Joyce, David W. Novina, Eirini P. Papapetrou, Akiko Shimamura. Pulmonary fibrosis is a devastating disease characterized by accumulation of activated fibroblasts and scarring in the lung. While fibroblast activation in physiological wound repair reverses spontaneously, fibroblast activation in fibrosis is aberrantly sustained.
Here we identified histone 3 lysine 9 methylation H3K9me as a critical epigenetic modification that sustains fibroblast activation by repressing the transcription of genes essential to returning lung fibroblasts to an inactive state. Our results demonstrate that epigenetic silencing mediated by H3K9 methylation is essential for both biochemical and biomechanical fibroblast activation and that targeting this epigenetic pathway may provide therapeutic benefit by returning lung fibroblasts to quiescence.
Meridew, Dakota L. Haak, Aja Aravamudhan, Anja C. Roden, Y. Prakash, Gwen Lomberk, Raul A. Urrutia, Daniel J. Benign prostatic hyperplasia BPH is the most common cause of lower urinary tract symptoms in men. Current treatments target prostate physiology rather than BPH pathophysiology and are only partially effective. Here, we applied next-generation sequencing to gain insight into BPH. In particular, BPH tissues exhibited enrichment of myofibroblast subsets but also depletion of neuroendocrine cells and an estrogen receptor—positive fibroblast cell type residing near the epithelium.
By whole-exome sequencing, we uncovered somatic single-nucleotide variants in BPH, of uncertain pathogenic significance but indicative of clonal cell expansions. Thus, genomic characterization of BPH has identified a clinically relevant stromal signature and new candidate disease pathways including a likely role for BMP5 signaling and reveals BPH to be not merely a hyperplasia, but rather a fundamental relandscaping of cell types.
Lance W. Foley, Sujay Vennam, Robert T. Brooks, Robert B. West, Jonathan R. Despite current immunosuppressive strategies, long-term lung transplant outcomes remain poor due to rapid allogenic responses. Using a stringent mouse model of allo-airway transplantation, we identified the CCR4-ligand axis as a central node driving secondary lymphoid tissue homing and activation of the allogeneic T cells that prevent long-term allograft survival.
CCR4 deficiency on transplant recipient T cells diminished allograft injury and when combined with CTLA4-Ig led to lung allograft accommodation lasting longer than in any previous study to our knowledge. Thus, we identify CCR4-ligand interactions as a central mechanism driving allogeneic transplant rejection and suggest it as a potential target to enhance long-term lung transplant survival.
Weigt, Aric L. Gregson, Sophie X. Song, Michael C. Fishbein, Cory M. Hogaboam, David M. Sayah, Joseph P. Keane, David G. Brooks, John A. Most at risk are individuals who reconstitute their T cell pool by proliferating residual cells, rather than producing new T cells in the thymus, raising the possibility that autoimmunity might be prevented by increasing thymopoiesis. Keratinocyte growth factor palifermin promotes thymopoiesis in nonhuman primates. No difference was observed in the rate of autoimmunity between the 2 groups.
Alasdair J. Sadler, J. William L. Georgieva, Adam E. Douek, John D. Isaacs, Joanne L. Impaired insulin secretion in type 2 diabetes T2D is linked to reduced insulin granule docking, disorganization of the exocytotic site, and impaired glucose-dependent facilitation of insulin exocytosis. The compartmentalization of events occurs within regions defined by concurrent or recent membrane-resident secretory granules.
Mechanistically, multichannel Kv2. Thus, a glucose-dependent compartmentalization of fusion, regulated in part by a structural role for Kv2. Manning Fox, Herbert Y. Gaisano, Patrick E. TRIOBP remodels the cytoskeleton by forming unusually dense F-actin bundles and is implicated in human cancer, schizophrenia, and deafness. Using 3 new Triobp mouse models, we report that TRIOBP-5 is essential for thickening bundles of F-actin in rootlets, establishing their mature dimensions and for stiffening supporting cells of the auditory sensory epithelium.
The coiled-coil domains of this isoform are required for reinforcement and maintenance of stereocilia rootlets. A loss of TRIOBP-5 in mouse results in dysmorphic rootlets that are abnormally thin in the cuticular plate but have increased widths and lengths within stereocilia cores, and causes progressive deafness recapitulating the human phenotype. Tatsuya Katsuno, Inna A. Belyantseva, Alexander X. Crump, Ronald S. Riordan, Elisabeth A. Wilson, Tracy S. Frolenkov, Thomas B. Friedman, Shin-ichiro Kitajiri.
Long-term effectiveness of these therapies is not yet fully known. Moreover, the existence of alternative therapies has resulted in an urgent need to identify patient characteristics that predict response to each therapy. These patients were followed for a period of 18—66 months, after which they were classified by an expert as responders, partial responders, or nonresponders. Correlations between baseline demographic and clinical characteristics, as well as plasma biomarkers and response to therapy, were investigated.
We determined that disease severity, sex, and native TTR concentration at the outset of treatment were the most relevant predictors of response to tafamidis. Plasma tafamidis concentration after 12 months of therapy was also a predictor of response for male patients. Using these variables, we built a model to predict responsiveness to tafamidis.
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Moreover, we created a predictive model that can be potentially used in the clinical setting to inform patients and clinicians in their therapeutic decisions. Brighty, David L. Powers, Evan T. Powers, Teresa Coelho, Jeffery W. The diagnostic biomarker of a CASH in the prior year was derived as that minimizing the Akaike information criterion and validated using machine learning, and was compared with the prognostic CASH biomarker predicting bleeding in the subsequent year. Biomarkers were longitudinally followed in a subset of cases.
The biomarkers may be applied for risk stratification in clinical trials and developed as a tool in clinical practice. Whitehead, Mark L. Kahn, Mark H. Ginsberg, Douglas A. Marchuk, Issam A. Th1 and Th17 are important in the pathogenesis of autoimmune diseases and they depend on glycolysis as a source of energy. Based on these findings we hypothesized that CaMK4 promotes glycolysis. Pull-down of CaMK4 and mass spectrometry identified pyruvate kinase muscle isozyme PKM , the final rate-limiting enzyme in glycolysis, as a binding partner. Silencing or pharmacological inhibition of PKM2 reduced glycolysis and in vitro differentiation to Th1 and Th17 cells, while PKM2 overexpression restored Th17 cell differentiation.
PKM2 represents a therapeutic target for T cell—dependent autoimmune diseases. Orite, Milena Vukelic, Maria G. Tsokos, Nobuya Yoshida, George C. African Americans develop end-stage renal disease at a higher rate compared with European Americans due to 2 polymorphisms G1 and G2 risk variants in the apolipoprotein L1 APOL1 gene common in people of African ancestry. Although this compelling genetic evidence provides an exciting opportunity for personalized medicine in chronic kidney disease, drug discovery efforts have been greatly hindered by the fact that APOL1 expression is lacking in rodents.
Here, we describe a potentially novel physiologically relevant genomic mouse model of APOL1-associated renal disease that expresses human APOL1 from the endogenous human promoter, resulting in expression in similar tissues and at similar relative levels as humans. Mariam Aghajan, Sheri L. Booten, Magnus Althage, Christopher E. Watt, Jeffery A. Engelhardt, Brett P. The increased formation of methylglyoxal MG under hyperglycemia is associated with the development of microvascular complications in patients with diabetes mellitus; however, the effects of elevated MG levels in vivo are poorly understood.
In zebrafish, a transient knockdown of glyoxalase 1, the main MG detoxifying system, led to the elevation of endogenous MG levels and blood vessel alterations. Thus, the data have identified a defective MG detoxification as a metabolic prerequisite and glyoxalase 1 alterations as a genetic susceptibility to the development of type 2 diabetes mellitus under high nutrition intake. Elisabeth Lodd, Lucas M. Wiggenhauser, Jakob Morgenstern, Thomas H. Tabler, David P. Wohlfart, Peter P. Nawroth, Jens Kroll. During chronic HIV infection, immune cells become increasingly dysfunctional and exhausted.
Little is known about how immune functions are restored after initiation of antiretroviral therapy ART. In this study, we assessed cellular and metabolic activity and evaluated the effect of individual antiretrovirals on cellular subsets ex vivo in ART-treated and treatment-naive chronically HIV-infected individuals. We observed that cellular respiration was significantly decreased in most immune cells in chronic HIV infection. This was particularly the case for individuals receiving integrase strand transfer inhibitors. There was no effect on glycolysis, consistent with impaired mitochondrial function.
We detected increased levels of mitochondrial ROS and mitochondrial mass. Schultz, Patrick Juszczak, Julie A. Ake, Anuradha Ganesan, Jason F. Okulicz, Merlin L. Burgess, Stefan Esser, Nelson L. Michael, Brian K. Agan, Hendrik Streeck. Inhibition of Bruton tyrosine kinase BTK is a breakthrough therapy for certain B cell lymphomas and B cell chronic lymphatic leukemia. Covalent BTK inhibitors e. This has led to the development of noncovalent BTK inhibitors that do not require binding to cysteine C These new compounds are now entering clinical trials.
In a systematic BTK mutagenesis screen, we identify residues that are critical for the activity of noncovalent inhibitors. These include a gatekeeper residue T and mutations in the kinase domain. Strikingly, co-occurrence of gatekeeper and kinase domain lesions LM, EG, FL, LP in cis results in a to fold gain of BTK kinase activity and de novo transforming potential in vitro and in vivo.
Computational BTK structure analyses reveal how these lesions disrupt an intramolecular mechanism that attenuates BTK activation. Seshan, Robert Abel, Michael R. Here, we test the theory that dietary carbohydrate intolerance i. Protein was constant and fat was exchanged isocalorically for carbohydrate across all diets. Carbohydrate restriction also improved abnormal fatty acid composition, an emerging MetS feature. Despite containing 2. Parker N. Hyde, Teryn N. Sapper, Christopher D. Crabtree, Richard A. LaFountain, Madison L. McSwiney, Ryan M. Dickerson, Vincent J. Miller, Debbie Scandling, Orlando P.
Simonetti, Stephen D.
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Phinney, William J. Kraemer, Sarah A. King, Ronald M. Krauss, Jeff S. The activation and recruitment of NK cells to the site of viral infection are crucial for virus control. However, it remains largely unknown what controls the recruitment of the activated NK cells to the infection site. Taken together, our results reveal a potentially previously unknown role for PARP-1—dependent CCL2 production in NK cell migration and viral control and may provide important insights into the design of effective NK cell—based therapies for viral infections and cancer.
Myasthenia gravis MG is a chronic autoimmune disorder characterized by muscle weakness and caused by pathogenic autoantibodies that bind to membrane proteins at the neuromuscular junction. Most patients have autoantibodies against the acetylcholine receptor AChR , but a subset of patients have autoantibodies against muscle-specific tyrosine kinase MuSK instead.
MuSK is an essential component of the pathway responsible for synaptic differentiation, which is activated by nerve-released agrin. We sought to establish individual MuSK autoantibody clones so that the autoimmune mechanisms could be better understood. Fichtner, Erik S. Nowak, Kevin C. An imbalance of nephroprotective factors and renal damaging molecules contributes to development and progression of chronic kidney disease CKD.
We investigated associations of renoprotective factor gene expression patterns with CKD severity and outcome. Gene expression profiles of previously reported renoprotective factors were analyzed in a discovery cohort in renal biopsies of 63 CKD patients. Downregulation of dicarbonyl and L-xylulose reductase DCXR showed the strongest association with disease progression. This significant association was validated in an independent set of patients with nephrotic syndrome from the multicenter NEPTUNE cohort.
Reduced expression of DCXR was significantly associated with degree of histological damage as well as with lower estimated glomerular filtration rate and increased urinary protein levels. Expression of DCXR showed positive correlations to enzymes that are involved in dicarbonyl stress detoxification based on transcriptomics profiles. The sodium glucose cotransporter-2 SGLT2 inhibitors canagliflozin and empagliflozin showed a beneficial effect on renal proximal tubular cells under diabetic stimuli—enhanced DCXR gene expression.
In summary, lower expression of the renoprotective factor DCXR in renal tissue is associated with more severe disease and worse outcome in human CKD. Hormones produced by the anterior pituitary gland regulate an array of important physiological functions, but pituitary hormone disorders are not fully understood. Alan R. Liss, Inc. Thrombin clotting activity measurement and standardization with lyophilized plasma.
Clin Chem , Interrelationships of proficiency testing programs and standardization in laboratory practice. College of American Pathologists, pp. Effects of exposure to factor concentrates containing donations from identified AIDS patients. A matched cohort study. Antibody to human immunodeficiency virus in factordeficient plasma. Am J Clin Pathol , The course of the epidemic of acquired immunodeficiency syndrome in the United States hemophilia population. Hemophiliaassociated acquired immunodeficiency syndrome. Bick RL, ed. ThiemeStratton, Inc. Transfusionassociated AIDS. Chapman and Hall Ltd.
Using a monoclonal antibody to identify patients with type I and type II von Willebrand's disease. Thrombosis Haemostasis 57 3 , Hemophiliac patients' knowledge and educational needs concerning AIDS. Am J Hematol 6 , Prevention of occlusive coronary artery thrombosis by a murine monoclonal antibody to porcine von Willebrand factor. An outbreak of necrotizing enterocolitis. Association with transfusions of packed red blood cells. Am J Epidemiol 6 , Platelet structure and function. American Association of Blood Banks, pp.
Hemisphere Publishing Corporation, pp. Human immunodeficiency virus infection in hemophilic children. Pediatrics 82 4 , The effects of thrombopoietic activity of rabbit plasma fractions on megakaryocytopoiesis in agar cultures. Exp Hematol 16 4 , Am J Public Health 78 4 , Lancet 1 , Acquired immune deficiency syndrome associated with hemophilia in the United States. Barr JS, ed. HIV and hemophilic children's growth.
J Acquired Immune Deficiency Syndrome 2 3 , Sex practice correlates of human immunodeficiency virus transmission and acquired immunodeficiency syndrome incidence in heterosexual partners and offspring of U. Am J Hematology 30 2 , Am J Hematol 31 2 , Multiple arteriovenous malformations of the small intestine in a patient with protein S deficiency.
Amer J Clin Pathol 92 3 , Duration of human immunodeficiency virus infection before detection of antibody. Lancet , Sept. Absence of human Tcell lymphotropic virus type I coinfection in human immunodeficiency virusinfected hemophilic men. Blood 74 7 , Prevalence of human immunodeficiency virus type 1 DNA in hemophilic men and their sex partners. J Infect Dis 5 , Am J Hematol 32 3 , Transforming growth factor-beta induces hemoglobin synthesis in a human erythroleukemia cell line.
Biochem Biophys Res Commun 1 , Maintenance of normal platelet mass in anemic Belgrade rats and their response to iron. Exp Hematol 18 9 , Concordance of polymerase chain reaction with human immunodeficiency virus antibody detection. J Infect Dis 2 , Age and human immunodeficiency virus infection in persons with hemophilia in California.
Am J Public Health 80 8 , Relationship of partially purified factor concentrates to immune tests and AIDS. Am J Hematol 34 4 , Pregnancies in human immunodeficiency virus-infected sex partners of hemophilic men. Am J Dis Child 4 , Free protein S deficiency in a family with venous thrombosis. J Vasc Surg 12 5 , Pathobiology 58 4 , Studies of myeloperoxidase gene expression at the cellular level by in situ hybridization.
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Leukemia 4 12 , Human markers for IgG2 and IgG4 appear to be on the same molecule in the chimpanzee. Immunology 72 1 , Sinonasal papillomas and human papillomavirus; human papillomavirus 11 detected in fungiform Schneiderian papillomas by in situ hybriization the polymerase chain reaction. Human Path. Presenting transfusion-transmitted infections in persons with hemophilia.
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The synergistic effect of hemin and transforming growth factor-beta on hemoglobin accumulation in HEL erythroleukmia cells. Leukmia Research. Cellular kinetics of transforming growth factor-beta induced hemoglobin accumulation in the HEL erythroleukemia cell line.
Leukemia Research. Effects of human interleukin-6 on megakaryocyte development and thrombocytopoiesis in primates. Recombinant human granulocyte-macrophage colony-stimulating factor promotes megakaryocyte maturation in nonhuman primates. Experimental Hematology. Human papillomavirus type 6 detected by the polymerase chain reaction in invasive sinonasal papillary squamous cell carcinoma.
IgG subclass values in black and white children. Hematology , Human immunodeficiency virus infection due to clotting factor concentrates: results of the Seroconversion Surveillance Project. Human papillomavirus infection and anl carcinoma. Retrospective analysis by in situ hybridization and the polymerase chain reaction. Amer Journ Path. Use of the polymerase chain reaction to detect hypermethylation in the calcitonin gene. A new, sensitive approach to monitor tumor cells in acute myelogenous leukemia. Differential effects of sequential, simultaneous, and single agent interleukin-3 and granulocyte-macrophage colony-stimulating factor on megakaryocyte maturation and platelet response in primates.
Blood, 80 10 , Heterosexual and mother-to-child transmission of AIDS in the hemophilia community. Hlth Rep 1 , Replication of Colorado tick fever virus within human hematopoietic progenitor cells. J Virol 67 4 , Hemophilia growth and development study.
Design, methods and entry data. Am J Pediatr Hematol Oncol 15 2 , HIV Infection at home and in the workplace. Protein S, an antithrombotic factor, is synthesized and released by neural tumor cells. J Neurochem. Cross-reactivity of 75 monoclonal antibodies to human immunoglobulin with sera of non-human primates.
Immunology Letters. Anticoagulant protein C pathway defective in majority of thrombophilic patients. Blood coagulation factor Va abnormality associated with resistance to activated protein C in venous thrombophilia. Lancet , Blood, Vol. J Immunoassay, 15 4 , Tumor necrosis factor-alpha downregulates protein S secretion in human microvascular and umbilical vein endothelial cells but not in the HepG-2 hepatoma cell line. Thrombosis and Haemostasis, 73 5 , Thromb Research.
Endothelial cell protein S synthesis is upregulated by the complex of IL-6 and soluble IL-6 receptor. Throm Haemostasis. Throm Research. Thrombosis Research. Throm Res 81 3 , Throm Res 81 5 , Evatt, BL. Infection Control and Hospital Epidemiology. Episodic versus prophylactic infusions for hemophilia A: A cost-effectiveness analysis.
J Peds. AIDS in Hemophilia. Proceedings of the 4th Technicon International Symposium pp , Thromb Haemost , Infectious Complications of Blood Products. Haemophilia 4 Suppl. Hepatitis A virus associated with clotting factor concentrate in the United States. Transfusion , J Immunology , The role of activated protein C resistance in the pathogenesis of venous thrombosis. Am J Med Sci. Thromb Res 86 5 , The Occurrence of Hemophilia in the United States.
AM J Hematol. Surveillance of Creutzfeldt-Jakob disease among persons with hemophilia. Transfusion, , Changes in longevity and causes of death among persons with hemophilia A. American J Hematology , Hemophilia 6 Suppl 1 , Biologicals , Thromb Haemostasis , Hemophilia 5,, Transfusion Med Rev , BL Evatt. World Federation of Hemophilia Monograph January Hooper WC. Lally C. Austin H. Benson J. Dilley A. Wenger NK. Whitsett C. Rawlins P. The relationship between polymorphisms in the endothelial cell nitric oxide synthase gene and the platelet GPIIIa gene with myocardial infarction and venous thromboembolism in African Americans.
Kisker CT. Mahoney EM. Arkin S. Maeder MA. Donfield SM. Benson JM. Ellingsen D.
Bruce Lee’s Death: Conspiracy or Accident?
Renshaw MA. Resler AG. Multiplex analysis of mutations in four genes using fluorescence scanning technology. J Clin Epi , Genetic factors associated with thrombosis in pregnancy in a United States population. Am J Obstet Gynecol , Mortality among males with hemophilia: relations with source of medical care. Evatt BL, Robillard L. Establishing haemophilia care in developing countries: using data to overcome the barrier of pessimism. Haemophilia , Renshaw M. Phillips DJ. Thromb Res 99 3 , Survival of haemophilia care in the developed world.
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Fenstermacher MJ. Lynn HS. Incidence of focal white matter lesions in a population of hemophiliac children and their normal siblings. Ped Radiology. Hematol ; Hooper C. Stokes M. El-Jamil M. The beta-fibrinogen gene GA polymorphism is a risk factor for Legg-Perthes disease. Thromb Res.
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