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Human Trafficking

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181. Phosphoinositides, Major Actors in Membrane Trafficking and Lipid Signaling Pathways (PubMed)

Phosphoinositides, Major Actors in Membrane Trafficking and Lipid Signaling Pathways Phosphoinositides are lipids involved in the vesicular transport of proteins and lipids between the different compartments of eukaryotic cells. They act by recruiting and/or activating effector proteins and thus are involved in regulating various cellular functions, such as vesicular budding, membrane fusion and cytoskeleton dynamics. Although detected in small concentrations in membranes, their role (...) is essential to cell function, since imbalance in their concentrations is a hallmark of many cancers. Their synthesis involves phosphorylating/dephosphorylating positions D3, D4 and/or D5 of their inositol ring by specific lipid kinases and phosphatases. This process is tightly regulated and specific to the different intracellular membranes. Most enzymes involved in phosphoinositide synthesis are conserved between yeast and human, and their loss of function leads to severe diseases (cancer, myopathy

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2017 International journal of molecular sciences

182. Quality control and organelle trafficking: ensuring functional organelles and cells (PubMed)

Quality control and organelle trafficking: ensuring functional organelles and cells 28292912 2018 12 24 2018 12 24 1939-4586 28 6 2017 03 15 Molecular biology of the cell Mol. Biol. Cell Quality control and organelle trafficking: ensuring functional organelles and cells. 701-702 10.1091/mbc.E16-11-0798 Brill Julie A JA Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada julie.brill@sickkids.ca rutter@biochem.utah.edu. Rutter Jared J Department of Biochemistry (...) , University of Utah/Howard Hughes Medical Institute, Salt Lake City, UT 84112 julie.brill@sickkids.ca rutter@biochem.utah.edu. eng HHMI Howard Hughes Medical Institute United States Journal Article Research Support, Non-U.S. Gov't United States Mol Biol Cell 9201390 1059-1524 IM Animals Biological Transport Congresses as Topic Drosophila melanogaster metabolism Humans Organelles metabolism Quality Control 2017 3 16 6 0 2017 3 16 6 0 2018 12 26 6 0 ppublish 28292912 28/6/701 10.1091/mbc.E16-11-0798

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2017 Molecular biology of the cell

183. An Aberrant Phosphorylation of Amyloid Precursor Protein Tyrosine Regulates Its Trafficking and the Binding to the Clathrin Endocytic Complex in Neural Stem Cells of Alzheimer's Disease Patients (PubMed)

destinations inside neurons and identifying the mechanisms responsible for the generation of Aβ are thus the keys for the advancement of new therapies. We previously developed a mouse model with a mutation at tyrosine (Tyr) 682 in the C-terminus of APP. This residue is needed for APP to bind to the coating protein Clathrin and to the Clathrin adaptor protein AP2 as well as for the correct APP trafficking and sorting in neurons. By extending these findings to humans, we found that APP binding to Clathrin (...) An Aberrant Phosphorylation of Amyloid Precursor Protein Tyrosine Regulates Its Trafficking and the Binding to the Clathrin Endocytic Complex in Neural Stem Cells of Alzheimer's Disease Patients Alzheimer's disease (AD) is the most common cause of dementia and is likely caused by defective amyloid precursor protein (APP) trafficking and processing in neurons leading to amyloid plaques containing the amyloid-β (Aβ) APP peptide byproducts. Understanding how APP is targeted to selected

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2017 Frontiers in molecular neuroscience

184. Endocytic Trafficking of HIV gp120 is Mediated by Dynamin and Plays a Role in gp120 Neurotoxicity (PubMed)

Endocytic Trafficking of HIV gp120 is Mediated by Dynamin and Plays a Role in gp120 Neurotoxicity Neurons that endocytose the human immunodeficiency virus-1 (HIV) protein gp120 exhibit neurite retraction and activation of caspase-3, suggesting that the endocytic process may be crucial for gp120-mediated neuronal injury. The goal of this study is to demonstrate that internalization and accumulation of gp120 play a role in its neurotoxic effects. In mammalian cells, endocytosis is primarily

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2017 Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology

185. Tpl2 promotes neutrophil trafficking, oxidative burst, and bacterial killing (PubMed)

Tpl2 promotes neutrophil trafficking, oxidative burst, and bacterial killing Tumor progression locus 2 (Tpl2) is a serine/threonine kinase that promotes inflammatory cytokine production by activating the MEK/ERK pathway. Tpl2 has been shown to be important for eliciting the inflammatory properties of macrophages; however, there is relatively little known about the contribution of Tpl2 to neutrophil effector functions. This is an important consideration, as neutrophils provide the first line (...) of defense against infection in the innate immune system. We found that Tpl2 is expressed in both human and murine neutrophils, suggesting a potential function for Tpl2 in this lineage. Despite significantly higher proportions of bone marrow (BM) neutrophils in Tpl2-deficient (Tpl2-/- ) mice compared with wild-type (WT) mice, Tpl2-/- mice have significantly reduced proportions of circulating neutrophils. Tpl2-/- neutrophils show impaired recruitment to thioglycollate, which was primarily a result

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2017 Journal of leukocyte biology

186. Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer (PubMed)

Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer T cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.Patients with metastatic colorectal cancer (CRC) were treated (...) , but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum

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2017 Journal for immunotherapy of cancer

187. Differential Disruption of Nucleocytoplasmic Trafficking Pathways by Rhinovirus 2A Proteases (PubMed)

Differential Disruption of Nucleocytoplasmic Trafficking Pathways by Rhinovirus 2A Proteases The RNA rhinoviruses (RV) encode 2A proteases (2Apro) that contribute essential polyprotein processing and host cell shutoff functions during infection, including the cleavage of Phe/Gly-containing nucleoporin proteins (Nups) within nuclear pore complexes (NPC). Within the 3 RV species, multiple divergent genotypes encode diverse 2Apro sequences that act differentially on specific Nups. Since only (...) subsets of Phe/Gly motifs, particularly those within Nup62, Nup98, and Nup153, are recognized by transport receptors (karyopherins) when trafficking large molecular cargos through the NPC, the processing preferences of individual 2Apro predict RV genotype-specific targeting of NPC pathways and cargos. To test this idea, transformed HeLa cell lines were created with fluorescent cargos (mCherry) for the importin α/β, transportin 1, and transportin 3 import pathways and the Crm1-mediated export pathway

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2017 Journal of virology

188. The CFTR trafficking mutation F508del inhibits the constitutive activity of SLC26A9 (PubMed)

with SLC26A9, a SLC26A family member found in airway epithelia. We have previously shown that primary, human bronchial epithelia (HBE) from non-CF donors exhibit constitutive anion secretion attributable to SLC26A9. However, constitutive anion secretion is absent in HBE from CF donors. We examined whether changes in SLC26A9 constitutive activity could be attributed to a loss of CFTR trafficking, and what role PDZ interactions played. HEK293 coexpressing SLC26A9 with the trafficking mutant F508del CFTR (...) The CFTR trafficking mutation F508del inhibits the constitutive activity of SLC26A9 Several members of the SLC26A family of anion transporters associate with CFTR, forming complexes in which CFTR and SLC26A functions are reciprocally regulated. These associations are thought to be facilitated by PDZ scaffolding interactions. CFTR has been shown to be positively regulated by NHERF-1, and negatively regulated by CAL in airway epithelia. However, it is unclear which PDZ-domain protein(s) interact

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2017 American Journal of Physiology - Lung Cellular and Molecular Physiology

189. Loss of dynein-2 intermediate chain Wdr34 results in defects in retrograde ciliary protein trafficking and Hedgehog signaling in the mouse (PubMed)

Loss of dynein-2 intermediate chain Wdr34 results in defects in retrograde ciliary protein trafficking and Hedgehog signaling in the mouse The Wdr34 gene encodes an intermediate chain of cytoplasmic dynein 2, the motor for retrograde intraflagellar transport (IFT) in primary cilia. Although mutations in human WDR34 have recently been reported, the association of WDR34 function with Hedgehog (Hh) signaling has not been established, and actual cilia defects in the WDR34 mutant cells have also (...) in the Hh pathway. Therefore, like Dnchc2, Wdr34 is required for ciliogenesis, retrograde ciliary protein trafficking, and the regulation of Gli2/Gli3 activators and repressors. Furthermore, both Wdr34 and Dnchc2 promote microtubule growth, a novel dynein 2 function in a non-cilia structure.© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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2017 Human molecular genetics

190. Coordination chemistry controls the thiol oxidase activity of the B12-trafficking protein CblC (PubMed)

Coordination chemistry controls the thiol oxidase activity of the B12-trafficking protein CblC The cobalamin or B12 cofactor supports sulfur and one-carbon metabolism and the catabolism of odd-chain fatty acids, branched-chain amino acids, and cholesterol. CblC is a B12-processing enzyme involved in an early cytoplasmic step in the cofactor-trafficking pathway. It catalyzes the glutathione (GSH)-dependent dealkylation of alkylcobalamins and the reductive decyanation of cyanocobalamin. CblC from (...) . The crystal structure of ceCblC provides insights into how architectural differences at the α- and β-faces of cobalamin promote the thiol oxidase activity of ceCblC but mute it in wild-type human CblC. The R161G and R161Q mutations in human CblC unmask its latent thiol oxidase activity and are correlated with increased cellular oxidative stress disease. In summary, we have uncovered key architectural features in the cobalamin-binding pocket that support unusual cob(II)alamin coordination chemistry

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2017 The Journal of biological chemistry

191. Hepatic Tm6sf2 overexpression affects cellular ApoB-trafficking, plasma lipid levels, hepatic steatosis and atherosclerosis (PubMed)

Hepatic Tm6sf2 overexpression affects cellular ApoB-trafficking, plasma lipid levels, hepatic steatosis and atherosclerosis The human transmembrane 6 superfamily member 2 (TM6SF2) gene has been implicated in plasma lipoprotein metabolism, alcoholic and non-alcoholic fatty liver disease and myocardial infarction in multiple genome-wide association studies. To investigate the role of Tm6sf2 in metabolic homeostasis, we generated mice with elevated expression using adeno-associated virus (AAV (...) within the endoplasmic reticulum (ER) suggesting impaired ER-to-Golgi trafficking of pre-very low-density lipoprotein (VLDL) particles. Analysis of two metabolic trait-associated coding polymorphisms in the human TM6SF2 gene (rs58542926 and rs187429064) revealed that both variants impact TM6SF2 expression by affecting the rate of protein turnover. These data demonstrate that rs58542926 (E167K) and rs187429064 (L156P) are functional variants and suggest that they influence metabolic traits through

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2017 Human molecular genetics

192. Membrane depolarization activates BK channels through ROCK-mediated β1 subunit surface trafficking to limit vasoconstriction (PubMed)

Membrane depolarization activates BK channels through ROCK-mediated β1 subunit surface trafficking to limit vasoconstriction Membrane depolarization of smooth muscle cells (myocytes) in the small arteries that regulate regional organ blood flow leads to vasoconstriction. Membrane depolarization also activates large-conductance calcium (Ca2+)-activated potassium (BK) channels, which limits Ca2+ channel activity that promotes vasoconstriction, thus leading to vasodilation. We showed (...) that in human and rat arterial myocytes, membrane depolarization rapidly increased the cell surface abundance of auxiliary BK β1 subunits but not that of the pore-forming BKα channels. Membrane depolarization stimulated voltage-dependent Ca2+ channels, leading to Ca2+ influx and the activation of Rho kinase (ROCK) 1 and 2. ROCK1/2-mediated activation of Rab11A promoted the delivery of β1 subunits to the plasma membrane by Rab11A-positive recycling endosomes. These additional β1 subunits associated with BKα

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2017 Science signaling

193. Effector and Regulatory T Cell Trafficking in Corneal Allograft Rejection (PubMed)

Effector and Regulatory T Cell Trafficking in Corneal Allograft Rejection Corneal transplantation is among the most prevalent and successful forms of solid tissue transplantation in humans. Failure of corneal allograft is mainly due to immune-mediated destruction of the graft, a complex and highly coordinated process that involves elaborate interactions between cells of innate and adaptive immunity. The migration of immune cells to regional lymphoid tissues and to the site of graft plays (...) a central role in the immunopathogenesis of graft rejection. Intricate interactions between adhesion molecules and their counter receptors on immune cells in conjunction with tissue-specific chemokines guide the trafficking of these cells to the draining lymph nodes and ultimately to the site of graft. In this review, we discuss the cascade of chemokines and adhesion molecules that mediate the trafficking of effector and regulatory T cells during corneal allograft rejection.

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2017 Mediators of inflammation

194. Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy (PubMed)

Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy Effector T cells have the capability of recognizing and killing cancer cells. However, whether tumors can become immune resistant through exclusion of effector T cells from the tumor microenvironment is not known. By using a tumor model resembling non-T cell-inflamed human tumors, we assessed whether adoptive T cell transfer might overcome failed spontaneous priming. Flow cytometric (...) assays combined with intra-vital imaging indicated failed trafficking of effector T cells into tumors. Mechanistically, this was due to the absence of CXCL9/10, which we found to be produced by CD103+ dendritic cells (DCs) in T cell-inflamed tumors. Our data indicate that lack of CD103+ DCs within the tumor microenvironment dominantly resists the effector phase of an anti-tumor T cell response, contributing to immune escape.Copyright © 2017 Elsevier Inc. All rights reserved.

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2017 Cancer cell

195. A Rab20-Dependent Membrane Trafficking Pathway Controls M. tuberculosis Replication by Regulating Phagosome Spaciousness and Integrity (PubMed)

-gamma-stimulated and Rab20-dependent membrane trafficking pathway in macrophages that maintains Mtb in spacious proteolytic phagolysosomes. This pathway functions to promote endosomal membrane influx in infected macrophages, and is required to preserve Mtb phagosome integrity and control Mtb replication. Rab20 is specifically and significantly upregulated in the sputum of human patients with active tuberculosis. Altogether, we uncover an immune-regulated cellular pathway of defense that promotes (...) A Rab20-Dependent Membrane Trafficking Pathway Controls M. tuberculosis Replication by Regulating Phagosome Spaciousness and Integrity The intracellular pathogen Mycobacterium tuberculosis (Mtb) lives within phagosomes and also disrupts these organelles to access the cytosol. The host pathways and mechanisms that contribute to maintaining Mtb phagosome integrity have not been investigated. Here, we examined the spatiotemporal dynamics of Mtb-containing phagosomes and identified an interferon

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2017 Cell host & microbe

196. A genetic screen in combination with biochemical analysis in Saccharomyces cerevisiae indicates that phenazine-1-carboxylic acid is harmful to vesicular trafficking and autophagy (PubMed)

A genetic screen in combination with biochemical analysis in Saccharomyces cerevisiae indicates that phenazine-1-carboxylic acid is harmful to vesicular trafficking and autophagy The environmentally friendly antibiotic phenazine-1-carboxylic acid (PCA) protects plants, mammals and humans effectively against various fungal pathogens. However, the mechanism by which PCA inhibits or kills fungal pathogens is not fully understood. We analyzed the effects of PCA on the growth of two fungal model (...) organisms, Saccharomyces cerevisiae and Candida albicans, and found that PCA inhibited yeast growth in a dose-dependent manner which was inversely dependent on pH. In contrast, the commonly used antibiotic hygromycin B acted in a dose-dependent manner as pH increased. We then screened a yeast mutant library to identify genes whose mutation or deletion conferred resistance or sensitivity to PCA. We isolated 193 PCA-resistant or PCA-sensitive mutants in clusters, including vesicle-trafficking

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2017 Scientific reports

197. Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations (PubMed)

that PGRN facilitates neuronal uptake and lysosomal delivery of prosaposin (PSAP), the precursor of saposin peptides that are essential for lysosomal glycosphingolipid degradation. We found reduced levels of PSAP in neurons both in mice deficient in PGRN and in human samples from FTLD patients due to GRN mutations. Furthermore, mice with reduced PSAP expression demonstrated FTLD-like pathology and behavioural changes. Thus, our data demonstrate a role of PGRN in PSAP lysosomal trafficking and suggest (...) Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations Haploinsufficiency of progranulin (PGRN) due to mutations in the granulin (GRN) gene causes frontotemporal lobar degeneration (FTLD), and complete loss of PGRN leads to a lysosomal storage disorder, neuronal ceroid lipofuscinosis (NCL). Accumulating evidence suggests that PGRN is essential for proper lysosomal function, but the precise mechanisms involved are not known. Here, we show

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2017 Nature communications

198. Microtubule-assisted altered trafficking of astrocytic gap junction protein connexin 43 is associated with depletion of connexin 47 during mouse hepatitis virus infection (PubMed)

Microtubule-assisted altered trafficking of astrocytic gap junction protein connexin 43 is associated with depletion of connexin 47 during mouse hepatitis virus infection Gap junctions (GJs) are important for maintenance of CNS homeostasis. GJ proteins, connexin 43 (Cx43) and connexin 47 (Cx47), play a crucial role in production and maintenance of CNS myelin. Cx43 is mainly expressed by astrocytes in the CNS and forms gap junction intercellular communications between astrocytes-astrocytes (Cx43 (...) -Cx43) and between astrocytes-oligodendrocytes (Cx43-Cx47). Mutations of these connexin (Cx) proteins cause dysmyelinating diseases in humans. Previously, it has been shown that Cx43 localization and expression is altered due to mouse hepatitis virus (MHV)-A59 infection both in vivo and in vitro; however, its mechanism and association with loss of myelin protein was not elaborated. Thus, we explored potential mechanisms by which MHV-A59 infection alters Cx43 localization and examined the effects

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2017 The Journal of biological chemistry

199. Treating Posttraumatic Stress Disorder in Female Victims of Trafficking Using Narrative Exposure Therapy: A Retrospective Audit (PubMed)

Treating Posttraumatic Stress Disorder in Female Victims of Trafficking Using Narrative Exposure Therapy: A Retrospective Audit Human trafficking is a form of modern slavery that involves the forced movement of people internally within countries, or externally across borders. Victims who are trafficked for sexual exploitation are subject to repeated, multiple trauma, and high rates of mental health problems including posttraumatic stress disorder (PTSD) have been found. Narrative exposure (...) therapy (NET) is an evidence-based treatment for PTSD.In this retrospective audit, we record the results of NET to treat 10 women who had been trafficked for sexual exploitation who were diagnosed with PTSD.All 10 women completed the therapy and experienced a reduction in PTSD severity scores at posttreatment, with improvements that were maintained or further improved at 3-month follow-up. General distress was also significantly reduced following treatment.Although limited by sample size

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2017 Frontiers in Psychiatry

200. Linaclotide activates guanylate cyclase‐C/cGMP/protein kinase‐II‐dependent trafficking of CFTR in the intestine (PubMed)

Linaclotide activates guanylate cyclase‐C/cGMP/protein kinase‐II‐dependent trafficking of CFTR in the intestine The transmembrane receptor guanylyl cyclase-C (GC-C), expressed on enterocytes along the intestine, is the molecular target of the GC-C agonist peptide linaclotide, an FDA-approved drug for treatment of adult patients with Irritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipation. Polarized human colonic intestinal cells (T84, CaCo-2BBe) rat and human (...) intestinal tissues were employed to examine cellular signaling and cystic fibrosis transmembrane conductance regulator (CFTR)-trafficking pathways activated by linaclotide using confocal microscopy, in vivo surface biotinylation, and protein kinase-II (PKG-II) activity assays. Expression and activity of GC-C/cGMP pathway components were determined by PCR, western blot, and cGMP assays. Fluid secretion as a marker of CFTR cell surface translocation was determined using in vivo rat intestinal loops

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2017 Physiological reports

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