A Viral Immunoevasin Controls Innate Immunity by Targeting the Prototypical Natural Killer Cell Receptor Family

Natural killer (NK) cells play a key role in innate immunity by detecting alterations in self and non-self ligands via paired NK cell receptors (NKRs). Despite identification of numerous NKR-ligand interactions, physiological ligands for the prototypical NK1.1 orphan receptor remain elusive. Here, we identify a viral ligand for the inhibitory and activating NKRP1(NK1.1) receptors. This murine cytomegalovirus(MCMV)-encoded protein, m12, restrains NK cell effector function by directly engaging the inhibitory NKR-P1B receptor. However, m12 also interacts with the activating NKR-P1A/C receptors to counterbalance m12 decoy function. Structural analyses reveal that m12 sequesters a large NKR-P1 surface area via a ‘‘polar claw’’ mechanism. Polymorphisms in, and ablation of, the viral m12 protein and host NKR-P1B/C alleles impact NK cell responses in vivo. Thus, we identify the long-sought foreign ligand for this key immunoregulatory NKR family and reveal how it controls the evolutionary balance of immune recognition during host-pathogen interplay

Application of alternative anthropometric measurements to predict metabolic syndrome

OBJECTIVE: The association between rarely used anthropometric measurements (e.g., mid-upper arm, forearm, and calf circumference) and metabolic syndrome has not been proven. The aim of this study was to assess whether mid-upper arm, forearm, calf, and waist circumferences, as well as waist/height ratio and waist-to-hip ratio, were associated with metabolic syndrome. METHODS: We enrolled 387 subjects (340 women, 47 men) who were admitted to the obesity outpatient department of Istanbul Medeniyet University Goztepe Training and Research Hospital between September 2010 and December 2010. The following measurements were recorded: waist circumference, hip circumference, waist/height ratio, waist-to-hip ratio, mid-upper arm circumference, forearm circumference, calf circumference, and body composition. Fasting blood samples were collected to measure plasma glucose, lipids, uric acid, insulin, and HbA1c. RESULTS: The odds ratios for visceral fat (measured via bioelectric impedance), hip circumference, forearm circumference, and waist circumference/hip circumference were 2.19 (95% CI, 1.30-3.71), 1.89 (95% CI, 1.07-3.35), 2.47 (95% CI, 1.24-4.95), and 2.11(95% CI, 1.26-3.53), respectively. The bioelectric impedance-measured body fat percentage correlated with waist circumference only in subjects without metabolic syndrome; the body fat percentage was negatively correlated with waist circumference/hip circumference in the metabolic syndrome group. All measurements except for forearm circumference were equally well correlated with the bioelectric impedance-measured body fat percentages in both groups. Hip circumference was moderately correlated with bioelectric impedance-measured visceral fat in subjects without metabolic syndrome. Muscle mass (measured via bioelectric impedance) was weakly correlated with waist and forearm circumference in subjects with metabolic syndrome and with calf circumference in subjects without metabolic syndrome. CONCLUSION: Waist circumference was not linked to metabolic syndrome in obese and overweight subjects; however, forearm circumference, an unconventional but simple and appropriate anthropometric index, was associated with metabolic syndrome and bioelectric impedance-measured visceral fat, hip circumference, and waist-to-hip ratio

MEFV mutation analysis in Turkish familial Mediterranean fever families.

WOS: 000082879802752

miRNA-95 mediates radioresistance in tumors by targeting the sphingolipid phosphatase SGPP1

Abstract Radiation resistance poses a major clinical challenge in cancer treatment, but little is known about how microRNA (miR) may regulate this phenomenon. In this study, we used next-generation sequencing to perform an unbiased comparison of miR expression in PC3 prostate cancer cells rendered resistant to fractionated radiation treatment. One miR candidate found to be upregulated by ionizing radiation was miR-95, the enforced expression of which promoted radiation resistance in a variety of cancer cells. miR-95 overexpression recapitulated an aggressive phenotype including increased cellular proliferation, deregulated G2–M checkpoint following ionizing radiation, and increased invasive potential. Using combined in silico prediction and microarray expression analyses, we identified and validated the sphingolipid phosphatase SGPP1, an antagonist of sphingosine-1-phosphate signaling, as a target of miR-95 that promotes radiation resistance. Consistent with this finding, cell treatment with FTY720, a clinically approved small molecule inhibitor of S1P signaling, sensitized miR-95 overexpressing cells to radiation treatment. In vivo assays extended the significance of these results, showing that miR-95 overexpression increased tumor growth and resistance to radiation treatment in tumor xenografts. Furthermore, reduced tumor necrosis and increased cellular proliferation were seen after radiation treatment of miR-95 overexpressing tumors compared with control tumors. Finally, miR-95 expression was increased in human prostate and breast cancer specimens compared with normal tissue. Together, our work reveals miR-95 expression as a critical determinant of radiation resistance in cancer cells. Cancer Res; 73(23); 6972–86. ©2013 AACR.</jats:p