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https://www.readbyqxmd.com/read/28340352/human-epistatic-interaction-controls-il7r-splicing-and-increases-multiple-sclerosis-risk
#1
Gaddiel Galarza-Muñoz, Farren B S Briggs, Irina Evsyukova, Geraldine Schott-Lerner, Edward M Kennedy, Tinashe Nyanhete, Liuyang Wang, Laura Bergamaschi, Steven G Widen, Georgia D Tomaras, Dennis C Ko, Shelton S Bradrick, Lisa F Barcellos, Simon G Gregory, Mariano A Garcia-Blanco
Multiple sclerosis (MS) is an autoimmune disorder where T cells attack neurons in the central nervous system (CNS) leading to demyelination and neurological deficits. A driver of increased MS risk is the soluble form of the interleukin-7 receptor alpha chain gene (sIL7R) produced by alternative splicing of IL7R exon 6. Here, we identified the RNA helicase DDX39B as a potent activator of this exon and consequently a repressor of sIL7R, and we found strong genetic association of DDX39B with MS risk. Indeed, we showed that a genetic variant in the 5' UTR of DDX39B reduces translation of DDX39B mRNAs and increases MS risk...
March 23, 2017: Cell
https://www.readbyqxmd.com/read/28340094/nlrp2-is-a-suppressor-of-nf-%C3%A6-b-signaling-and-hla-c-expression-in-human-trophoblasts
#2
Tamara Tilburgs, Torsten B Meissner, Leonardo M R Ferreira, Arend Mulder, Kiran Musunuru, Junqiang Ye, Jack L Strominger
During human pregnancy, fetal extravillous trophoblasts (EVT) play a key role in the regulation of maternal T cell and NK cell responses. EVT display a unique combination of Human Leukocyte Antigens (HLA); EVT do not express HLA-A and HLA-B, but do express HLA-C, HLA-E and HLA-G. The mechanisms establishing this unique HLA expression pattern have not been fully elucidated. The MHC class I and class II transcriptional activators NLRC5 and CIITA are expressed neither by EVT nor by the EVT model cell line JEG3, which has an MHC expression pattern identical to that of EVT...
March 7, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/28339909/il-17-and-cd40-ligand-synergistically-stimulate-the-chronicity-of-diabetic-nephropathy
#3
Huey-Liang Kuo, Chiu-Ching Huang, Tze-Yi Lin, Ching-Yuang Lin
Background.: Early stages of diabetic nephropathy (DN) are characterized by an influx of inflammatory cells. Interactions between infiltrating T cells and podocytes may play an important role in the ongoing inflammatory response and remodelling. The aim of this study was to explore the role of IL-17 and CD40 ligand (CD40L) in DN. Methods.: The study design involved a case series. Kidney biopsy samples of 69 patients with type 2 diabetes were assessed for the presence of CD4 +  IL-17 +  T cells...
March 1, 2017: Nephrology, Dialysis, Transplantation
https://www.readbyqxmd.com/read/28335502/catechins-and-their-therapeutic-benefits-to-inflammatory-bowel-disease
#4
REVIEW
Fei-Yan Fan, Li-Xuan Sang, Min Jiang
Catechins are natural polyphenolic phytochemicals that exist in food and medicinal plants, such as tea, legume and rubiaceae. An increasing number of studies have associated the intake of catechins-rich foods with the prevention and treatment of chronic diseases in humans, such as inflammatory bowel disease (IBD). Some studies have demonstrated that catechins could significantly inhibit the excessive oxidative stress through direct or indirect antioxidant effects and promote the activation of the antioxidative substances such as glutathione peroxidases (GPO) and glutathione (GSH), reducing the oxidative damages to the colon...
March 19, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28334900/cdk12-regulates-alternative-last-exon-mrna-splicing-and-promotes-breast-cancer-cell-invasion
#5
Jerry F Tien, Alborz Mazloomian, S-W Grace Cheng, Christopher S Hughes, Christalle C T Chow, Leanna T Canapi, Arusha Oloumi, Genny Trigo-Gonzalez, Ali Bashashati, James Xu, Vicky C-D Chang, Sohrab P Shah, Samuel Aparicio, Gregg B Morin
CDK12 (cyclin-dependent kinase 12) is a regulatory kinase with evolutionarily conserved roles in modulating transcription elongation. Recent tumor genome studies of breast and ovarian cancers highlighted recurrent CDK12 mutations, which have been shown to disrupt DNA repair in cell-based assays. In breast cancers, CDK12 is also frequently co-amplified with the HER2 (ERBB2) oncogene. The mechanisms underlying functions of CDK12 in general and in cancer remain poorly defined. Based on global analysis of mRNA transcripts in normal and breast cancer cell lines with and without CDK12 amplification, we demonstrate that CDK12 primarily regulates alternative last exon (ALE) splicing, a specialized subtype of alternative mRNA splicing, that is both gene- and cell type-specific...
March 17, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28333195/genome-wide-genetic-analyses-highlight-mitogen-activated-protein-kinase-mapk-signaling-in-the-pathogenesis-of-endometriosis
#6
Outi Uimari, Nilufer Rahmioglu, Dale R Nyholt, Katy Vincent, Stacey A Missmer, Christian Becker, Andrew P Morris, Grant W Montgomery, Krina T Zondervan
STUDY QUESTION: Do genome-wide association study (GWAS) data for endometriosis provide insight into novel biological pathways associated with its pathogenesis? SUMMARY ANSWER: GWAS analysis uncovered multiple pathways that are statistically enriched for genetic association signals, analysis of Stage A disease highlighted a novel variant in MAP3K4, while top pathways significantly associated with all endometriosis and Stage A disease included several mitogen-activated protein kinase (MAPK)-related pathways...
February 9, 2017: Human Reproduction
https://www.readbyqxmd.com/read/28332901/regulation-of-humoral-immunity-by-gut-microbial-products
#7
Myunghoo Kim, Chang H Kim
The intestinal tract provides ideal niches for several different microbial species, which are collectively called the gut microbiota. A key host immune effector that controls the microbiota and prevents mucosal infection is IgA. Gut microbiota-derived factors are largely classified into molecular pattern recognition receptor ligands and nutrient-derived metabolites including short-chain fatty acids and adenosine triphosphate. Along with host-derived factors such as retinoic acid, various cytokines and cytokine-like molecules, gut microbial products profoundly shape B cell responses...
February 28, 2017: Gut Microbes
https://www.readbyqxmd.com/read/28331448/antibody-mediated-rejection-a-review
#8
Jorge Carlos Garces, Sixto Giusti, Catherine Staffeld-Coit, Humberto Bohorquez, Ari J Cohen, George E Loss
BACKGROUND: Chronic antibody injury is a serious threat to allograft outcomes and is therefore the center of active research. In the continuum of allograft rejection, the development of antibodies plays a critical role. In recent years, an increased recognition of molecular and histologic changes has provided a better understanding of antibody-mediated rejection (AMR), as well as potential therapeutic interventions. However, several pathways are still unknown, which accounts for the lack of efficacy of some of the currently available agents that are used to treat rejection...
2017: Ochsner Journal
https://www.readbyqxmd.com/read/28331190/natural-killer-cell-activation-contributes-to-hepatitis-b-viral-control-in-a-mouse-model
#9
Shiwen Tong, Guangze Liu, Minghong Li, Xiumei Li, Qian Liu, Hong Peng, Shiying Li, Hong Ren, Wenwei Yin
The roles of CD4 + T cells and CD8 + T cells in hepatitis B virus (HBV) infection have been well documented. However, the role of innate immunity in HBV infection remains obscure. Here we examined the effect of activation of innate immunity by polyinosinic: polycytidylic acid (PolyI:C) on HBV infection. A chronic HBV replication mouse model was established by hydrodynamical injection of pAAV/HBV1.2 plasmid into C57BL/6 mice. We found that HBV did not seem to induce an active NK-cell response in the mouse model...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28331180/ccr5-promoter-activity-correlates-with-hiv-disease-progression-by-regulating-ccr5-cell-surface-expression-and-cd4-t-cell-apoptosis
#10
Anjali Joshi, Erin B Punke, Melina Sedano, Bethany Beauchamp, Rima Patel, Cassady Hossenlopp, Ogechika K Alozie, Jayanta Gupta, Debabrata Mukherjee, Himanshu Garg
CCR5 is the major co-receptor for HIV and polymorphisms in the CCR5 gene as well as promoter region that alter cell surface expression have been associated with disease progression. We determined the relationship between CCR5 promoter polymorphisms and CD4 decline and other immunopathological features like immune activation and CD4+ T cell apoptosis in HIV patients. CCR5 promoter haplotype HHC was significantly associated with higher CD4 counts in patients. The relative promoter activity (RPA) of each haplotype was determined in vitro and combined promoter activity based on both alleles (CRPA) was assigned to each patients...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28331090/hili-inhibits-hiv-replication-in-activated-t-cells
#11
B Matija Peterlin, Pingyang Liu, Xiaoyun Wang, Daniele Cary, Wei Shao, Marie Leoz, Tian Hong, Tao Pan, Koh Fujinaga
Piwil proteins restrict the replication of mobile genetic elements in the germline. They are also expressed in many transformed cell lines. In this report, we discovered that the human piwil 2 (hili) can also inhibit HIV replication, especially in activated CD4+ T cells that are the preferred target cells for this virus in the infected host. Although resting cells did not express hili, it was rapidly induced following T cell activation. In these cells and transformed cell lines, depletion of hili increased levels of viral proteins and new viral particles...
March 22, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28331088/bst-2-expression-modulates-small-cd4-mimetic-sensitization-of-hiv-1-infected-cells-to-adcc
#12
Jonathan Richard, Jérémie Prévost, Benjamin von Bredow, Shilei Ding, Nathalie Brassard, Halima Medjahed, Mathieu Coutu, Bruno Melillo, Frédéric Bibollet-Ruche, Beatrice H Hahn, Daniel E Kaufmann, Amos B Smith, Joseph Sodroski, Daniel Sauter, Frank Kirchhoff, Katrina Gee, Stuart J Neil, David T Evans, Andrés Finzi
Antibodies recognizing conserved CD4-induced (CD4i) epitopes on HIV-1 Env and able to mediate antibody-dependent cellular cytotoxicity (ADCC) have been shown to be present in sera from most HIV-1-infected individuals. These antibodies preferentially recognize Env in its CD4-bound conformation. CD4 downregulation by Nef and Vpu dramatically reduces exposure of CD4i HIV-1 Env epitopes and therefore reduce the susceptibility of HIV-1-infected cells to ADCC mediated by HIV+ sera. Importantly, this mechanism of immune evasion can be circumvented with small-molecule CD4-mimetics (CD4mc) which are able to transition Env into the CD4-bound conformation and sensitize HIV-1-infected cells to ADCC mediated by HIV+ sera...
March 22, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28330473/dynamic-and-specific-immune-responses-against-multiple-tumor-antigens-were-elicited-in-patients-with-hepatocellular-carcinoma-after-cell-based-immunotherapy
#13
Yanyan Han, Yeting Wu, Chou Yang, Jing Huang, Yabing Guo, Li Liu, Ping Chen, Dongyun Wu, Junyun Liu, Jin Li, Xiangjun Zhou, Jinlin Hou
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cancers in China and frequently occurs with chronic hepatitis B virus infection. To investigate whether cell-based cancer immunotherapy induces tumor specific immune responses in patients with HCC and provides clinical benefits, as well as to elucidate the most immunogenic tumor associated antigens (TAAs), multiple antigen stimulating cellular therapy (MASCT) was applied in addition to standard of care. METHODS: Mature dendritic cells (DCs) and activated T cells prepared for MASCT were generated from autologous peripheral blood mononuclear cells (PBMCs)...
March 22, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28330372/car-t-cell-therapy-progress-and-prospects
#14
Olivia Wilkins, Allison May Keeler, Terence R Flotte
Lentivirus-mediated transduction of autologous T-cells with a chimeric antigen receptor (CAR) to confer a desired epitope-specificity as a targeted immunotherapy for cancer has been among the first human gene therapy techniques to demonstrate widespread therapeutic efficacy. Other approaches to using gene therapy to enhance anti-tumor immunity have been less specific and less effective. These included amplification, marking, and cytokine transduction of tumor infiltrating lymphocytes (TIL), recombinant virus-based expression of tumor antigens as a tumor vaccine, and transduction of antigen-presenting cells (APCs) with tumor antigens...
March 23, 2017: Human Gene Therapy Methods
https://www.readbyqxmd.com/read/28328926/frequency-and-role-of-nkp46-and-nkg2a-in-hepatitis-b-virus-infection
#15
Teppei Yoshioka, Tomohide Tatsumi, Takuya Miyagi, Kaori Mukai, Kumiko Nishio, Akira Nishio, Yoshinobu Yokoyama, Takahiro Suda, Tadashi Kegasawa, Minoru Shigekawa, Hayato Hikita, Ryotaro Sakamori, Tetsuo Takehara
BACKGROUND AND AIM: Natural Killer (NK) cells are involved in the control of viral infection. However, the role of NK cells in chronic hepatitis B (CHB) remains unclear. This study investigated the frequencies and roles of NK cells in CHB, with a focus on activating receptor NKp46 and inhibitory receptor NKG2A. PATIENTS/METHOD: Peripheral blood lymphocytes were obtained from 71 CHB patients and 37 healthy subjects (HS). The expressions of NKp46 and NKG2A were analyzed using flow cytometry...
2017: PloS One
https://www.readbyqxmd.com/read/28327181/soluble-oligomeric-amyloid-%C3%AE-induces-calcium-dyshomeostasis-that-precedes-synapse-loss-in-the-living-mouse-brain
#16
Michal Arbel-Ornath, Eloise Hudry, Josiah R Boivin, Tadafumi Hashimoto, Shuko Takeda, Kishore V Kuchibhotla, Steven Hou, Carli R Lattarulo, Arianna M Belcher, Naomi Shakerdge, Pariss B Trujillo, Alona Muzikansky, Rebecca A Betensky, Bradley T Hyman, Brian J Bacskai
BACKGROUND: Amyloid-β oligomers (oAβ) are thought to mediate neurotoxicity in Alzheimer's disease (AD), and previous studies in AD transgenic mice suggest that calcium dysregulation may contribute to these pathological effects. Even though AD mouse models remain a valuable resource to investigate amyloid neurotoxicity, the concomitant presence of soluble Aβ species, fibrillar Aβ, and fragments of amyloid precursor protein (APP) complicate the interpretation of the phenotypes. METHOD: To explore the specific contribution of soluble oligomeric Aβ (oAβ) to calcium dyshomeostasis and synaptic morphological changes, we acutely exposed the healthy mouse brain, at 3 to 6 months of age, to naturally occurring soluble oligomers and investigated their effect on calcium levels using in vivo multiphoton imaging...
March 21, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28326297/coronary-artery-calcium-score-and-bone-metabolism-a-pilot-study-in-postmenopausal-women
#17
Pooneh Salari, Abbasali Keshtkar, Shapour Shirani, Leila Mounesan
BACKGROUND: Since 1991 many studies evaluated the link between cardiovascular diseases and osteoporosis, two age-related conditions, but the main common pathologic pathway has not been determined yet. The histological similarity between arterial calcified plaque and bone matrix and involvement of similar cells and mediators provide a special field of research. Therefore in the present study, we aimed to evaluate the relationship between coronary artery calcium score (CACS) as a surrogate marker of atherosclerosis and bone mediators and parameters in postmenopausal women...
February 2017: Journal of Bone Metabolism
https://www.readbyqxmd.com/read/28325905/evidence-for-c1q-mediated-crosslinking-of-cd33-lair-1-inhibitory-immunoreceptors-and-biological-control-of-cd33-lair-1-expression
#18
Myoungsun Son, Betty Diamond, Bruce T Volpe, Cynthia B Aranow, Meggan C Mackay, Frances Santiago-Schwarz
C1q collagen-like region (CLR) engaging and activating the LAIR-1 inhibitory immunoreceptor represents a non-complement mechanism for maintaining immune quiescence. Given the binding promiscuity of C1q's globular region (gC1q), we hypothesized that C1q concurrently associates with distinct inhibitory immunoreceptors to produce C1q-mediated modulatory networking. Like LAIR-1, CD33 inhibitory immunoreceptors are highly expressed on monocytes. Binding CD33 restricts cell activation/differentiation; however, natural ligands for CD33 remain elusive...
March 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28325822/structural-basis-for-chemokine-recognition-by-a-g-protein-coupled-receptor-and-implications-for-receptor-activation
#19
Joshua J Ziarek, Andrew B Kleist, Nir London, Barak Raveh, Nicolas Montpas, Julien Bonneterre, Geneviève St-Onge, Crystal J DiCosmo-Ponticello, Chad A Koplinski, Ishan Roy, Bryan Stephens, Sylvia Thelen, Christopher T Veldkamp, Frederick D Coffman, Marion C Cohen, Michael B Dwinell, Marcus Thelen, Francis C Peterson, Nikolaus Heveker, Brian F Volkman
Chemokines orchestrate cell migration for development, immune surveillance, and disease by binding to cell surface heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs). The array of interactions between the nearly 50 chemokines and their 20 GPCR targets generates an extensive signaling network to which promiscuity and biased agonism add further complexity. The receptor CXCR4 recognizes both monomeric and dimeric forms of the chemokine CXCL12, which is a distinct example of ligand bias in the chemokine family...
March 21, 2017: Science Signaling
https://www.readbyqxmd.com/read/28324015/paternally-inherited-dlk1-deletion-associated-with-familial-central-precocious-puberty
#20
Andrew Dauber, Marina Cunha-Silva, Delanie B Macedo, Vinicius N Brito, Ana Paula Abreu, Stephanie A Roberts, Luciana R Montenegro, Melissa Andrew, Andrew Kirby, Matthew T Weirauch, Guillaume Labilloy, Danielle S Bessa, Rona S Carroll, Dakota C Jacobs, Patrick E Chappell, Berenice B Mendonca, David Haig, Ursula B Kaiser, Ana Claudia Latronico
Context: Central precocious puberty (CPP) results from premature activation of the hypothalamic-pituitary-gonadal axis. Few genetic causes of CPP have been identified with the most common being mutations in the paternally expressed imprinted gene MKRN3. Objective: To identify the genetic etiology of CPP in a large multigenerational family. Design: Linkage analysis followed by whole genome sequencing was performed in a family with 5 female members with nonsyndromic CPP...
January 27, 2017: Journal of Clinical Endocrinology and Metabolism
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