This could be mimicked in both β-cell models and isolated islets by short-term exposure to the β-catenin inhibitory drug pyrvinium...
October 24, 2016: Journal of Biological Chemistry
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