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https://www.readbyqxmd.com/read/28222538/vps35-the-retromer-complex-and-parkinson-s-disease
#1
Erin T Williams, Xi Chen, Darren J Moore
Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene encoding a core component of the retromer complex, have recently emerged as a new cause of late-onset, autosomal dominant familial Parkinson's disease (PD). A single missense mutation, AspD620Asn (D620N), has so far been unambiguously identified to cause PD in multiple individuals and families worldwide. The exact molecular mechanism(s) by which VPS35 mutations induce progressive neurodegeneration in PD are not yet known. Understanding these mechanisms, as well as the perturbed cellular pathways downstream of mutant VPS35, is important for the development of appropriate therapeutic strategies...
February 8, 2017: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/28222218/reduced-inflammatory-responses-of-follicular-helper-t-cell-promote-the-development-of-regulatory-b-cells-after-roux-en-y-gastric-bypass
#2
Junfang Zhan, Liyu Huang, Haiyong Ma, Huan Chen, Yuan Yang, Sheng Tan, Wendy Song, Weiguo Zhao, Xiaojiang Dai
Bariatric surgery is currently the most effective strategy in treating severe obesity and its comorbidities, such as type 2 diabetes (T2D). However, the mechanism through which bariatric surgery mediates its benefits is not completely understood. Since obesity and T2D represent yet another inflammatory disease, and follicular helper T (Tfh) cells play important roles in inflammatory disorders, we investigated whether the Tfh activity was altered after Roux-en-Y gastric bypass (RYGB), one of the most common bariatric surgery procedures...
February 21, 2017: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/28222098/multicenter-study-of-skin-rashes-and-hepatotoxicity-in-antiretroviral-na%C3%A3-ve-hiv-positive-patients-receiving-non-nucleoside-reverse-transcriptase-inhibitor-plus-nucleoside-reverse-transcriptase-inhibitors-in-taiwan
#3
Pei-Ying Wu, Chien-Yu Cheng, Chun-Eng Liu, Yi-Chien Lee, Chia-Jui Yang, Mao-Song Tsai, Shu-Hsing Cheng, Shih-Ping Lin, De-Yu Lin, Ning-Chi Wang, Yi-Chieh Lee, Hsin-Yun Sun, Hung-Jen Tang, Chien-Ching Hung
OBJECTIVES: Two nucleos(t)ide reverse-transcriptase inhibitors (NRTIs) plus 1 non-NRTI (nNRTI) remain the preferred or alternative combination antiretroviral therapy (cART) for antiretroviral-naive HIV-positive patients in Taiwan. The three most commonly used nNRTIs are nevirapine (NVP), efavirenz (EFV) and rilpivirine (RPV). This study aimed to determine the incidences of hepatotoxicity and skin rashes within 4 weeks of initiation of cART containing 1 nNRTI plus 2 NRTIs. METHODS: Between June, 2012 and November, 2015, all antiretroviral-naive HIV-positive adult patients initiating nNRTI-containing cART at 8 designated hospitals for HIV care were included in this retrospective observational study...
2017: PloS One
https://www.readbyqxmd.com/read/28221884/neural-network-model-for-thermal-inactivation-of-salmonella-typhimurium-to-elimination-in-ground-chicken-acquisition-of-data-by-whole-sample-enrichment-miniature-most-probable-number-method
#4
T P Oscar
Predictive models are valuable tools for assessing food safety. Existing thermal inactivation models for Salmonella and ground chicken do not provide predictions above 71°C, which is below the recommended final cooked temperature of 73.9°C for chicken. They also do not predict when all Salmonella are eliminated without extrapolating beyond the data used to develop them. Thus, a study was undertaken to develop a model for thermal inactivation of Salmonella to elimination in ground chicken at temperatures above those of existing models...
January 2017: Journal of Food Protection
https://www.readbyqxmd.com/read/28221346/synthesis-of-ent-be-43547a1-reveals-a-potent-hypoxia-selective-anticancer-agent-and-uncovers-the-biosynthetic-origin-of-the-apd-cld-natural-products
#5
Nikolaj L Villadsen, Kristian M Jacobsen, Ulrik B Keiding, Esben T Weibel, Bjørn Christiansen, Thomas Vosegaard, Morten Bjerring, Frank Jensen, Mogens Johannsen, Thomas Tørring, Thomas B Poulsen
Tumour hypoxia is speculated to be a key driver of therapeutic resistance and metastatic dissemination. Consequently, the discovery of new potent agents that selectively target the hypoxic cell population may reveal new and untapped antitumour mechanisms. Here we demonstrate that the BE-43547 subclass of the APD-CLD (amidopentadienoate-containing cyclolipodepsipeptides) natural products possesses highly hypoxia-selective growth-inhibitory activity against pancreatic cancer cells. To enable this discovery, we have developed the first synthesis of the BE-43547-macrocyclic scaffold in 16 steps (longest linear sequence), which also allowed access to the full panel of relative stereoisomers and ultimately to the assignment of stereochemical configuration...
March 2017: Nature Chemistry
https://www.readbyqxmd.com/read/28220931/the-role-of-extracorporeal-photopheresis-in-the-management-of-cutaneous-t-cell-lymphoma-graft-versus-host-disease-and-organ-transplant-rejection-a-consensus-statement-update-from-the-uk-photopheresis-society
#6
Arun Alfred, Peter C Taylor, Fiona Dignan, Khaled El-Ghariani, James Griffin, Andrew R Gennery, Denise Bonney, Emma Das-Gupta, Sarah Lawson, Ram K Malladi, Kenneth W Douglas, Tracey Maher, Julie Guest, Laura Hartlett, Andrew J Fisher, Fiona Child, Julia J Scarisbrick
Extracorporeal photopheresis (ECP) has been used for over 35 years in the treatment of erythrodermic cutaneous T-cell lymphoma (CTCL) and over 20 years for chronic and acute graft-versus-host disease (GvHD) and solid organ transplant rejection. ECP for CTCL and GvHD is available at specialised centres across the UK. The lack of prospective randomised trials in ECP led to the development of UK Consensus Statements for patient selection, treatment schedules, monitoring protocols and patient assessment criteria for ECP...
February 21, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28220803/tcf7-is-suppressed-by-the-androgen-receptor-via-microrna-1-mediated-downregulation-and-is-involved-in-the-development-of-resistance-to-androgen-deprivation-in-prostate-cancer
#7
M K Siu, W-Y Chen, H-Y Tsai, H-Y Chen, J J Yin, C-L Chen, Y-C Tsai, Y-N Liu
BACKGROUND: Resistance to androgen deprivation therapy (ADT) represents a key step in the malignant progression of prostate cancer, and mutation to androgen receptor (AR) is one major driver to an androgen-independent phenotype. However, alternative oncogenic pathways that bypass AR signaling have emerged as an important mechanism promoting resistance to ADT. It is known that AR activation can prevent the interaction between β-catenin and T cell factor/lymphoid enhancer-binding factor (TCF/LEF) family, inhibiting the Wnt signaling pathway...
February 21, 2017: Prostate Cancer and Prostatic Diseases
https://www.readbyqxmd.com/read/28220772/tumour-and-host-cell-pd-l1-is-required-to-mediate-suppression-of-anti-tumour-immunity-in-mice
#8
Janet Lau, Jeanne Cheung, Armando Navarro, Steve Lianoglou, Benjamin Haley, Klara Totpal, Laura Sanders, Hartmut Koeppen, Patrick Caplazi, Jacqueline McBride, Henry Chiu, Rebecca Hong, Jane Grogan, Vincent Javinal, Robert Yauch, Bryan Irving, Marcia Belvin, Ira Mellman, Jeong M Kim, Maike Schmidt
Expression of PD-L1, the ligand for T-cell inhibitory receptor PD-1, is one key immunosuppressive mechanism by which cancer avoids eradication by the immune system. Therapeutic use of blocking antibodies to PD-L1 or its receptor PD-1 has produced unparalleled, durable clinical responses, with highest likelihood of response seen in patients whose tumour or immune cells express PD-L1 before therapy. The significance of PD-L1 expression in each cell type has emerged as a central and controversial unknown in the clinical development of immunotherapeutics...
February 21, 2017: Nature Communications
https://www.readbyqxmd.com/read/28220250/differing-roles-for-sur-2-med23-in-c-elegans-and-c-briggsae-vulval-development
#9
Karley K Mahalak, Abdulrahman M Jama, Steven J Billups, Adriana T Dawes, Helen M Chamberlin
Normal vulval development in the nematode Caenorhabditis briggsae is identical to that in the related Caenorhabditis elegans. However, several experiments suggest that there are differences between the two species with respect to the contribution of EGF/Ras signaling. To investigate these differences genetically, we have characterized a C. briggsae mutant strain that phenocopies the effect observed when C. briggsae animals are treated with U0126, an inhibitor of the EGF pathway component MEK. We identify that the gene affected in the mutant strain is Cbr-sur-2, which encodes a MED23 mediator complex protein that acts downstream of EGF signaling in C...
February 20, 2017: Development Genes and Evolution
https://www.readbyqxmd.com/read/28220116/cpg-odn-shapes-alum-adjuvant-activity-signaling-via-myd88-and-il-10
#10
Luciana Mirotti, Ricardo Wesley Alberca Custódio, Eliane Gomes, Florencia Rammauro, Eliseu Frank de Araujo, Vera Lucia Garcia Calich, Momtchilo Russo
Aluminum-containing adjuvants usually referred as Alum are considered as T helper type-2 (Th2) adjuvants, while agonists of toll-like receptors (TLRs) are viewed as adjuvants that favor Th1/Th17 immunity. Alum has been used in numerous vaccine formulations; however, its undesired pro-Th2 adjuvant activity constitutes a caveat for Alum-based vaccines. Combining Alum with TLR-dependent, pro-Th1/Th17 adjuvants might dampen the pro-Th2 activity and improve the effectiveness of vaccine formulations. Here, using the ovalbumin (OVA) model of allergic lung inflammation, we found that sensitization with the synthetic TLR9 agonist, which is composed of oligodeoxynucleotides containing CpG motifs adsorbed to Alum, inhibited the development of OVA-induced lung allergic Th2 responses without shifting toward a Th1 pattern...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28219981/the-role-of-natural-killer-t-cells-in-a-mouse-model-with-spontaneous-bile-duct-inflammation
#11
Elisabeth Schrumpf, Xiaojun Jiang, Sebastian Zeissig, Marion J Pollheimer, Jarl Andreas Anmarkrud, Corey Tan, Mark A Exley, Tom H Karlsen, Richard S Blumberg, Espen Melum
Natural killer T (NKT) cells are activated by lipid antigens presented by CD1d molecules and represent a major lymphocyte subset of the liver. NODc3c4 mice spontaneously develop biliary inflammation in extra- and intrahepatic bile ducts. We demonstrated by flow cytometry that invariant NKT (iNKT) cells were more abundant in the thymus, spleen, and liver of NODc3c4 mice compared to NOD mice. iNKT cells in NODc3c4 mice displayed an activated phenotype. Further, NOD and NODCd1d(-/-) mice were irradiated and injected with NODc3c4 bone marrow, and injection of NODc3c4 bone marrow resulted in biliary infiltrates independently of CD1d expression in recipient mice...
February 2017: Physiological Reports
https://www.readbyqxmd.com/read/28219888/cd74-deficiency-mitigates-systemic-lupus-erythematosus-like-autoimmunity-and-pathological-findings-in-mice
#12
Yi Zhou, Huimei Chen, Li Liu, Xueqing Yu, Galina K Sukhova, Min Yang, Lijun Zhang, Vasileios C Kyttaris, George C Tsokos, Isaac E Stillman, Takaharu Ichimura, Joseph V Bonventre, Peter Libby, Guo-Ping Shi
CD74 mediates MHC class-II antigenic peptide loading and presentation and plays an important role in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus. C57BL/6 Fas(lpr) mice that develop spontaneous lupus-like autoimmunity and pathology showed elevated CD74 expression in the inflammatory cell infiltrates and the adjacent tubular epithelial cells (TECs) in kidneys affected by lupus nephritis but negligible levels in kidneys from age-matched wild-type mice. The inflammatory cytokine IFN-γ or IL-6 induced CD74 expression in kidney TECs in vitro...
February 20, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28219887/disruption-of-pathogenic-cellular-networks-by-il-21-blockade-leads-to-disease-amelioration-in-murine-lupus
#13
Jin-Young Choi, Abhinav Seth, Michael Kashgarian, Sonia Terrillon, Emma Fung, Lili Huang, Li Chun Wang, Joe Craft
Systemic lupus erythematosus (lupus) is characterized by autoantibody-mediated organ injury. Follicular Th (Tfh) cells orchestrate physiological germinal center (GC) B cell responses, whereas in lupus they promote aberrant GC responses with autoreactive memory B cell development and plasma cell-derived autoantibody production. IL-21, a Tfh cell-derived cytokine, provides instructional cues for GC B cell maturation, with disruption of IL-21 signaling representing a potential therapeutic strategy for autoantibody-driven diseases such as systemic lupus erythematosus...
February 20, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28219834/incidence-and-outcomes-of-central-nervous-system-hemophagocytic-lymphohistiocytosis-relapse-after-reduced-intensity-conditioning-hematopoietic-stem-cell-transplant
#14
Dana T Lounder, Pooja Khandelwal, Sharat Chandra, Michael B Jordan, Ashish R Kumar, Michael Grimley, Stella M Davies, Jack J Bleesing, Rebecca A Marsh
Hemophagocytic Lymphohistiocytosis (HLH) is an immune regulatory disorder that commonly presents with CNS involvement. The only cure for genetic HLH is hematopoietic stem cell transplantation (HSCT), typically treated with reduced intensity conditioning (RIC) regimens. We sought to estimate the incidence of CNS relapse after RIC HSCT, determine risk factors, and evaluate outcomes. We performed a retrospective chart review of 94 consecutive children and young adults with primary HLH who received RIC HSCT. CNS relapse within 1 year after transplant was diagnosed by review of clinical symptoms, cerebral spinal fluid (CSF), and radiologic findings...
February 17, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/28219703/immunomodulatory-properties-of-1-2-dihydro-4-hydroxy-2-oxo-1-8-naphthyridine-3-carboxamide-derivative-vl15
#15
Anna Maria Malfitano, Chiara Laezza, Simone Bertini, Daniela Marasco, Tiziano Tuccinardi, Maurizio Bifulco, Clementina Manera
1,2-dihydro-4-hydroxy-2-oxo-1,8-naphthyridine-3-carboxamide derivative VL15 has been recently developed as a selective cannabinoid CB2 receptor compound. Given the high selectivity of this compound at the cannabinoid CB2 receptor and the well-known protective function of this receptor in neurological disorders with autoimmune component like multiple sclerosis, we assessed the immunomodulatory properties of VL15. We assessed on activated peripheral blood mononuclear cells (PBMC), proliferation and viability, cell cycle progression and measured activation markers and the expression of phosphorylated proteins...
February 17, 2017: Biochimie
https://www.readbyqxmd.com/read/28219680/the-regulation-of-transcriptional-repression-in-hypoxia
#16
Miguel A S Cavadas, Alex Cheong, Cormac T Taylor
A sufficient supply molecular oxygen is essential for the maintenance of physiologic metabolism and bioenergetic homeostasis for most metazoans. For this reason, mechanisms have evolved for eukaryotic cells to adapt to conditions where oxygen demand exceeds supply (hypoxia). These mechanisms rely on the modification of pre-existing proteins, translational arrest and transcriptional changes. The hypoxia inducible factor (HIF; a master regulator of gene induction in response to hypoxia) is responsible for the majority of induced gene expression in hypoxia...
February 17, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28219660/modelling-and-investigation-of-the-cd4-t-cells-macrophages-paradox-in-melanoma-immunotherapies
#17
Raluca Eftimie, Haneen Hamam
It is generally accepted that tumour cells can be eliminated by M1 anti-tumour macrophages and CD8(+) T cells. However, experimental results over the past 10-15 years have shown that B16 mouse melanoma cells can be eliminated by the CD4(+) T cells alone (either Th1 or Th2 sub-types), in the absence of CD8(+) T cells. In some studies, elimination of B16 melanoma was associated with a Th1 immune response (i.e., elimination occurred in the presence of cytokines produced by Th1 cells), while in other studies melanoma elimination was associated with a Th2 immune response (i...
February 17, 2017: Journal of Theoretical Biology
https://www.readbyqxmd.com/read/28218996/hypoxia-stimulated-membrane-trafficking-requires-t-plastin
#18
Marieke Wottawa, Stephanie Naas, Johannes Böttger, Gijsbert J van Belle, Wiebke Möbius, Natalia H Revelo, Doris Heidenreich, Melanie von Ahlen, Anke Zieseniss, Katharina Kröhnert, Susanne Lutz, Christof Lenz, Henning Urlaub, Silvio O Rizzoli, Dörthe M Katschinski
Traffic between the plasma membrane and the endomembrane compartments is an essential feature of eukaryotic cells. The secretory pathway sends cargoes from biosynthetic compartments to the plasma membrane. This is counterbalanced by a retrograde endocytotic route and is essential for cell homeostasis. Cells need to adapt rapidly to environmental challenges like the reduction of pO2 which, however, has not been analyzed in relation to membrane trafficking in detail. Therefore we determined changes in the plasma membrane trafficking in normoxia, hypoxia, and after reoxygenation METHODS: Membrane trafficking was analyzed by using the bulk membrane endocytosis marker FM 1-43, the newly developed membrane probe mCLING, wheat germ agglutinin as well as fluorescently labeled choleratoxin subunit B...
February 20, 2017: Acta Physiologica
https://www.readbyqxmd.com/read/28218888/using-clinical-signs-and-symptoms-for-medical-management-of-radiation-casualties-2015-nato-exercise
#19
H Dörr, M Abend, W F Blakely, D L Bolduc, D Boozer, T Costeira, T Dant, A De Amicis, S De Sanctis, M Dondey, M Drouet, F Entine, S Francois, G Gagna, N Guitard, F Hérodin, M Hoefer, A Lamkowski, G La Sala, F Lista, P Loiacono, M Majewski, P Martigne, D Métivier, X Michel, J Pateux, J Pejchal, G Reeves, D Riccobono, Z Sinkorova, L Soyez, D Stricklin, A Tichy, M Valente, C R Woodruff, L Zarybnicka, M Port
The utility of early-phase (≤5 days) radiation-induced clinical signs and symptoms (e.g., vomiting, diarrhea, erythema and changes in blood cell counts) was examined for the prediction of later occurring acute radiation syndrome (ARS) severity and the development of medical management strategies. Medical treatment protocols for radiation accident victims (METREPOL) was used to grade ARS severities, which were assigned response categories (RCs). Data on individuals (n = 191) with mild (RC1, n = 45), moderate (RC2, n = 19), severe (RC3, n = 20) and fatal (RC4, n = 18) ARS, as well as nonexposed individuals (RC0, n = 89) were generated using either METREPOL (n = 167) or the system for evaluation and archiving of radiation accidents based on case histories (SEARCH) database (n = 24), the latter comprised of real-case descriptions...
February 20, 2017: Radiation Research
https://www.readbyqxmd.com/read/28218626/building-discontinuous-liver-sinusoidal-vessels
#20
Courtney T Griffin, Siqi Gao
Blood vessels have a unified mission to circulate blood throughout the body; however, they have additional diverse and specialized roles in various organs. For example, in the liver, discontinuous sinusoids, which are fenestrated capillaries with intercellular gaps and a fragmented basement membrane, facilitate delivery of macromolecules to highly metabolic hepatocytes. During embryonic development, discontinuous sinusoids also allow circulating hematopoietic progenitor and stem cells to populate the liver and promote blood cell differentiation...
February 20, 2017: Journal of Clinical Investigation
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