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Browsing by Subject "homeostasis"
Item The emerging role of zinc transporters in cellular homeostasis and cancer(Nature Publishing group, 2017-07-28) Bafaro, Elizabeth; Liu, Yuting; Xu, Yan; Dempski, Robert E; Obstetrics and Gynecology, School of MedicineZinc is an essential micronutrient that plays a role in the structural or enzymatic functions of many cellular proteins. Cellular zinc homeostasis involves the opposing action of two families of metal transporters: the ZnT (SLC30) family that functions to reduce cytoplasmic zinc concentrations and the ZIP (SLC39) family that functions to increase cytoplasmic zinc concentrations. Fluctuations in intracellular zinc levels mediated by these transporter families affect signaling pathways involved in normal cell development, growth, differentiation and death. Consequently, changes in zinc transporter localization and function resulting in zinc dyshomeostasis have pathophysiological effects. Zinc dyshomeostasis has been implicated in the progression of cancer. Here we review recent progress toward understanding the structural basis for zinc transport by ZnT and ZIP family proteins, as well as highlight the roles of zinc as a signaling molecule in physiological conditions and in various cancers. As zinc is emerging as an important signaling molecule in the development and progression of cancer, the ZnT and ZIP transporters that regulate cellular zinc homeostasis are promising candidates for targeted cancer therapy.Item Functional organisation of Escherichia coli transcriptional regulatory network(2008-08) Martinez-Antonio, Agustino; Janga, Sarath Chandra; Thieffry, DenisTaking advantage of available functional data associated with 115 transcription and 7 sigma factors, we have performed a structural analysis of the regulatory network of Escherichia coli. While the mode of regulatory interaction between transcription factors (TFs) is predominantly positive, TFs are frequently negatively autoregulated. Furthermore, feedback loops, regulatory motifs and regulatory pathways are unevenly distributed in this network. Short pathways, multiple feed-forward loops and negative autoregulatory interactions are particularly predominant in the subnetwork controlling metabolic functions such as the use of alternative carbon sources. In contrast, long hierarchical cascades and positive autoregulatory loops are overrepresented in the subnetworks controlling developmental processes for biofilm and chemotaxis. We propose that these long transcriptional cascades coupled with regulatory switches (positive loops) for external sensing enable the coexistence of multiple bacterial phenotypes. In contrast, short regulatory pathways and negative autoregulatory loops enable an efficient homeostatic control of crucial metabolites despite external variations. TFs at the core of the network coordinate the most basic endogenous processes by passing information onto multi-element circuits. Transcriptional expression data support broader and higher transcription of global TFs compared to specific ones. Global regulators are also more broadly conserved than specific regulators in bacteria, pointing to varying functional constraints.Item Rare coding variants and X-linked loci associated with age at menarche(Nature Publishing Group, 2015-08-04) Lunetta, Kathryn L.; Day, Felix R.; Sulem, Patrick; Ruth, Katherine S.; Tung, Joyce Y.; Hinds, David A.; Esko, Tõnu; Elks, Cathy E.; Altmaier, Elisabeth; He, Chunyan; Huffman, Jennifer E.; Mihailov, Evelin; Porcu, Eleonora; Robino, Antonietta; Rose, Lynda M.; Schick, Ursula M.; Stolk, Lisette; Teumer, Alexander; Thompson, Deborah J.; Traglia, Michela; Wang, Carol A.; Yerges-Armstrong, Laura M.; Antoniou, Antonis C.; Barbieri, Caterina; Coviello, Andrea D.; Cucca, Francesco; Demerath, Ellen W.; Dunning, Alison M.; Gandin, Ilaria; Grove, Megan L.; Gudbjartsson, Daniel F.; Hocking, Lynne J.; Hofman, Albert; Huang, Jinyan; Jackson, Rebecca D.; Karasik, David; Kriebel, Jennifer; Lange, Ethan M.; Lange, Leslie A.; Langenberg, Claudia; Li, Xin; Luan, Jian'an; Mägi, Reedik; Morrison, Alanna C.; Padmanabhan, Sandosh; Pirie, Ailith; Polasek, Ozren; Porteous, David; Reiner, Alex P.; Rivadeneira, Fernando; Rudan, Igor; Sala, Cinzia F.; Schlessinger, David; Scott, Robert A.; Stöckl, Doris; Visser, Jenny A.; Völker, Uwe; Vozzi, Diego; Wilson, James G.; Zygmunt, Marek; Boerwinkle, Eric; Buring, Julie E.; Crisponi, Laura; Easton, Douglas F.; Hayward, Caroline; Hu, Frank B.; Liu, Simin; Metspalu, Andres; Pennell, Craig E.; Ridker, Paul M.; Strauch, Konstantin; Streeten, Elizabeth A.; Toniolo, Daniela; Uitterlinden, André G.; Ulivi, Sheila; Völzke, Henry; Wareham, Nicholas J.; Wellons, Melissa; Franceschini, Nora; Chasman, Daniel I.; Thorsteinsdottir, Unnur; Murray, Anna; Stefansson, Kari; Murabito, Joanne M.; Ong, Ken K.; Perry, John R. B.; Department of Epidemiology, Richard M. Fairbanks School of Public HealthMore than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ~3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08–4.6%; effect sizes 0.08–1.25 years per allele; P<5 × 10−8). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10−13) and FAAH2 (rs5914101, P=4.9 × 10−10). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10−11), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ~0.5% variance, indicating that these overlooked sources of variation do not substantially explain the ‘missing heritability’ of this complex trait.Item Rationale to reduce calcium intake in adult patients with chronic kidney disease(Wolters Kluwer, 2018-07) Moe, Sharon M.; Medicine, School of MedicinePurpose of review Calcium is an essential ion for the maintenance of normal bone health and physiologic functions. The extracellular and intracellular levels of calcium are maintained through hormonal regulation called homeostasis. Balance, the net intake minus excretion of calcium, is maintained by hormonal regulation of intestinal absorption and fecal/urinary excretion. Homeostasis and balance are disconnected in patients with chronic kidney disease (CKD). The purpose of this review is to understand how calcium homeostasis and balance are impaired in CKD. Recent findings Two formal calcium balance studies have found that an oral intake of 800–1000 mg of calcium in adults with CKD leads to neutral calcium balance, whereas amounts greater than that lead to positive calcium balance. In patients with CKD, the main determinant of positive calcium balance is the intake and the lack of urinary calcium excretion. Summary Calcium balance is different in patients with advanced CKD compared with patients without CKD. Thus, the oral intake of calcium in the form of diet and binders should not exceed 800–1000 mg/day to achieve neutral calcium balance in adult patients with CKD stages 3b/4.