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https://www.readbyqxmd.com/read/28917639/protein-oxidation-involved-in-cys-tyr-post-translational-modification
#1
Susan E Hromada, Adam M Hilbrands, Elysa M Wolf, Jackson L Ross, Taylor R Hegg, Andrew G Roth, Matthew T Hollowell, Carolyn E Anderson, David E Benson
Some post-translationally modified tyrosines can perform reversible redox chemistry similar to metal cofactors. The most studied of these tyrosine modifications is the intramolecular thioether-crosslinked 3'-(S-cysteinyl)-tyrosine (Cys-Tyr) in galactose oxidase. This Cu-mediated tyrosine modification in galactose oxidase involves direct electron transfer (inner-sphere) to the coordinated tyrosine. Mammalian cysteine dioxygenase enzymes also contain a Cys-Tyr that is formed, presumably, through outer-sphere electron transfer from a non-heme iron center ~6Å away from the parent residues...
September 14, 2017: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/28916443/aq-13-an-investigational-antimalarial-versus-artemether-plus-lumefantrine-for-the-treatment-of-uncomplicated-plasmodium-falciparum-malaria-a-randomised-phase-2-non-inferiority-clinical-trial
#2
Ousmane A Koita, Lansana Sangaré, Haiyan D Miller, Aliou Sissako, Moctar Coulibaly, Trevor A Thompson, Saharé Fongoro, Youssouf Diarra, Mamadou Ba, Ababacar Maiga, Boubakar Diallo, David M Mushatt, Frances J Mather, Jeffrey G Shaffer, Asif H Anwar, Donald J Krogstad
BACKGROUND: Chloroquine was used for malaria treatment until resistant Plasmodium falciparum was identified. Because 4-aminoquinolines with modified side chains, such as AQ-13, are active against resistant parasites, we compared AQ-13 against artemether plus lumefantrine for treatment of uncomplicated P falciparum malaria. METHODS: We did a randomised, non-inferiority trial. We screened men (≥18 years) with uncomplicated malaria in Missira (northeast Mali) and Bamako (capital of Mali) for eligibility (≥2000 asexual P falciparum parasites per μL of blood)...
September 12, 2017: Lancet Infectious Diseases
https://www.readbyqxmd.com/read/28915668/nsc30049-inhibits-chk1-pathway-in-5-fu-resistant-crc-bulk-and-stem-cell-populations
#3
Satya Narayan, Aruna S Jaiswal, Ritika Sharma, Akbar Nawab, Lizette Vila Duckworth, Brian K Law, Maria Zajac-Kaye, Thomas J George, Jay Sharma, Arun K Sharma, Robert A Hromas
The 5-fluorouracil (5-FU) treatment induces DNA damage and stalling of DNA replication forks. These stalled replication forks then collapse to form one sided double-strand breaks, leading to apoptosis. However, colorectal cancer (CRC) stem cells rapidly repair the stalled/collapsed replication forks and overcome treatment effects. Recent evidence suggests a critical role of checkpoint kinase 1 (Chk1) in preventing the replicative stress. Therefore, Chk1 kinase has been a target for developing mono or combination therapeutic agents...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28912303/gpr62-constitutively-activates-camp-signaling-but-is-dispensable-for-male-fertility-in-mice
#4
Tomoyuki Muroi, Yuri Matsushima, Ryota Kanamori, Hikari Inoue, Wataru Fujii, Keiichiro Yogo
G-protein-coupled receptors (GPCRs) participate in diverse physiological functions and are promising targets for drug discovery. However, there are still over 140 orphan GPCRs whose functions remain to be elucidated. Gpr62 is one of the orphan GPCRs that is expressed in the rat and human brain. In this study, we found that Gpr62 is also expressed in male germ cells in mice, and its expression increases along with sperm differentiation. GPR62 lacks the BBXXB and DRY motifs, which are conserved across many GPCRs, and it was able to induce cAMP signaling in the absence of a ligand...
September 14, 2017: Reproduction: the Official Journal of the Society for the Study of Fertility
https://www.readbyqxmd.com/read/28904822/a-parental-perspective-concerning-barriers-to-care-for-neural-tube-defects-in-china
#5
Andrew Campion, Clement Lee, Nan Bao, Jorge Lazareff
BACKGROUND: The People's Republic of China (PRC) has the highest incidence of neural tube defects (NTDs) in the world. NTDs remain a significant contributor to the global burden of disease amendable to surgical care; however, no studies to date have evaluated the patients' perspective regarding perceived barriers to care. METHODS: The study was conducted at the Shanghai Children's Medical Center (SCMC) between 6/11/2014 and 7/17/2014. Surveys were administered to families presenting to the clinic of the SCMC director for Pediatric Neurosurgery...
2017: Surgical Neurology International
https://www.readbyqxmd.com/read/28902267/-public-production-as-a-key-factor-for-access-to-antivenoms-in-the-region-of-the-americas
#6
Guillermo Temprano, Patricia Aprea, José Christian Dokmetjian
Injuries caused by venomous animals affect vast areas of Latin America, Southern Asia, Southeast Asia, sub-Saharan Africa, and Oceania, and pose a serious problem for global public health. Based on an analysis of the current panorama of global production of ophidian and arachnid antivenoms, it is concluded that they are semi-orphaned products. This is a favorable scenario in which to strengthen public laboratory production. Governments should make a political decision in this regard in the interest of equity in population health...
August 21, 2017: Revista Panamericana de Salud Pública, Pan American Journal of Public Health
https://www.readbyqxmd.com/read/28901441/profiling-of-differentially-expressed-genes-in-adipose-tissues-of-multiple-symmetric-lipomatosis
#7
Ke Chen, Linghao Wang, Wenjun Yang, Changfa Wang, Gui Hu, Zhaohui Mo
Multiple symmetric lipomatosis (MSL) is a rare disorder characterized by aberrant multiple and symmetric subcutaneous adipose tissue accumulation in the face, neck, shoulders, back, chest and abdomen, severely affecting the quality of life of patients. At present, precise MSL etiology and pathogenesis remain to be elucidated. The present study first utilized a digital gene expression technique with a next‑generation sequencing platform to profile differentially expressed genes in three cases of MSL vs. normal control tissue...
September 7, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28901277/repositioning-of-tak-475-in-mevalonate-kinase-disease-translating-theory-into-practice
#8
Annalisa Marcuzzi, Claudia Loganes, Claudio Celeghini, Giulio Kleiner
Mevalonate Kinase Deficiency (MKD, OMIM #610377) is a rare autosomal recessive metabolic and inflammatory disease. In MKD, defective function of the enzyme mevalonate kinase (MK), due to a mutation in the MVK gene, leads to the shortage of mevalonate-derived intermediates, which results in unbalanced prenylation of proteins and altered metabolism of sterols. These defects lead to a complex multisystem inflammatory and metabolic syndrome. Although biologic therapies aimed at blocking the inflammatory cytokine interleukin-1 (IL-1) can significantly reduce inflammation, they cannot completely control the clinical symptoms that affects the nervous system...
September 11, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28900816/critical-appraisal-of-genotype-assessment-in-molybdenum-cofactor-deficiency
#9
Katrin Hinderhofer, Konstantin Mechler, Georg F Hoffmann, Anette Lampert, William K Mountford, Markus Ries
INTRODUCTION: Molybdenum cofactor deficiency (MoCD) is an ultra-orphan, life-threatening disease. Substrate substitution therapy has successfully been performed in single cases of MoCD type A and clinical trials are underway for drug registration. We present an innovative approach for classification of genotype severity to test the hypothesis that milder sequence variants in MoCD result in a less severe disease phenotype quantitated by patient survival. METHODS: All available worldwide published cases with clinical and genetic data were included (n = 40)...
September 12, 2017: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/28900043/a-natural-ligand-for-the-orphan-receptor-gpr15-modulates-lymphocyte-recruitment-to-epithelia
#10
Thomas Suply, Sébastien Hannedouche, Nathalie Carte, Jianping Li, Bianka Grosshans, Michael Schaefer, Layla Raad, Valérie Beck, Solange Vidal, Agnès Hiou-Feige, Noémie Beluch, Samuel Barbieri, Johann Wirsching, Nadine Lageyre, Frank Hillger, Corinne Debon, Janet Dawson, Philip Smith, Vincent Lannoy, Michel Detheux, Francis Bitsch, Rocco Falchetto, Tewis Bouwmeester, Jeffrey Porter, Birgit Baumgarten, Keith Mansfield, José M Carballido, Klaus Seuwen, Frédéric Bassilana
GPR15 is an orphan G protein-coupled receptor (GPCR) that is found in lymphocytes. It functions as a co-receptor of simian immunodeficiency virus and HIV-2 and plays a role in the trafficking of T cells to the lamina propria in the colon and to the skin. We describe the purification from porcine colonic tissue extracts of an agonistic ligand for GPR15 and its functional characterization. In humans, this ligand, which we named GPR15L, is encoded by the gene C10ORF99 and has some features similar to the CC family of chemokines...
September 12, 2017: Science Signaling
https://www.readbyqxmd.com/read/28898928/importance-of-the-second-extracellular-loop-for-melatonin-mt1-receptor-function-and-absence-of-melatonin-binding-in-gpr50
#11
Nathalie Clement, Nicolas Renault, Jean-Luc Guillaume, Erika Cecon, Anne-Sophie Journé, Xavier Laurent, Kenjiro Tadagaki, Francis Cogé, Arnaud Gohier, Philippe Delagrange, Philippe Chavatte, Ralf Jockers
BACKGROUND AND PURPOSE: Recent crystal structures of G protein-coupled receptors (GPCRs) highlight the previously unappreciated role of the 2(nd) extracellular (E2) loop in ligand binding and gating and receptor activation. Here we studied the role of the E2 loop in the activation of the melatonin MT1 receptor (MT1 ) and in the inactivation of the closely related orphan GPR50 receptor. EXPERIMENTAL APPROACH: Chimeric MT1 -GPR50 receptors were generated and analyzed for 2-[(125) I]iodomelatonin binding, Gi /cAMP signaling and β-arrestin 2 recruitment assisted by computational molecular dynamics (MD) simulations...
September 12, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28893954/the-orphan-nuclear-receptor-nr4a3-is-involved-in-the-function-of-dendritic-cells
#12
Masanori Nagaoka, Takuya Yashiro, Yuna Uchida, Tomoaki Ando, Mutsuko Hara, Hajime Arai, Hideoki Ogawa, Ko Okumura, Kazumi Kasakura, Chiharu Nishiyama
NR4A3/NOR1 belongs to the NR4A subfamily of the nuclear hormone receptor superfamily, which is activated in a ligand-independent manner. To examine the role of NR4A3 in gene expression of dendritic cells (DCs), we introduced NR4A3 small interfering RNA (siRNA) into bone marrow-derived DCs and determined the expression levels of mRNA and proteins of cytokines, cell surface molecules, NF-κB signaling-related proteins, and transcription factors. The expression level of NR4A3 was markedly upregulated by TLR-mediated stimulation in DCs...
September 11, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28893754/failures-to-further-developing-orphan-medicinal-products-after-designation-granted-in-europe-an-analysis-of-marketing-authorisation-failures-and-abandoned-drugs
#13
Viviana Giannuzzi, Annalisa Landi, Enrico Bosone, Floriana Giannuzzi, Stefano Nicotri, Josep Torrent-Farnell, Fedele Bonifazi, Mariagrazia Felisi, Donato Bonifazi, Adriana Ceci
OBJECTIVES: The research and development process in the field of rare diseases is characterised by many well-known difficulties, and a large percentage of orphan medicinal products do not reach the marketing approval.This work aims at identifying orphan medicinal products that failed the developmental process and investigating reasons for and possible factors influencing failures. DESIGN: Drugs designated in Europe under Regulation (European Commission) 141/2000 in the period 2000-2012 were investigated in terms of the following failures: (1) marketing authorisation failures (refused or withdrawn) and (2) drugs abandoned by sponsors during development...
September 11, 2017: BMJ Open
https://www.readbyqxmd.com/read/28892130/fgl2-deteriorates-cardiac-function-in-experimental-autoimmune-myocarditis-rats-through-regulation-of-pd-1-and-inflammatory-cytokines
#14
Zhenzhong Zheng, Yinghui Yu, Ratnakar Potla, Yujing Wu, Hao Wu
PD-1 plays an important role in protecting against inflammation and myocyte damage in T cell mediated myocarditis. To understand whether FGL2 can affect the role of PD-1/PD-L1 pathway in experimental autoimmune myocarditis (EAM),we investigated the cardiac function in EAM rats overexpressing FGL2. Overexpression of FGL2 significantly decreased PD-1 and deteriorated cardiac function in autoimmune myocarditis rats. Histopathology revealed increased inflammatory cell infiltrate in EAM-FGL2 rats compared to the control groups (EAM, EAM-GFP, and NC)...
September 11, 2017: Immunology
https://www.readbyqxmd.com/read/28890840/err%C3%AE-regulates-the-growth-of-triple-negative-breast-cancer-cells-via-s6k1-dependent-mechanism
#15
Adi Y Berman, Subrata Manna, Naomi S Schwartz, Yardena E Katz, Yang Sun, Catherine A Behrmann, Jane J Yu, David R Plas, Anya Alayev, Marina K Holz
Estrogen-related receptor alpha (ERRα) is an orphan nuclear factor that is a master regulator of cellular energy metabolism. ERRα is overexpressed in a variety of tumors, including ovarian, prostate, colorectal, cervical and breast, and is associated with a more aggressive tumor and a worse outcome. In breast cancer, specifically, high ERRα expression is associated with an increased rate of recurrence and a poor prognosis. Because of the common functions of ERRα and the mTORC1/S6K1 signaling pathway in regulation of cellular metabolism and breast cancer pathogenesis, we focused on investigating the biochemical relationship between ERRα and S6K1...
2017: Signal Transduction and Targeted Therapy
https://www.readbyqxmd.com/read/28889403/do-paediatric-investigation-plans-pips-advance-paediatric-healthcare
#16
Klaus Rose, Philip D Walson
Since 2007, new drugs need a paediatric investigation plan (PIP) for EU registration. The PIPs' justifications can be traced back to concerns expressed by Shirkey that label warnings against paediatric use made children "therapeutic orphans", and the American Academy of Pediatrics' claim that all children differ considerably from adults. US legislation first encouraged, then also required, separate, adult-style safety and efficacy studies in all paediatric subpopulations. This triggered paediatric regulatory studies by the pharmaceutical industry...
September 9, 2017: Paediatric Drugs
https://www.readbyqxmd.com/read/28889016/the-effect-of-melatonin-from-slow-release-implants-on-basic-and-tlr-4-mediated-gene-expression-of-inflammatory-cytokines-and-their-receptors-in-the-choroid-plexus-in-ewes
#17
M Kowalewska, A P Herman, A Szczepkowska, J Skipor
The present study concerns the effect of melatonin from slow-release implants on the expression of genes coding interleukin-1β (Il1B), inerleukin-6 (Il6), tumour necrosis factor α (Tnf) and their receptors: IL-1 receptor type I (Il1r1) and type II (Il1r2), IL-6 receptor (Il6r) and signal transducer (Il6st), TNFα receptor type I (Tnfrsf1a) and II (Tnfrsf1b) and retinoid-related orphan receptor α (RorA) and Rev.-erbα in the ovine choroid plexus (CP) under basal and lipopolysaccharide (LPS)-challenged conditions...
September 5, 2017: Research in Veterinary Science
https://www.readbyqxmd.com/read/28884035/cooccurrence-of-chorea-acanthocytosis-and-mesial-temporal-sclerosis-a-possible-role-of-caudate-nucleus
#18
Mehri Salari, Alexander C Lehn, Masoud Etemadifar, Seyed Amir Hejazi
Chorea-acanthocytosis (ChAc) is an orphan disease, caused by mutations on chromosome 9. Epileptic seizures of mesial temporal origin can be a predominant symptom. We report on a 29-year-old woman with ChAc and bilateral MTS. Previously, few patients with coexisting ChAc and MTS were reported. The underlying pathophysiology is unknown, and further studies are needed.
2017: Case Reports in Neurological Medicine
https://www.readbyqxmd.com/read/28882502/design-and-synthesis-of-benzoacridines-as-estrogenic-and-anti-estrogenic-agents
#19
Kohei Torikai, Rintaro Koga, Xiaohui Liu, Kaoru Umehara, Tatsuya Kitano, Kenji Watanabe, Tohru Oishi, Hiroshi Noguchi, Yasuyuki Shimohigashi
Estrogens play undisputedly important physiological roles, but lifetime exposure to estrogens has also been linked to the development of breast cancer. Moreover, imbalanced estrogen levels have been associated with various symptoms such as osteoporosis and menopausal disorders. For the improvement of such estrogen imbalances, estrogenic reagents with regulatory properties have shown promising potential. Herein, we report the construction of a 12-arylbenzoacridine library via a diversity-oriented strategy that furnished non-toxic estrogenic and anti-estrogenic agents...
August 24, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28882062/remodeling-of-sensorimotor-brain-connectivity-in-gpr88-deficient-mice
#20
Tanzil Arefin, Anna E Mechling, Carole Aura Meirsman, Thomas Bienert, Neele Saskia Huebner, Hsu-Lei Lee, Sami Ben Hamida, Aliza Ehrlich, Daniel Roquet, Juergen Hennig, Dominik von Elverfeldt, Brigitte Lina Kieffer, Laura-Adela Harsan
Recent studies have demonstrated that orchestrated gene activity and expression supports synchronous activity of brain networks. However, there is a paucity of information on the consequences of single gene function on overall brain functional organization and connectivity, and how this translates at behavioral level. Here we combined mouse mutagenesis with functional and structural magnetic resonance imaging (MRI) to determine whether targeted inactivation of a single gene would modify whole brain connectivity in live animals...
September 7, 2017: Brain Connectivity
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