Genes That Act Downstream of Sensory Neurons to Influence Longevity, Dauer Formation, and Pathogen Responses in <i>Caenorhabditis elegans</i>

Gaglia, Marta M.,Jeong, Dae-Eun,Ryu, Eun-A,Lee, Dongyeop,Kenyon, Cynthia,Lee, Seung-Jae Public Library of Science 2012 PLoS genetics Vol.8 No.12

<▼1><P>The sensory systems of multicellular organisms are designed to provide information about the environment and thus elicit appropriate changes in physiology and behavior. In the nematode <I>Caenorhabditis elegans</I>, sensory neurons affect the decision to arrest during development in a diapause state, the dauer larva, and modulate the lifespan of the animals in adulthood. However, the mechanisms underlying these effects are incompletely understood. Using whole-genome microarray analysis, we identified transcripts whose levels are altered by mutations in the intraflagellar transport protein <I>daf-10</I>, which result in impaired development and function of many sensory neurons in <I>C. elegans</I>. In agreement with existing genetic data, the expression of genes regulated by the transcription factor DAF-16/FOXO was affected by <I>daf-10</I> mutations. In addition, we found altered expression of transcriptional targets of the DAF-12/nuclear hormone receptor in the <I>daf-10</I> mutants and showed that this pathway influences specifically the dauer formation phenotype of these animals. Unexpectedly, pathogen-responsive genes were repressed in <I>daf-10</I> mutant animals, and these sensory mutants exhibited altered susceptibility to and behavioral avoidance of bacterial pathogens. Moreover, we found that a solute transporter gene <I>mct-1/2</I>, which was induced by <I>daf-10</I> mutations, was necessary and sufficient for longevity. Thus, sensory input seems to influence an extensive transcriptional network that modulates basic biological processes in <I>C. elegans</I>. This situation is reminiscent of the complex regulation of physiology by the mammalian hypothalamus, which also receives innervations from sensory systems, most notably the visual and olfactory systems.</P></▼1><▼2><P><B>Author Summary</B></P><P>The senses provide animals with information about their environment, which affects not only their behavior but also their internal state and physiological outputs. How this information is processed is still unclear. In this study, we used mutant <I>C. elegans</I> roundworms that had defective sensory neurons to investigate how changes in sensation alter the expression of genes and regulate physiology, specifically the worms' choice to hibernate during growth and their longevity as fully-grown adults. We showed that defects in sensory neurons change the pattern of gene expression and regulate these outputs through known hormonal pathways, including insulin/IGF-1 and steroid pathways. We also identified a new regulator of longevity, MCT-1, that is predicted to transport small metabolites and hormones in the body. Unexpectedly, we found that sensory impairment altered yet another physiological output, the response to infectious agents. It prevented the worms from avoiding infectious bacteria and reduced the expression of potentially protective factors, but also increased the worms' resistance to infection, suggesting a complex network of responses to environmental stimuli. Understanding how sensory information is relayed in this relatively simple organism may inform our understanding of sensory processing in higher organisms like mammals.</P></▼2>

Bravo 48-hour Wireless pH Monitoring in Patients With Non-cardiac Chest Pain. Objective Gastroesophageal Reflux Disease Parameters Predict the Responses to Proton Pump Inhibitors

( Georgios Karamanolis ),( Konstantinos Triantafyllou ),( Panagiota Psatha ),( Ioannis Vlachogiannakos ),( Asimina Gaglia ),( Dimitrios Polymeros ),( Smaragdi Fessatou ),( Maria Triantafyllou ),( Ioan 대한소화기기능성질환·운동학회(구 대한소화관운동학회) 2012 Journal of Neurogastroenterology and Motility (JNM Vol.18 No.2

Background/Aims In patients with non-cardiac chest pain (NCCP), gastroesophageal reflux disease (GERD) is the commonest cause and ambulatory pH is of great value in identifying these patients. However, parameters in the context of predicting therapeutic response are still unknown. By extending the monitoring period, we could better evaluate the best evidence for GERD association. Our aims were (1) to compare the outcomes of 48-hour pH monitoring to 24-hour and (2) to determine whether objective param - eters could predict the treatment success in patients with NCCP using Bravo pH system. Methods Pathological esophageal acid reflux (PEAR) and positive symptom index (SI) were calculated after 24-hour and compared to the 48-hour study. Evidence suggestive of GERD diagnosis was considered if PEAR and/or SI (+) were present on each different day. After pH study, all patients received proton pump inhibitor twice a day for 4 weeks. Treatment success was determined at the end of therapy. Results Thirty-two patients with NCCP participated. GERD was identified in 20 (62.5%) patients; 17 (53.1%) had PEAR, 3 (9.4%) SI (+) and 7 (22%) both. Twelve (41%) patients exhibited PEAR values on day 1, while 17 after 2 days; a 12.1 % gain. SI (+) was found in 6 patients (18.8%) on day 1 and in 4 more on day 2, a gain of 12.5%. Significantly higher proportion of patients with GERD indicators showed improvement compared to those without (90% vs 16.7%, P < 0.005). Conclusions In patients with NCCP, 48-hour pH measurement identified GERD as the cause of NCCP with an increased yield by almost 12% compared to 12 hours. Objective GERD parameters could predict response to antireflux therapy.

Yield of Combined Impedance-pH Monitoring for Refractory Reflux Symptoms in Clinical Practice

( Georgios Karamanolis ),( Georgios Kotsalidis ),( Konstantinos Triantafyllou ),( Dimitrios Polymeros ),( Asimina Gaglia ),( Smaragdi Fessatou ),( Maria Triantafyllou ),( Ioannis Papanikolaou ),( Spir 대한소화기기능성질환·운동학회(구 대한소화관운동학회) 2011 Journal of Neurogastroenterology and Motility (JNM Vol.17 No.2

Background/Aims In patients with gastroesophageal reflux disease, persistent symptoms on proton pump inhibitor (PPI) therapy may be due to residual acid or non-acid reflux. Combined impedance-pH has been suggested to be superior to pH alone in the management of refractory patients to PPI. The utility of implementation of this technique in every day clinical practice is still unknown. The aim of this study was to investigate the outcomes of patients studied with combined impedance-pH and to evaluate the yield of additional impedance monitoring over pH alone in patients with persistent gastroesophageal reflux disease symptoms. Methods Seventy-one patients (31 men; mean age, 49.1 ± 15.5 years) on PPI therapy underwent combined impedance-pH for persistent typical (76%) or atypical (49%) symptoms. Results During impedance-pH study, 44 (62%) patients reported symptoms. A positive symptom index (SI) was found in 21 (48%) patients: 8 (18.2%) had a positive SI for acid reflux, 9 (20.5%) for non-acid reflux and 4 (9.1%) for mixed reflux. Addition of impedance allowed association between reflux and symptoms in 20.5% of patients who would have been missed by pH study alone. Heartburn was the most prevalent symptom associated with acid reflux, whereas regurgitation and ear, nose and throat symptoms were associated with non-acid reflux. Conclusions The use of combined impedance-pH monitoring substantially increased the diagnostic yield compared to pH alone. With SI analysis, 20.5% of patients received a diagnosis that could not have been achieved with pH testing alone. (J Neurogastroenterol Motil 2011;17:158-163)

The Somatic Reproductive Tissues of <i>C. elegans</i> Promote Longevity through Steroid Hormone Signaling

Yamawaki, Tracy M.,Berman, Jennifer R.,Suchanek-Kavipurapu, Monika,McCormick, Mark,Gaglia, Marta Maria,Lee, Seung-Jae,Kenyon, Cynthia Public Library of Science 2010 PLoS biology Vol.8 No.8

<▼1><P>Removal of the germ cells of <I>C. elegans</I> extends lifespan in part because signals from the somatic reproductive tissues activate the nuclear hormone receptor DAF-12.</P></▼1><▼2><P>In <I>Caenorhabditis elegans</I> and <I>Drosophila melanogaster</I>, removing the germline precursor cells increases lifespan. In worms, and possibly also in flies, this lifespan extension requires the presence of somatic reproductive tissues. How the somatic gonad signals other tissues to increase lifespan is not known. The lifespan increase triggered by loss of the germ cells is known to require sterol hormone signaling, as reducing the activity of the nuclear hormone receptor DAF-12, or genes required for synthesis of the DAF-12 ligand dafachronic acid, prevents germline loss from extending lifespan. In addition to sterol signaling, the FOXO transcription factor DAF-16 is required to extend lifespan in animals that lack germ cells. DAF-12/NHR is known to assist with the nuclear accumulation of DAF-16/FOXO in these animals, yet we find that loss of DAF-12/NHR has little or no effect on the expression of at least some DAF-16/FOXO target genes. In this study, we show that the DAF-12-sterol signaling pathway has a second function to activate a distinct set of genes and extend lifespan in response to the somatic reproductive tissues. When germline-deficient animals lacking somatic reproductive tissues are given dafachronic acid, their expression of DAF-12/NHR-dependent target genes is restored and their lifespan is increased. Together, our findings indicate that in <I>C. elegans</I> lacking germ cells, the somatic reproductive tissues promote longevity via steroid hormone signaling to DAF-12.</P></▼2><▼3><P><B>Author Summary</B></P><P>Reproductive tissues are known to generate important intercellular signals. For example, in mammals, the reproductive tissues produce steroid hormones such as estrogen and testosterone that have profound effects on development and physiology. Studies of the nematode <I>C. elegans</I> and other organisms have shown that the reproductive system can also affect the rate at which an animal ages. Removal of <I>C. elegans</I>' germ cells extends lifespan but this effect is not simply due to sterility, as removal of both the somatic reproductive tissues and the germ cells does not extend lifespan. Instead, loss of the germ cells extends lifespan by activating a pathway that requires input from the somatic gonad. In this study, we demonstrate that the somatic reproductive tissues promote longevity by controlling the activity of a steroid signaling pathway that regulates the DAF-12 nuclear hormone receptor.</P></▼3>