Read by QxMD icon Read


Elisabeth Salzer, Deniz Cagdas, Miroslav Hons, Emily M Mace, Wojciech Garncarz, Özlem Yüce Petronczki, René Platzer, Laurène Pfajfer, Ivan Bilic, Sol A Ban, Katharina L Willmann, Malini Mukherjee, Verena Supper, Hsiang Ting Hsu, Pinaki P Banerjee, Papiya Sinha, Fabienne McClanahan, Gerhard J Zlabinger, Winfried F Pickl, John G Gribben, Hannes Stockinger, Keiryn L Bennett, Johannes B Huppa, Loïc Dupré, Özden Sanal, Ulrich Jäger, Michael Sixt, Ilhan Tezcan, Jordan S Orange, Kaan Boztug
RASGRP1 is an important guanine nucleotide exchange factor and activator of the RAS-MAPK pathway following T cell antigen receptor (TCR) signaling. The consequences of RASGRP1 mutations in humans are unknown. In a patient with recurrent bacterial and viral infections, born to healthy consanguineous parents, we used homozygosity mapping and exome sequencing to identify a biallelic stop-gain variant in RASGRP1. This variant segregated perfectly with the disease and has not been reported in genetic databases. RASGRP1 deficiency was associated in T cells and B cells with decreased phosphorylation of the extracellular-signal-regulated serine kinase ERK, which was restored following expression of wild-type RASGRP1...
October 24, 2016: Nature Immunology
Dominic P Golec, Laura M Henao Caviedes, Troy A Baldwin
T cell development is dependent on the migration of progenitor cells from the bone marrow to the thymus. Upon reaching the thymus, progenitors undergo a complex developmental program that requires inputs from various highly conserved signaling pathways including the Notch and Wnt pathways. To date, Ras signaling has not been implicated in the very earliest stages of T cell differentiation, but members of a family of Ras activators called RasGRPs have been shown to be involved at multiple stages of T cell development...
September 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Xiaoping Wu, Bernt Guldbrandtsen, Mogens Sandø Lund, Goutam Sahana
Identification of genetic variants associated with feet and legs disorders (FLD) will aid in the genetic improvement of these traits by providing knowledge on genes that influence trait variations. In Denmark, FLD in cattle has been recorded since the 1990s. In this report, we used deregressed breeding values as response variables for a genome-wide association study. Bulls (5,334 Danish Holstein, 4,237 Nordic Red Dairy Cattle, and 1,180 Danish Jersey) with deregressed estimated breeding values were genotyped with the Illumina Bovine 54k single nucleotide polymorphism (SNP) genotyping array...
September 2016: Journal of Dairy Science
Andrew Ferretti, Jarrod R Fortwendel, Sarah A Gebb, Robert A Barrington
Pulmonary alveolar proteinosis (PAP) is a rare lung syndrome caused by the accumulation of surfactants in the alveoli. The most prevalent clinical form of PAP is autoimmune PAP (aPAP) whereby IgG autoantibodies neutralize GM-CSF. GM-CSF is a pleiotropic cytokine that promotes the differentiation, survival, and activation of alveolar macrophages, the cells responsible for surfactant degradation. IgG-mediated neutralization of GM-CSF thereby inhibits alveolar macrophage homeostasis and function, leading to surfactant accumulation and innate immunodeficiency...
July 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Luka Brčić, Ana Barić, Sanda Gračan, Dubravka Brdar, Vesela Torlak Lovrić, Nikolina Vidan, Tatijana Zemunik, Ozren Polašek, Maja Barbalić, Ante Punda, Vesna Boraska Perica
Hashimoto's thyroiditis (HT) is the most common form of autoimmune thyroid diseases (AITD) characterized by progressive destruction of thyroid tissue that may lead to hypothyroidism. High thyroid autoantibodies against thyroid peroxidase (TPOAb) levels are present in 90% of patients with HT and serve as a clinical marker for the detection of early AITD/HT. The main aim of our study was to test whether recently identified genetic variants associated with TPOAb are also involved in HT development. A total of 504 unrelated individuals, including 200 patients with HT and 304 controls, were involved in this study...
June 7, 2016: Autoimmunity
Christopher Smith, Janet E Buhlmann, Xiaogan Wang, Amber Bartlett, Bing Lim, Robert A Barrington
T cells undergo homeostatic expansion and acquire an activated phenotype in lymphopenic microenvironments. Restoration of normal lymphocyte numbers typically re-establishes normal homeostasis, and proinflammatory cytokine production returns to baseline. Mice deficient in guanine nucleotide exchange factor RasGRP1 exhibit dysregulated homeostatic expansion, which manifests as lymphoproliferative disease with autoantibody production. Our previous work revealed that autoreactive B cells lacking RasGRP1 break tolerance early during development, as well as during germinal center responses, suggesting that T cell-independent and T cell-dependent mechanisms are responsible...
June 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Marsilius Mues, Jeroen P Roose
T cell acute lymphoblastic leukemia/lymphoma (T-ALL) is an aggressive bone marrow cancer in children and adults, and chemotherapy often fails for relapsing patients. Molecularly targeted therapy is hindered by heterogeneity in T-ALL and mechanistic details of the affected pathways in T-ALL are needed. Deregulation of Ras signals is common in T-ALL. Ras is genetically mutated to a constitutively active form in about 15% of all hematopoietic malignancies, but there is a range of other ways to augment signaling through the Ras pathway...
May 9, 2016: Small GTPases
Agnes Czikora, Daniel J Lundberg, Adelle Abramovitz, Nancy E Lewin, Noemi Kedei, Megan L Peach, Xiaoling Zhou, Raymond C Merritt, Elizabeth A Craft, Derek C Braun, Peter M Blumberg
The C1 domain represents the recognition module for diacylglycerol and phorbol esters in protein kinase C, Ras guanine nucleotide releasing protein (RasGRP), and related proteins. RasGRP2 is exceptional in that its C1 domain has very weak binding affinity (Kd = 2890 ± 240 nm for [(3)H]phorbol 12,13-dibutyrate. We have identified four amino acid residues responsible for this lack of sensitivity. Replacing Asn(7), Ser(8), Ala(19), and Ile(21) with the corresponding residues from RasGRP1/3 (Thr(7), Tyr(8), Gly(19), and Leu(21), respectively) conferred potent binding affinity (Kd = 1...
May 20, 2016: Journal of Biological Chemistry
Otsanda Ruiz-Larrañaga, Maria Uribarri, Maria C Alcaro, Sergio Escorza-Treviño, Jokin Del Amo, Mikel Iriondo, Carmen Manzano, Paola Migliorini, Veronika Lóránd, Andone Estonba
OBJECTIVES: To replicate the association of rheumatoid arthritis (RA) susceptibility loci in an independent European sample and to assess their specificity with anti-citrullinated protein antibodies (ACPA) status. METHODS: A selection of 64 SNP previously associated with RA have been typed in a cohort of 267 RA patients (169 ACPA-positive and 98 ACPA-negative) and 152 controls from the Rheumatology Units of the University Hospital of Pisa (Italy) and the University of Pécs Medical Center (Hungary)...
March 2016: Clinical and Experimental Rheumatology
Benchang Guo, Thomas L Rothstein
B1a cells, particularly the PD-L2(+) B1a cell subset, are enriched with autoantigen-specific receptors. However, the underlying molecular mechanism responsible for the skewed selection of autoreactive B1a cells remains unclear. In this study, we find that B1 cells express only Ras guanyl nucleotide-releasing protein (RasGRP) 1, whereas B2 cells express mostly RasGRP3 and little RasGRP1. RasGRP1 is indispensable for transduction of weak signals. RasGRP1 deficiency markedly impairs B1a cell development and reduces serum natural IgM production; in particular, B1a cells that express autoantigen receptors, such as anti-phosphatidylcholine B1a cells, are virtually eliminated...
March 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Celi Sun, Julio E Molineros, Loren L Looger, Xu-Jie Zhou, Kwangwoo Kim, Yukinori Okada, Jianyang Ma, Yuan-Yuan Qi, Xana Kim-Howard, Prasenjeet Motghare, Krishna Bhattarai, Adam Adler, So-Young Bang, Hye-Soon Lee, Tae-Hwan Kim, Young Mo Kang, Chang-Hee Suh, Won Tae Chung, Yong-Beom Park, Jung-Yoon Choe, Seung Cheol Shim, Yuta Kochi, Akari Suzuki, Michiaki Kubo, Takayuki Sumida, Kazuhiko Yamamoto, Shin-Seok Lee, Young Jin Kim, Bok-Ghee Han, Mikhail Dozmorov, Kenneth M Kaufman, Jonathan D Wren, John B Harley, Nan Shen, Kek Heng Chua, Hong Zhang, Sang-Cheol Bae, Swapan K Nath
Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,478 SLE cases and 12,656 controls from six East Asian cohorts to identify new SLE susceptibility loci and better localize known loci. We identified ten new loci and confirmed 20 known loci with genome-wide significance. Among the new loci, the most significant locus was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, Pmeta = 3.75 × 10(-117), odds ratio (OR) = 2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6...
March 2016: Nature Genetics
Michael Rudnicki, Paul Perco, Barbara D Haene, Johannes Leierer, Andreas Heinzel, Irmgard Mühlberger, Ninella Schweibert, Judith Sunzenauer, Heinz Regele, Andreas Kronbichler, Pieter Mestdagh, Jo Vandesompele, Bernd Mayer, Gert Mayer
BACKGROUND: MicroRNAs (miRNAs) contribute to chronic kidney disease (CKD) progression via regulating mRNAs involved in renal homeostasis. However, their association with clinical outcome remains poorly understood. MATERIALS AND METHODS: We performed miRNA and mRNA expression profiling on renal biopsy sections by qPCR (miRNA) and microarrays (mRNA) in a discovery (n = 43) and in a validation (n = 29) cohort. miRNAs differentiating stable and progressive cases were inversely correlated with putative target mRNAs, which were further characterized by pathway analysis using KEGG pathways...
March 2016: European Journal of Clinical Investigation
Robert S Hoover, Viktor Tomilin, Lauren Hanson, Oleh Pochynyuk, Benjamin Ko
Since parathyroid hormone (PTH) is known to increase transient receptor potential vanilloid (TRPV)5 activity and decrease Na(+)-Cl(-) cotransporter (NCC) activity, we hypothesized that decreased NCC-mediated Na(+) reabsorption contributes to the enhanced TRPV5 Ca(2+) reabsorption seen with PTH. To test this, we used mDCT15 cells expressing functional TRPV5 and ruthenium red-sensitive (45)Ca(2+) uptake. PTH increased (45)Ca(2+) uptake to 8.8 ± 0.7 nmol·mg(-1)·min(-1) (n = 4, P < 0.01) and decreased NCC activity from 75...
January 15, 2016: American Journal of Physiology. Renal Physiology
O Ksionda, A A Melton, J Bache, M Tenhagen, J Bakker, R Harvey, S S Winter, I Rubio, J P Roose
Ras GTPases are activated by RasGEFs and inactivated by RasGAPs, which stimulate the hydrolysis of RasGTP to inactive RasGDP. GTPase-impairing somatic mutations in RAS genes, such as KRAS(G12D), are among the most common oncogenic events in metastatic cancer. A different type of cancer Ras signal, driven by overexpression of the RasGEF RasGRP1 (Ras guanine nucleotide-releasing protein 1), was recently implicated in pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients and murine models, in which RasGRP1 T-ALLs expand in response to treatment with interleukins (ILs) 2, 7 and 9...
July 14, 2016: Oncogene
Jun-Yan Li, Feng Tao, Xin-Xing Wu, Ying-Zi Tan, Lin He, Hao Lu
BACKGROUND: Genome-wide association studies have validated the RAS guanyl nucleotide-releasing protein 1 (RASGRP1) gene as a type 2 diabetes (T2D) susceptibility locus. AIMS: This study aimed to replicate and verify the association of RASGRP1 tag single-nucleotide polymorphisms with T2D in a Chinese Han population. METHODS: Eleven common variants of RASGRP1 were detected using TaqMan technology in 1272 healthy controls and 1234 T2D patients...
August 2015: Genetic Testing and Molecular Biomarkers
Philippe Depeille, Linda M Henricks, Robert A H van de Ven, Ed Lemmens, Chih-Yang Wang, Mary Matli, Zena Werb, Kevin M Haigis, David Donner, Robert Warren, Jeroen P Roose
The character of EGFR signals can influence cell fate but mechanistic insights into intestinal EGFR-Ras signalling are limited. Here we show that two distinct Ras nucleotide exchange factors, RasGRP1 and SOS1, lie downstream of EGFR but act in functional opposition. RasGRP1 is expressed in intestinal crypts where it restricts epithelial growth. High RasGRP1 expression in colorectal cancer (CRC) patient samples correlates with a better clinical outcome. Biochemically, we find that RasGRP1 creates a negative feedback loop that limits proliferative EGFR-SOS1-Ras signals in CRC cells...
June 2015: Nature Cell Biology
Hsin-Chou Yang, Han-Wei Li
Homozygosity disequilibrium (HD), a nonrandom sizable run of homozygosity in the genome, may be related to the evolution of populations and may also confer susceptibility to disease. No studies have investigated HD using whole genome sequencing (WGS) analysis. In this study, we used an enhanced version of Loss-Of-Heterozygosity Analysis Suite (LOHAS) software to investigate HD through analysis of real and simulated WGS data sets provided by Genetic Analysis Workshop 18. Using a local polynomial model, we derived whole-genome profiles of homozygosity intensities for 959 individuals and characterized the patterns of HD...
2014: BMC Proceedings
Michael A Meyer
As the CA1 sector has been implicated to play a key role in memory formation, a dedicated search for highly expressed genes within this region was made from an on-line atlas of gene expression within the mouse brain (GENSAT). From a data base of 1013 genes, 16 were identified that had selective localization of gene expression within the CA1 region, and included Angpt2, ARHGEF6, CCK, Cntnap1, DRD3, EMP1, Epha2, Itm2b, Lrrtm2, Mdk, PNMT, Ppm1e, Ppp2r2d, RASGRP1, Slitrk5, and Sstr4. Of the 16 identified, the most selective and intense localization for both adult and post-natal day 7 was noted for ARHGEF6, which is known to be linked to non-syndromic mental retardation, and has also been localized to dendritic spines...
April 22, 2014: Neurology International
Mateusz Poltorak, Ines Meinert, James C Stone, Burkhart Schraven, Luca Simeoni
The duration and/or the magnitude of Ras-Erk activation are known to be crucial for cell-fate decisions. In T cells, sustained Erk activation correlates with differentiation/proliferation, whereas transient Erk activation parallels with unresponsiveness/apoptosis. The mechanism by which Son of sevenless (Sos) proteins and Ras guanyl-releasing protein 1 (RasGRP1) contribute to dynamics of Erk activation in mature T cells is not yet known. Here, we have assessed this issue using stimuli inducing either transient or sustained TCR signaling and RNA interference mediated suppression of Sos1, Sos2, and RasGRP1 expression in primary human T cells...
May 2014: European Journal of Immunology
Amrish Sharma, Lauren L Fonseca, Cynthia Rajani, Jodi K Yanagida, Yuka Endo, J Mark Cline, James C Stone, Junfang Ji, Joe W Ramos, Patricia S Lorenzo
Ras is frequently activated in cutaneous squamous cell carcinoma, a prevalent form of skin cancer. However, the pathways that contribute to Ras-induced transformation have not been entirely elucidated. We have previously demonstrated that in transgenic mice, overexpression of the Ras activator RasGRP1 promotes the formation of spontaneous skin tumors and enhances malignant progression in the multistage carcinogenesis skin model that relies on the oncogenic activation of H-Ras. Utilizing a RasGRP1 knockout mouse model (RasGRP1 KO), we now show that lack of RasGRP1 reduced the susceptibility to skin tumorigenesis...
May 2014: Carcinogenesis
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"