J. Dooley - Academia.edu (original) (raw)

Papers by J. Dooley

Research paper thumbnail of Histamine Receptor H1-mediated Sensitization of TRPV1 Mediates Visceral Hypersensitivity and Symptoms in Patients With Irritable Bowel Syndrome

Gastroenterology, Jan 2, 2016

Histamine sensitizes the nociceptor TRPV1 and has been shown to contribute to visceral hypersensi... more Histamine sensitizes the nociceptor TRPV1 and has been shown to contribute to visceral hypersensitivity in animals. We investigated the role of TRPV1 in irritable bowel syndrome (IBS) and evaluated if an antagonist of histamine receptor H1 (HRH1) could reduce symptoms of patients in a randomized placebo controlled trial. Using live calcium imaging, we compared activation of submucosal neurons by the TRPV1 agonist capsaicin in rectal biopsies collected from 9 patients with IBS (ROME 3 critera) and 15 healthy subjects. Sensitization of TRPV1 by histamine, its metabolite imidazole acetaldehyde, and supernatants from biopsies was assessed by calcium imaging of mouse dorsal root ganglion neurons. We then performed a double-blind trial of patients with IBS (mean age, 31 years; range, 18-65 years; 34 female). After a 2 week run-in period, subjects were randomly assigned to groups given either the HRH1 antagonist ebastine (20 mg/day; n=28) or placebo (n=27) for 12 weeks. Rectal biopsies wer...

Research paper thumbnail of Assessment of basic research needs for greenhouse gas control technologies

Greenhouse Gas Control Technologies 4, 1999

This paper is an outgrowth of an effort undertaken by the Department of Energy's... more This paper is an outgrowth of an effort undertaken by the Department of Energy's Office of Energy Research to assess the fundamental research needs to support a national program in carbon management. Five topics were identified as areas where carbon management strategies and technologies might be developed: (1) capture of carbon dioxide, decarbonization strategies, and carbon dioxide disposal and utilization; (2) hydrogen development and fuel cells; (3) enhancement of the natural carbon cycle; (4) biomass production and utilization; and (5) improvement of the efficiency of energy production, conversion, and utilization. Within each of these general areas, experts came together to identify targets of opportunity for fundamental research likely to lead to the development of mid- to long-term solutions for stabilizing or decreasing carbon dioxide and other greenhouse gases in the atmosphere. Basic research to support the options outlined above are far reaching-from understanding natural global processes such as the ocean and terrestrial carbon cycles to development of new materials and concepts for chemical separation. Examples of fundamental research needs are described in this paper.

Research paper thumbnail of 137: Altered Th1-Th2 response during infection is predictive for development of post-infectious Irritable Bowel Syndrome

Research paper thumbnail of Models of Aire-Dependent Gene Regulation for Thymic Negative Selection

Frontiers in Immunology, 2011

Mutations in the autoimmune regulator (AIRE) gene lead to autoimmune polyendocrinopathy syndrome ... more Mutations in the autoimmune regulator (AIRE) gene lead to autoimmune polyendocrinopathy syndrome type 1 (APS1), characterized by the development of multi-organ autoimmune damage. The mechanism by which defects in AIRE result in autoimmunity has been the subject of intense scrutiny. At the cellular level, the working model explains most of the clinical and immunological characteristics of APS1, with AIRE driving the expression of tissue-restricted antigens (TRAs) in the epithelial cells of the thymic medulla. This TRA expression results in effective negative selection of TRA-reactive thymocytes, preventing autoimmune disease. At the molecular level, the mechanism by which AIRE initiates TRA expression in the thymic medulla remains unclear. Multiple different models for the molecular mechanism have been proposed, ranging from classical transcriptional activity, to random induction of gene expression, to epigenetic tag recognition effect, to altered cell biology. In this review, we evaluate each of these models and discuss their relative strengths and weaknesses.

Research paper thumbnail of Lessons from Thymic Epithelial Heterogeneity: FoxN1 and Tissue-Restricted Gene Expression by Extrathymic, Endodermally Derived Epithelium

The Journal of Immunology, 2009

Research paper thumbnail of An Organized Medullary Epithelial Structure in the Normal Thymus Expresses Molecules of Respiratory Epithelium and Resembles the Epithelial Thymic Rudiment of Nude Mice

The Journal of Immunology, 2005

Research paper thumbnail of Cervical Thymus in the Mouse

The Journal of Immunology, 2006

Research paper thumbnail of Alterations of the Medullary Epithelial Compartment in the Aire-Deficient Thymus: Implications for Programs of Thymic Epithelial Differentiation

The Journal of Immunology, 2008

Research paper thumbnail of Aire-Dependent Alterations in Medullary Thymic Epithelium Indicate a Role for Aire in Thymic Epithelial Differentiation

The Journal of Immunology, 2007

Research paper thumbnail of Rac2 Function in Eosinophil Superoxide Generation and Allergic Airway Inflammation

Journal of Allergy and Clinical Immunology, 2008

Research paper thumbnail of miR-29a maintains hematopoietic stem cell self-renewal and is required for leukemic transformation

Experimental Hematology, 2013

Research paper thumbnail of An evolutionarily conserved mutual interdependence between Aire and microRNAs in promiscuous gene expression

European Journal of Immunology, 2013

The establishment and maintenance of central tolerance depends to a large extent on the ability o... more The establishment and maintenance of central tolerance depends to a large extent on the ability of medullary thymic epithelial cells to express a variety of tissue-restricted antigens, the so-called promiscuous gene expression (pGE). Autoimmune regulator (Aire) is to date the best characterised transcriptional regulator known to at least partially coordinate pGE. There is accruing evidence that the expression of Aire-dependent and -independent genes is modulated by higher order chromatin configuration, epigenetic modifications and post-transcriptional control. Given the involvement of microRNAs (miRNAs) as potent post-transcriptional modulators of gene expression, we investigated their role in the regulation of pGE in purified mouse and human thymic epithelial cells (TECs). Microarray profiling of TEC subpopulations revealed evolutionarily conserved cell type and differentiation-specific miRNA signatures with a subset of miRNAs being significantly upregulated during terminal medullary thymic epithelial cell differentiation. The differential regulation of this subset of miRNAs was correlated with Aire expression and some of these miRNAs were misexpressed in the Aire knockout thymus. In turn, the specific absence of miRNAs in TECs resulted in a progressive reduction of Aire expression and pGE, affecting both Aire-dependent and -independent genes. In contrast, the absence of miR-29a only affected the Aire-dependent gene pool. These findings reveal a mutual interdependence of miRNA and Aire.

Research paper thumbnail of Association between the primary biliary cirrhosis specific anti-sp100 antibodies and recurrent urinary tract infection

Digestive and Liver Disease, 2003

Background and aims. Recurrent urinary tract infections (rUTI) have been suggested to be involved... more Background and aims. Recurrent urinary tract infections (rUTI) have been suggested to be involved in the induction of anti-mitochondrial antibodies (AMA), the serological hallmark of primary biliary cirrhosis (PBC), in view of the presence of AMA in rUTI women without liver disease and conversely of a high prevalence of rUTI in women with PBC. This prompted us to investigate whether PBC-specific anti-nuclear antibodies (ANA) to sp100, gp210 and lamin B receptor (LBR) antigens may also be related to rUTI.

Research paper thumbnail of Histamine Receptor H1-mediated Sensitization of TRPV1 Mediates Visceral Hypersensitivity and Symptoms in Patients With Irritable Bowel Syndrome

Gastroenterology, Jan 2, 2016

Histamine sensitizes the nociceptor TRPV1 and has been shown to contribute to visceral hypersensi... more Histamine sensitizes the nociceptor TRPV1 and has been shown to contribute to visceral hypersensitivity in animals. We investigated the role of TRPV1 in irritable bowel syndrome (IBS) and evaluated if an antagonist of histamine receptor H1 (HRH1) could reduce symptoms of patients in a randomized placebo controlled trial. Using live calcium imaging, we compared activation of submucosal neurons by the TRPV1 agonist capsaicin in rectal biopsies collected from 9 patients with IBS (ROME 3 critera) and 15 healthy subjects. Sensitization of TRPV1 by histamine, its metabolite imidazole acetaldehyde, and supernatants from biopsies was assessed by calcium imaging of mouse dorsal root ganglion neurons. We then performed a double-blind trial of patients with IBS (mean age, 31 years; range, 18-65 years; 34 female). After a 2 week run-in period, subjects were randomly assigned to groups given either the HRH1 antagonist ebastine (20 mg/day; n=28) or placebo (n=27) for 12 weeks. Rectal biopsies wer...

Research paper thumbnail of Assessment of basic research needs for greenhouse gas control technologies

Greenhouse Gas Control Technologies 4, 1999

This paper is an outgrowth of an effort undertaken by the Department of Energy's... more This paper is an outgrowth of an effort undertaken by the Department of Energy's Office of Energy Research to assess the fundamental research needs to support a national program in carbon management. Five topics were identified as areas where carbon management strategies and technologies might be developed: (1) capture of carbon dioxide, decarbonization strategies, and carbon dioxide disposal and utilization; (2) hydrogen development and fuel cells; (3) enhancement of the natural carbon cycle; (4) biomass production and utilization; and (5) improvement of the efficiency of energy production, conversion, and utilization. Within each of these general areas, experts came together to identify targets of opportunity for fundamental research likely to lead to the development of mid- to long-term solutions for stabilizing or decreasing carbon dioxide and other greenhouse gases in the atmosphere. Basic research to support the options outlined above are far reaching-from understanding natural global processes such as the ocean and terrestrial carbon cycles to development of new materials and concepts for chemical separation. Examples of fundamental research needs are described in this paper.

Research paper thumbnail of 137: Altered Th1-Th2 response during infection is predictive for development of post-infectious Irritable Bowel Syndrome

Research paper thumbnail of Models of Aire-Dependent Gene Regulation for Thymic Negative Selection

Frontiers in Immunology, 2011

Mutations in the autoimmune regulator (AIRE) gene lead to autoimmune polyendocrinopathy syndrome ... more Mutations in the autoimmune regulator (AIRE) gene lead to autoimmune polyendocrinopathy syndrome type 1 (APS1), characterized by the development of multi-organ autoimmune damage. The mechanism by which defects in AIRE result in autoimmunity has been the subject of intense scrutiny. At the cellular level, the working model explains most of the clinical and immunological characteristics of APS1, with AIRE driving the expression of tissue-restricted antigens (TRAs) in the epithelial cells of the thymic medulla. This TRA expression results in effective negative selection of TRA-reactive thymocytes, preventing autoimmune disease. At the molecular level, the mechanism by which AIRE initiates TRA expression in the thymic medulla remains unclear. Multiple different models for the molecular mechanism have been proposed, ranging from classical transcriptional activity, to random induction of gene expression, to epigenetic tag recognition effect, to altered cell biology. In this review, we evaluate each of these models and discuss their relative strengths and weaknesses.

Research paper thumbnail of Lessons from Thymic Epithelial Heterogeneity: FoxN1 and Tissue-Restricted Gene Expression by Extrathymic, Endodermally Derived Epithelium

The Journal of Immunology, 2009

Research paper thumbnail of An Organized Medullary Epithelial Structure in the Normal Thymus Expresses Molecules of Respiratory Epithelium and Resembles the Epithelial Thymic Rudiment of Nude Mice

The Journal of Immunology, 2005

Research paper thumbnail of Cervical Thymus in the Mouse

The Journal of Immunology, 2006

Research paper thumbnail of Alterations of the Medullary Epithelial Compartment in the Aire-Deficient Thymus: Implications for Programs of Thymic Epithelial Differentiation

The Journal of Immunology, 2008

Research paper thumbnail of Aire-Dependent Alterations in Medullary Thymic Epithelium Indicate a Role for Aire in Thymic Epithelial Differentiation

The Journal of Immunology, 2007

Research paper thumbnail of Rac2 Function in Eosinophil Superoxide Generation and Allergic Airway Inflammation

Journal of Allergy and Clinical Immunology, 2008

Research paper thumbnail of miR-29a maintains hematopoietic stem cell self-renewal and is required for leukemic transformation

Experimental Hematology, 2013

Research paper thumbnail of An evolutionarily conserved mutual interdependence between Aire and microRNAs in promiscuous gene expression

European Journal of Immunology, 2013

The establishment and maintenance of central tolerance depends to a large extent on the ability o... more The establishment and maintenance of central tolerance depends to a large extent on the ability of medullary thymic epithelial cells to express a variety of tissue-restricted antigens, the so-called promiscuous gene expression (pGE). Autoimmune regulator (Aire) is to date the best characterised transcriptional regulator known to at least partially coordinate pGE. There is accruing evidence that the expression of Aire-dependent and -independent genes is modulated by higher order chromatin configuration, epigenetic modifications and post-transcriptional control. Given the involvement of microRNAs (miRNAs) as potent post-transcriptional modulators of gene expression, we investigated their role in the regulation of pGE in purified mouse and human thymic epithelial cells (TECs). Microarray profiling of TEC subpopulations revealed evolutionarily conserved cell type and differentiation-specific miRNA signatures with a subset of miRNAs being significantly upregulated during terminal medullary thymic epithelial cell differentiation. The differential regulation of this subset of miRNAs was correlated with Aire expression and some of these miRNAs were misexpressed in the Aire knockout thymus. In turn, the specific absence of miRNAs in TECs resulted in a progressive reduction of Aire expression and pGE, affecting both Aire-dependent and -independent genes. In contrast, the absence of miR-29a only affected the Aire-dependent gene pool. These findings reveal a mutual interdependence of miRNA and Aire.

Research paper thumbnail of Association between the primary biliary cirrhosis specific anti-sp100 antibodies and recurrent urinary tract infection

Digestive and Liver Disease, 2003

Background and aims. Recurrent urinary tract infections (rUTI) have been suggested to be involved... more Background and aims. Recurrent urinary tract infections (rUTI) have been suggested to be involved in the induction of anti-mitochondrial antibodies (AMA), the serological hallmark of primary biliary cirrhosis (PBC), in view of the presence of AMA in rUTI women without liver disease and conversely of a high prevalence of rUTI in women with PBC. This prompted us to investigate whether PBC-specific anti-nuclear antibodies (ANA) to sp100, gp210 and lamin B receptor (LBR) antigens may also be related to rUTI.