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Potent Regulator (potent + regulator)
Selected AbstractsFGF-23 Is a Potent Regulator of Vitamin D Metabolism and Phosphate Homeostasis,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2004Takashi Shimada Abstract We analyzed the effects of an FGF-23 injection in vivo. FGF-23 caused a reduction in serum 1,25-dihydroxyvitamin D by altering the expressions of key enzymes for the vitamin D metabolism followed by hypophosphatemia. This study indicates that FGF-23 is a potent regulator of the vitamin D and phosphate metabolism. Introduction: The pathophysiological contribution of FGF-23 in hypophosphatemic diseases was supported by animal studies in which the long-term administration of recombinant fibroblast growth factor-23 reproduced hypophosphatemic rickets with a low serum 1,25-dihydroxyvitamin D [1,25(OH)2D] level. However, there is no clear understanding of how FGF-23 causes these changes. Materials and Methods: To elucidate the molecular mechanisms of the FGF-23 function, we investigated the short-term effects of a single administration of recombinant FGF-23 in normal and parathyroidectmized animals. Results: An injection of recombinant FGF-23 caused a reduction in serum phosphate and 1,25(OH)2D levels. A decrease in serum phosphate was first observed 9 h after the injection and was accompanied with a reduction in renal mRNA and protein levels for the type IIa sodium-phosphate cotransporter (NaPi-2a). There was no increase in the parathyroid hormone (PTH) level throughout the experiment, and hypophosphatemia was reproduced by FGF-23 in parathyroidectomized rats. Before this hypophosphatemic effect, the serum 1,25(OH)2D level had already descended at 3 h and reached the nadir 9 h after the administration. FGF-23 reduced renal mRNA for 25-hydroxyvitamin D-1,-hydroxylase and increased that for 25-hydroxyvitamin D-24-hydroxylase starting at 1 h. In addition, an injection of calcitriol into normal mice increased the serum FGF-23 level within 4 h. Conclusions: FGF-23 regulates NaPi-2a independently of PTH and the serum 1,25(OH)2D level by controlling renal expressions of key enzymes of the vitamin D metabolism. In conclusion, FGF-23 is a potent regulator of phosphate and vitamin D homeostasis. [source] The effects of osmotic stress on the structure and function of the cell nucleusJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2010John D. Finan Abstract Osmotic stress is a potent regulator of the normal function of cells that are exposed to osmotically active environments under physiologic or pathologic conditions. The ability of cells to alter gene expression and metabolic activity in response to changes in the osmotic environment provides an additional regulatory mechanism for a diverse array of tissues and organs in the human body. In addition to the activation of various osmotically- or volume-activated ion channels, osmotic stress may also act on the genome via a direct biophysical pathway. Changes in extracellular osmolality alter cell volume, and therefore, the concentration of intracellular macromolecules. In turn, intracellular macromolecule concentration is a key physical parameter affecting the spatial organization and pressurization of the nucleus. Hyper-osmotic stress shrinks the nucleus and causes it to assume a convoluted shape, whereas hypo-osmotic stress swells the nucleus to a size that is limited by stretch of the nuclear lamina and induces a smooth, round shape of the nucleus. These behaviors are consistent with a model of the nucleus as a charged core/shell structure pressurized by uneven partition of macromolecules between the nucleoplasm and the cytoplasm. These osmotically-induced alterations in the internal structure and arrangement of chromatin, as well as potential changes in the nuclear membrane and pores are hypothesized to influence gene transcription and/or nucleocytoplasmic transport. A further understanding of the biophysical and biochemical mechanisms involved in these processes would have important ramifications for a range of fields including differentiation, migration, mechanotransduction, DNA repair, and tumorigenesis. J. Cell. Biochem. 109: 460,467, 2010. © 2009 Wiley-Liss, Inc. [source] Growth hormone regulates osteogenic marker mRNA expression in human periodontal fibroblasts and alveolar bone-derived cellsJOURNAL OF PERIODONTAL RESEARCH, Issue 4 2003H. R. Haase Background:, Growth hormone (GH) is a potent regulator of bone formation. The proposed mechanism of GH action is through the stimulation of osteogenic precursor cell proliferation and, following clonal expansion of these cells, promotion of differentiation along the osteogenic lineage. Objectives:, We tested this hypothesis by studying the effects of GH on primary cell populations of human periodontal ligament cells (PLC) and alveolar bone cells (ABC), which contain a spectrum of osteogenic precursors. Methods:, The cell populations were assessed for mineralization potential after long-term culture in media containing ,-glycerophosphate and ascorbic acid, by the demonstration of mineral deposition by Von Kossa staining. The proliferative response of the cells to GH was determined over a 48-h period using a crystal violet dye-binding assay. The profile of the cells in terms of osteogenic marker expression was established using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) for alkaline phosphatase (ALP), osteopontin, osteocalcin, bone sialoprotein (BSP), as well as the bone morphogenetic proteins BMP-2, BMP-4 and BMP-7. Results:, As expected, a variety of responses were observed ranging from no mineralization in the PLC populations to dense mineralized deposition observed in one GH-treated ABC population. Over a 48-h period GH was found to be non-mitogenic for all cell populations. Quantitative reverse transcriptase polymerase chain reaction (RT-PCR) BSP mRNA expression correlated well with mineralizing potential of the cells. The change in the mRNA expression of the osteogenic markers was determined following GH treatment of the cells over a 48-h period. GH caused an increase in ALP in most cell populations, and also in BMP expression in some cell populations. However a decrease in BSP, osteocalcin and osteopontin expression in the more highly differentiated cell populations was observed in response to GH. Conclusion:, The response of the cells indicates that while long-term treatment with GH may promote mineralization, short-term treatment does not promote proliferation of osteoblast precursors nor induce expression of late osteogenic markers. [source] Melatonin, a potent regulator of hemeoxygenase-1, reduces cardiopulmonary bypass-induced renal damage in ratsJOURNAL OF PINEAL RESEARCH, Issue 3 2009Zhongqiu Wang Abstract:, Acute renal dysfunction is a frequent complication after cardiac surgery with cardiopulmonary bypass (CPB). This study was designed to evaluate the potential protective effect of melatonin on CPB-induced renal damage in a rat model. Forty male Sprague,Dawley rats were randomly divided into four groups: sham, control (CPB + placebo), low dose of melatonin (CPB + 10 mg/kg melatonin) and high dose of melatonin (CPB + 20 mg/kg melatonin). Blood samples were collected at the beginning, at the end of CPB, and at 0.5, 1, 2, 3, and 24 hr postoperation. Serum creatinine and blood urea nitrogen levels were assayed. Rats were killed 24 hr after surgery, the histologic appearance of the kidney and malondialdehyde (MDA), myeloperoxidase (MPO), catalase (CAT) and superoxide dismutase (SOD) contents were determined. The expression levels of hemeoxygenase-1 (HO-1) protein and gene were determined using western blotting and real-time PCR, respectively. In the control group, CPB surgery significantly increased urea, creatinine levels in serum, MDA and MPO levels in tissues, while decreasing SOD and CAT activities in tissues. Histopathologic findings of the control group confirmed that there was renal impairment by cast formation and tubular necrosis in the tubular epithelium. These changes were markedly reversed in both low dose of melatonin and high dose of melatonin groups. Furthermore, HO-1 gene transcript and protein were significantly upregulated in the kidney tissues after melatonin treatment compared with the placebo treatment. Our findings show that melatonin was effective in preventing CPB-induced renal damage probably through its antioxidant function and upregulation of HO-1. [source] Ergocalciferol promotes in vivo differentiation of keratinocytes and reduces photodamage caused by ultraviolet irradiation in hairless micePHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, Issue 5 2004Hiroaki Mitani Background: Ergocalciferol (VD2) is usually administered orally and it is metabolized to produce its biologically active metabolites in the liver and kidney. Active vitamin D is a well-known potent regulator of cell growth and differentiation. Purpose: Active vitamin D such as 1,25-dihydroxyvitamin D3 (1,,25(OH)2D3) prevents photodamage, including wrinkles and morphologic alterations. However, its clinical and cosmetic use is limited because of its potent, associated effect on calcium metabolism. We examined the efficacy of vitamin D analogues with few adverse effects for preventing skin photodamage. Method: Topical application of VD2 to hairless mouse dorsal skin, and exposure to solar-simulating ultraviolet (UV) radiation at a dose of 10.8 J/cm2 (UVA) were performed for 15 weeks, five times a week on weekdays. At the end of the final irradiation, histological and analytical studies were performed. Results: Topical application of VD2 significantly prevented wrinkle formation and abnormal accumulation of extracellular matrix components. In addition, VD2 suppressed excessive secretion of IL-6 induced by UV irradiation in cultured human normal keratinocytes, in a dose-dependent manner. Conclusion: VD2 promoted keratinocytes differentiation in the epidermis and showed diverse physiological effects, the same as the active form of VD3. The results suggested that the suppression of skin photodamage involved the promotion of keratinocytes differentiation and suppression of IL-6 secretion induced by exposure to UV. Topical application of VD2 may become an effective means to suppress solar UV-induced human skin damage. [source] Proteomic and transcriptomic analysis for streptozotocin-induced diabetic rat pancreas in response to fungal polysaccharide treatmentsPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 11 2008Sang Woo Kim Abstract In an attempt to search for novel biomarkers for monitoring diabetes prognosis, we examined the influence of the hypoglycemic fungal extracellular polysaccharides (EPS) on the differential change in pancreatic proteome and transcriptome in streptozotocin (STZ)-induced diabetic rats using 2-DE-based protein mapping and oligonucleotide microarray analysis. The 2-DE system separated more than 2000 individual spots, demonstrating that 34 proteins out of about 500 matched spots were differentially expressed. A total of 22 overexpressed and 12 underexpressed proteins in 2-DE map were observed (p<0.05) between the healthy and diabetic rats, of which 26 spots were identified by PMF analysis. Of these, significant down regulation of carbonyl reductase (Cbr), hydroxymethylglutaryl-CoA synthase (HMGCS), and putative human mitogen-activated protein kinase activator with WD repeats-binding protein (MAWDBP) in diabetic pancreas were reported for the first time in this study. When treated with EPS, all these four proteins were reverted to normal levels. The microarray analysis revealed that 96 out of 1272 genes were down- or up-regulated in the diabetic rats and the altered transcript levels of many of these genes were reversed after EPS treatment. In particular, ROS generation in rat islets was significantly increased after STZ treatment, thereafter EPS treatment was likely to play a preventive role in ,-cell destruction mediated by STZ. Taken together, EPS may act as a potent regulator of gene expression for a wide variety of genes in diabetic rats, particularly in antioxidative stress, insulin biosynthesis, and cell proliferation. [source] Transforming growth factor-,1-regulated proteins in human endothelial cells identified by two-dimensional gel electrophoresis and mass spectrometryPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 4 2004Marta Lomnytska Abstract Transforming growth factor-, (TGF,) is a potent regulator of angiogenesis affecting proliferation, differentiation and migration of endothelial cells. The effect of TGF, on endothelial cells depends on the origin of the cells and on the experimental conditions. Global analysis of TGF, signalling is expected to unveil mechanisms of this variability and identify novel targets of the growth factor. Here, we report proteome profiling of human microvascular endothelial cells obtained from dermis, which were treated with TGF,1 and compared to nontreated cells. We identified 54 proteins affected by TGF,1 using two-dimensional gel electrophoresis and peptide mass fingerprinting. Thirteen of the identified proteins are involved in various signalling processes. Seven proteins are involved in cytoskeleton rearrangements and six are involved in regulation of metabolism. Ten proteins were identical to predicted hypothetical proteins with no assigned functions. In agreement with the effect of TGF,1 on components of the cytoskeleton, TGF,1 induces actin cytoskeleton rearrangements. TGF,1 also affected expression of E2F6, p57Kip2, G(q),, hnRNP A1 and myosin light chain proteins as shown by immunoblotting. Down-regulation of the transcriptional repressor E2F6 by TGF,1 correlated with a weak growth-inhibitory activity of TGF,1 on HMVEC-d cells. Twenty-five of the identified proteins have not previously been described as being regulated by TGF,1, providing new insights into TGF,1 signalling in endothelial cells. [source] Regulation of autophagy in human and murine cartilage: Hypoxia-inducible factor 2 suppresses chondrocyte autophagyARTHRITIS & RHEUMATISM, Issue 5 2009Jolene Bohensky Objective We have previously demonstrated that the transcription factor hypoxia-inducible factor 1 (HIF-1) promotes the onset of autophagy in chondrocytes. The overall goal of this study was to test the hypothesis that another HIF family transcription factor, HIF-2, modulates the induction of autophagy by chondrocytes. Methods Expression of HIF-1, HIF-2, and light chain 3 (LC3) in human and murine articular cartilage was visualized by immunohistochemistry. Suppression of HIF-2 was achieved using small interfering RNA technology. Assessments of autophagic flux and lysosomal activity, as well as ultrastructural analysis, were performed in chondrocytes in cell culture. Results HIF-2 was expressed abundantly by cells in human and murine articular cartilage and in the cartilage of mineralizing vertebrae from neonatal mice. Protein levels were reduced in articular cartilage from older mice, in end-plate cartilage from mice, and in chondrocytes from human osteoarthritic (OA) cartilage. HIF-2 was robustly expressed in the prehypertrophic cells of mouse growth cartilage. When HIF-2, was silenced, the generation of reactive oxygen species was found to be elevated, with a concomitant decrease in catalase and superoxide dismutase activity. Suppression of HIF-2 was associated with decreased Akt-1 and mammalian target of rapamycin activities, reduced Bcl-xL expression, and a robust autophagic response, even under nutrient-replete conditions. In these silenced chondrocytes, HIF-1 expression was elevated. Decreased HIF-2 expression was associated with autophagy in OA tissues and aging cartilage samples. The autophagic response of chondrocytes in HIF-2,,knockout mouse growth plate showed an elevated autophagic response throughout the plate. Conclusion Based on these observations, we conclude that HIF-2 is a potent regulator of autophagy in maturing chondrocytes. Our data suggest that this protein acts as a brake on the autophagy-accelerator function of HIF-1. [source] Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX-68ARTHRITIS & RHEUMATISM, Issue 1 2003M. Carmen Montesinos Objective Low-dose weekly methotrexate therapy remains a mainstay in the treatment of inflammatory arthritis. Results of previous studies demonstrated that adenosine, acting at one or more of its receptors, mediates the antiinflammatory effects of methotrexate in animal models of both acute and chronic inflammation. We therefore sought to establish which receptor(s) is involved in the modulation of acute inflammation by methotrexate and its nonpolyglutamated analog MX-68 (N -[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H -1,4-benzothiazin-7-yl]-carbonyl]- L -homoglutamic acid). Methods We studied the effects of low-dose methotrexate (0.75 mg/kg intraperitoneally [IP] every week for 5 weeks), MX-68 (2 mg/kg IP 2 days and 1 hour before induction of inflammation), dexamethasone (1.5 mg/kg IP 1 hour before induction of inflammation), or vehicle control on acute inflammation in an air-pouch model in A2A and A3 receptor knockout mice. Results Low-dose weekly methotrexate treatment increased the adenosine concentration in the exudates of all mice studied and reduced leukocyte and tumor necrosis factor , accumulation in the exudates of wild-type mice, but not in those of A2A or A3 receptor knockout mice. Dexamethasone, an agent that suppresses inflammation by a different mechanism, was equally effective at suppressing leukocyte accumulation in A2A knockout, A3 knockout, and wild-type mice, indicating that the lack of response was specific for methotrexate and MX-68. Conclusion These findings confirm that adenosine, acting at A2A and A3 receptors, is a potent regulator of inflammation. Moreover, these results provide strong evidence that adenosine, acting at either or both of these receptors, mediates the antiinflammatory effects of methotrexate and its analog MX-68. [source] Vitamin D and systemic cancer: is this relevant to malignant melanoma?BRITISH JOURNAL OF DERMATOLOGY, Issue 2 2002J.E. Osborne Summary 1,25-dihydroxyvitamin D3[1,25(OH)2D3] is a well-known potent regulator of cell growth and differentiation and there is recent evidence of an effect on cell death, tumour invasion and angiogenesis, which makes it a candidate agent for cancer regulation. The classical synthetic pathway of 1,25(OH)2D3 involves 25- and 1,-hydroxylation of vitamin D3, in the liver and kidney, respectively, of absorbed or skin-synthesized vitamin D3. There is recent focus on the importance in growth control of local metabolism of 1,25(OH)2D3, which is a function of local tissue synthetic hydroxylases and particularly the principal catabolizing enzyme, 24-hydroxylase. The classical signalling pathway of 1,25(OH)2D3 employs the vitamin D nuclear receptor (VDR), which is a transcription factor for 1,25(OH)2D3 target genes. Effects of this pathway include inhibition of cellular growth and invasion. Cytoplasmic signalling pathways are increasingly being recognized, which similarly may regulate growth and differentiation but also apoptosis. 1,25(OH)2D3 has a major inhibitory effect on the G1/S checkpoint of the cell cycle by upregulating the cyclin dependent kinase inhibitors p27 and p21, and by inhibiting cyclin D1. Indirect mechanisms include upregulation of transforming growth factor-, and downregulation of the epidermal growth factor receptor. 1,25(OH)2D3 may induce apoptosis either indirectly through effects on the insulin-like growth receptor and tumour necrosis factor-, or more directly via the Bcl-2 family system, the ceramide pathway, the death receptors (e.g. Fas) and the stress-activated protein kinase pathways (Jun N terminal kinase and p38). Inhibition of tumour invasion and metastasis potential has been demonstrated and mechanisms include inhibition of serine proteinases, metalloproteinases and angiogenesis. The lines of evidence for an effect of vitamin D3 in systemic cancer are the laboratory demonstration of relevant effects on cellular growth, differentiation, apoptosis, malignant cell invasion and metastasis; epidemiological findings of an association of the occurrence and outcome of cancers with derangements of vitamin D3/1,25(OH)2D3 and the association of functional polymorphisms of the VDR with the occurrence of certain cancers. In addition, vitamin D3 analogues are being developed as cancer chemotherapy agents. There is accumulating evidence that the vitamin D3/1,25(OH)2D3/VDR axis is similarly important in malignant melanoma (MM). MM cells express the VDR, and the antiproliferative and prodifferentiation effects of 1,25(OH)2D3 have been shown in cultured melanocytes, MM cells and MM xenografts. Recently, an inhibitory effect on the spread of MM cells has been demonstrated, low serum levels of 1,25(OH)2D3 have been reported in MM patients and the VDR polymorphisms have been shown to be associated with both the occurrence and outcome of MM. The relationship between solar irradiation and MM is more complex than for the systemic cancers. As in other cancers, there is evidence of a protective effect of vitamin D3 in MM, but ultraviolet radiation, which is a principal source of vitamin D3, is mutagenic. Further work is necessary on the influence of serum vitamin D3 levels on the occurrence and prognosis of MM, the effects of sun protection measures on serum vitamin D3 levels in temperate climates and epidemiological studies on geographical factors and skin type on the prognosis of MM. Meanwhile, it would seem mandatory to ensure an adequate vitamin D3 status if sun exposure were seriously curtailed, certainly in relation to carcinoma of breast, prostate and colon and probably also MM. [source] Neuronal p38 MAPK signalling: an emerging regulator of cell fate and function in the nervous systemGENES TO CELLS, Issue 11 2002Kohsuke Takeda p38 mitogen-activated protein kinases (MAPKs), together with extracellular signal-regulated kinases (ERKs) and c-Jun N-terminal kinases (JNKs), constitute the MAPK family. Multiple intracellular signalling pathways that converge on MAPKs exist in all eukaryotic cells and play pivotal roles in a wide variety of cellular functions. p38 MAPKs and JNKs, also termed stress-activated protein kinases (SAPKs), are preferentially activated by various cytotoxic stresses and cytokines and appear to be potent regulators of stress-induced apoptosis. Whereas JNKs have been shown to play pivotal roles in the regulation of neuronal apoptosis, the role of p38 MAPKs in the nervous system is poorly understood. However, accumulating evidence from mammalian cell culture systems and the strong genetic tool C. elegans suggests that neuronal p38 signalling has diverse functions beyond the control of cell death and survival. This review focuses on possible roles for the p38 pathway in the nervous system, with principal emphasis placed on the roles in neuronal cell fate decision and function. [source] Microglia express functional 11,-hydroxysteroid dehydrogenase type 1,GLIA, Issue 10 2010Andres Gottfried-Blackmore Abstract Glucocorticoids are potent regulators of inflammation exerting permissive, stimulatory, and suppressive effects. Glucocorticoid access to intracellular receptors is regulated by the activity of two distinct enzymes known as 11,-hydroxysteroid dehydrogenase (11,HSD) Type 1 and Type 2, which catalyze the activation or deactivation of glucocorticoids. Although expression of these enzymes in major organ systems and their roles in the metabolic effects of glucocorticoids have been described, their role in the inflammatory response has only recently started to be addressed. In this report, we have studied the expression and activity of 11,HSD Type 1 and Type 2 in microglia cells. Microglia, the brain's resident macrophages, initiate and orchestrate CNS inflammatory responses. Importantly, activated microglia are implicated in most neurodegenerative conditions, making them key subjects of study. We found that microglia expressed 11,HSD-1, but not 11,HSD-2, both in ex vivo FACS-sorted adult cells and in vitro primary cultures. 11,HSD-1 expression was increased in LPS-activated microglia. Moreover, 11,HSD-1 catalyzed the metabolic conversion of 11-dehydro-corticosterone into corticosterone (CORT), which potently reduced cytokine production in activated microglia. We propose that 11,HSD-1 may provide microglia with an intrinsic mechanism to autoregulate and inhibit proinflammatory mediator production through CORT formation. © 2010 Wiley-Liss, Inc. [source] Correlated expression patterns of microRNA genes with age-dependent behavioural changes in honeybeeINSECT MOLECULAR BIOLOGY, Issue 4 2010S. K. Behura Abstract The hive-living honeybees (Apis mellifera) show age-dependent behavioural changes; young bees usually nurse the broods in the colony and the older bees engage in foraging activities. These developmentally regulated behavioural changes were previously shown to be correlated with genome-wide transcriptional changes in the honeybee brain. The indigenous small regulatory RNA molecules, known as microRNAs (miRNAs), are potent regulators of gene expression and also are developmentally regulated. Thus, we wanted to study if there might be correlation of differential expression of miRNA genes in the brain with age-dependent behavioural changes of the bees. We determined expression patterns of a set (n= 20) of predicted miRNA genes, by quantitative real-time PCR assays, in the brains of young and old bees that were engaged in nursing or foraging activities in the colony, respectively. Our data show correlated up-regulation of miRNA-124, miRNA-14, miRNA-276, miRNA-13b, let-7 and miRNA-13a in the young nurse bees. miRNA-12, miRNA-9, miRNA-219, miRNA-210, miRNA-263, miRNA-92 and miRNA-283 showed correlated expression patterns in the old forager bees. The modular changes of miRNA genes in the young nurse and old forager bees suggest possible roles of miRNAs in age-dependent behavioural changes in bees. The correlated expression of intronic miRNA genes and their host genes as well as of miRNA genes physically clustered in the genome are also observed. [source] Intestinal Calcium Transporter Genes Are Upregulated by Estrogens and the Reproductive Cycle Through Vitamin D Receptor-Independent Mechanisms,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2003SJ Van Cromphaut Abstract 1,,25(OH)2 -vitamin D strongly regulates the expression of the epithelial calcium channel CaT1. CaT1 expression is reduced in ERKO, mice and induced by estrogen treatment, pregnancy, or lactation in VDR WT and KO mice. Estrogens and vitamin D are thus independent potent regulators of the expression of this calcium influx mechanism, which is involved in active intestinal calcium absorption. Introduction: Active duodenal calcium absorption consists of three major steps: calcium influx into, transfer through, and extrusion out of the enterocyte. These steps are carried out by the calcium transport protein 1 (CaT1), calbindin-D9K, and the plasma membrane calcium ATPase (PMCA1b), respectively. We investigated whether estrogens or hormonal changes during the female reproductive cycle influence the expression of these genes, and if so, whether these effects are vitamin D-vitamin D receptor (VDR) dependent. Materials and Methods: We evaluated duodenal expression patterns in estrogen receptor (ER), and -, knockout (KO) mice, as well as in ovariectomized, estrogen-treated, pregnant, and lactating VDR wild-type (WT) and VDR KO mice. Results: Expression of calcium transporter genes was not altered in ERKO, mice. CaT1 mRNA expression was reduced by 55% in ERKO, mice, while the two other calcium transporter genes were not affected. Ovariectomy caused no change in duodenal expression pattern of VDR WT and KO mice, whereas treatment with a pharmacologic dose of estrogens induced CaT1 mRNA expression in VDR WT (4-fold) and KO (8-fold) mice. Pregnancy enhanced CaT1 expression equally in VDR WT and KO mice (12-fold). Calbindin-D9K and PMCA1b expression increased to a lesser extent and solely in pregnant VDR WT animals. In lactating VDR WT and KO mice, CaT1 mRNA expression increased 13 times, which was associated with a smaller increase in calbindin-D9K protein content and PMCA1b mRNA expression. Conclusions: Estrogens or hormonal changes during pregnancy or lactation have distinct, vitamin D-independent effects at the genomic level on active duodenal calcium absorption mechanisms, mainly through a major upregulation of the calcium influx channel CaT1. The estrogen effects seem to be mediated solely by ER,. [source] Functional neuroimaging of belief, disbelief, and uncertaintyANNALS OF NEUROLOGY, Issue 2 2008Sam Harris Objective The difference between believing and disbelieving a proposition is one of the most potent regulators of human behavior and emotion. When one accepts a statement as true, it becomes the basis for further thought and action; rejected as false, it remains a string of words. The purpose of this study was to differentiate belief, disbelief, and uncertainty at the level of the brain. Methods We used functional magnetic resonance imaging (fMRI) to study the brains of 14 adults while they judged written statements to be "true" (belief), "false" (disbelief), or "undecidable" (uncertainty). To characterize belief, disbelief, and uncertainty in a content-independent manner, we included statements from a wide range of categories: autobiographical, mathematical, geographical, religious, ethical, semantic, and factual. Results The states of belief, disbelief, and uncertainty differentially activated distinct regions of the prefrontal and parietal cortices, as well as the basal ganglia. Interpretation Belief and disbelief differ from uncertainty in that both provide information that can subsequently inform behavior and emotion. The mechanism underlying this difference appears to involve the anterior cingulate cortex and the caudate. Although many areas of higher cognition are likely involved in assessing the truth-value of linguistic propositions, the final acceptance of a statement as "true" or its rejection as "false" appears to rely on more primitive, hedonic processing in the medial prefrontal cortex and the anterior insula. Truth may be beauty, and beauty truth, in more than a metaphorical sense, and false propositions may actually disgust us. Ann Neurol 2007 [source] | |||||||||||||