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131.
Reference concentrations of cholecalciferol in animals: a basis for establishing non-target exposure
AAC Fairweather CT Eason PA Elder CMF Eason D Arthur 《New Zealand journal of zoology.》2013,40(4):280-289
AbstractCholecalciferol (vitamin D3) is widely used as a vertebrate pesticide in New Zealand. However, cholecalciferol also occurs naturally in animals. Therefore, when trying to determine whether a non-target animal has been exposed to cholecalciferol baits, knowledge of the baseline cholecalciferol concentrations in the animal's plasma and tissue is required. We analysed cattle, sheep, pig, deer, dog and cat plasma and liver samples for the vitamin D3 metabolite 25-hydroxycholecalciferol (25-OHD), a sensitive biomarker for cholecalciferol. Based on these data and a literature search we present 25-OHD reference ranges. We also examined the literature for 25-OHD concentrations in poisoned animals and compared these to the reference ranges. Where plasma and liver samples have 25-OHD concentrations at least four times higher than our reference ranges it is likely that the animal has been exposed to cholecalciferol baits. 25-OHD concentrations 10 times higher than the reference range indicate ingestion of abnormally high amounts of cholecalciferol. 相似文献
132.
Distinct clinical phenotypes associated with a mutation in the mitochondrial translation elongation factor EFTs 总被引:3,自引:1,他引:2
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Smeitink JA Elpeleg O Antonicka H Diepstra H Saada A Smits P Sasarman F Vriend G Jacob-Hirsch J Shaag A Rechavi G Welling B Horst J Rodenburg RJ van den Heuvel B Shoubridge EA 《American journal of human genetics》2006,79(5):869-877
The 13 polypeptides encoded in mitochondrial DNA (mtDNA) are synthesized in the mitochondrial matrix on a dedicated protein-translation apparatus that resembles that found in prokaryotes. Here, we have investigated the genetic basis for a mitochondrial protein-synthesis defect associated with a combined oxidative phosphorylation enzyme deficiency in two patients, one of whom presented with encephalomyopathy and the other with hypertrophic cardiomyopathy. Sequencing of candidate genes revealed the same homozygous mutation (C997T) in both patients in TSFM, a gene coding for the mitochondrial translation elongation factor EFTs. EFTs functions as a guanine nucleotide exchange factor for EFTu, another translation elongation factor that brings aminoacylated transfer RNAs to the ribosomal A site as a ternary complex with guanosine triphosphate. The mutation predicts an Arg333Trp substitution at an evolutionarily conserved site in a subdomain of EFTs that interacts with EFTu. Molecular modeling showed that the substitution disrupts local subdomain structure and the dimerization interface. The steady-state levels of EFTs and EFTu in patient fibroblasts were reduced by 75% and 60%, respectively, and the amounts of assembled complexes I, IV, and V were reduced by 35%–91% compared with the amounts in controls. These phenotypes and the translation defect were rescued by retroviral expression of either EFTs or EFTu. These data clearly establish mutant EFTs as the cause of disease in these patients. The fact that the same mutation is associated with distinct clinical phenotypes suggests the presence of genetic modifiers of the mitochondrial translation apparatus. 相似文献
133.
P. Richard Grimm Tarvinder K. Taneja Jie Liu Richard Coleman Yang-Yi Chen Eric Delpire James B. Wade Paul A. Welling 《The Journal of biological chemistry》2012,287(45):37673-37690
STE20/SPS-1-related proline-alanine-rich protein kinase (SPAK) and oxidative stress-related kinase (OSR1) activate the potassium-dependent sodium-chloride co-transporter, NKCC2, and thiazide-sensitive sodium-chloride cotransporter, NCC, in vitro, and both co-localize with a kinase regulatory molecule, Cab39/MO25α, at the apical membrane of the thick ascending limb (TAL) and distal convoluted tubule (DCT). Yet genetic ablation of SPAK in mice causes a selective loss of NCC function, whereas NKCC2 becomes hyperphosphorylated. Here, we explore the underlying mechanisms in wild-type and SPAK-null mice. Unlike in the DCT, OSR1 remains at the TAL apical membrane of KO mice where it is accompanied by an increase in the active, phosphorylated form of AMP-activated kinase. We found an alterative SPAK isoform (putative SPAK2 form), which modestly inhibits co-transporter activity in vitro, is more abundant in the medulla than the cortex. Thus, enhanced NKCC2 phosphorylation in the SPAK knock-out may be explained by removal of inhibitory SPAK2, sustained activity of OSR1, and activation of other kinases. By contrast, the OSR1/SPAK/M025α signaling apparatus is disrupted in the DCT. OSR1 becomes largely inactive and displaced from M025α and NCC at the apical membrane, and redistributes to dense punctate structures, containing WNK1, within the cytoplasm. These changes are paralleled by a decrease in NCC phosphorylation and a decrease in the mass of the distal convoluted tubule, exclusive to DCT1. As a result of the dependent nature of OSR1 on SPAK in the DCT, NCC is unable to be activated. Consequently, SPAK−/− mice are highly sensitive to dietary salt restriction, displaying prolonged negative sodium balance and hypotension. 相似文献
134.
Molecular control of cold acclimation in trees 总被引:8,自引:0,他引:8
Frost tolerance is an acquired characteristic of plants that is induced in response to environmental cues preceding the onset of freezing temperatures and activation of a cold acclimation program. In addition to transient acclimation to low non-freezing temperatures and enhancing survival to short frost episodes during the growth season, perennial woody plants need additionally to survive the cold winter months. Trees have evolved a complex dynamic process controlling the development of dormancy and freezing tolerance that secures accurate initiation and termination of the overwintering process. Although the phenology of overwintering has been known for decades, only recently has there been progress in elucidating the molecular mechanisms of dormancy and freezing tolerance development in perennial plants. Current molecular and genomic studies indicate that herbaceous annual and woody perennial plants share similar cold acclimation mechanisms. Both the signal processes controlling cold acclimation and the cold-regulated target genes appear to be shared by herbaceous and woody plants. However, the dormancy development during overwintering brings new players in the molecular control of seasonal cold acclimation of woody perennials. 相似文献
135.
Cold acclimation in silver birch (Betula pendula). Development of freezing tolerance in different tissues and climatic ecotypes 总被引:1,自引:0,他引:1
Chunyang Li Tuula Puhakainen Annikki Welling Anneli Viherä-Aarnio Arild Ernstsen Olavi Junttila Pekka Heino E. Tapio Palva 《Physiologia plantarum》2002,116(4):478-488
A number of environmental cues including short day photoperiod (SD) and low temperature (LT) are known to interact in triggering growth cessation, cold acclimation and other adaptive responses in temperate-zone tree species. Proper timing of these responses is particularly important for survival of trees in the boreal and subarctic regions. Therefore, we used a northern tree species, silver birch ( Betula pendula Roth) as an experimental model to investigate the effect of SD and LT on development of freezing tolerance and on levels of endogenous abscisic acid (ABA) in short-term experiments under controlled conditions. We characterized differences in SD and LT-induced cold acclimation between three different climatic ecotypes from southern, central and northern habitats. The results demonstrated that cold acclimation was rapidly triggered by exposing the plants to SD or LT, and that a combination of the different treatments had an additive effect on freezing tolerance. Freezing tolerance induction was not uniform in the different tissues, the buds and leaves developed freezing tolerance more rapidly than the stem, and the young leaves had a higher freezing tolerance than the old leaves. The ability of the leaves to respond to SD and LT and similarity of the bud and leaf responses indicate that birch leaves provide a rapid and convenient system for studies on molecular mechanisms of cold acclimation. Development of freezing tolerance was dependent on the climatic ecotype, the northern ecotype was clearly more responsive to both SD and LT than the two more southern ecotypes. Development of freezing tolerance induced by SD and LT was accompanied by transient changes in ABA levels. These alterations in ABA levels were ecotype-dependent, the northern ecotype reacting more strongly to the environmental cues. 相似文献
136.
Welling LL Jones BC DeBruine LM Smith FG Feinberg DR Little AC Al-Dujaili EA 《Hormones and behavior》2008,(5):703-708
Many studies have shown that women's judgments of men's attractiveness are affected by changes in levels of sex hormones. However, no studies have tested for associations between changes in levels of sex hormones and men's judgments of women's attractiveness. To investigate this issue, we compared men's attractiveness judgments of feminized and masculinized women's and men's faces in test sessions where salivary testosterone was high and test sessions where salivary testosterone was relatively low. Men reported stronger attraction to femininity in women's faces in test sessions where salivary testosterone was high than in test sessions where salivary testosterone was low. This effect was found to be specific to judgments of opposite-sex faces. The strength of men's reported attraction to femininity in men's faces did not differ between high and low testosterone test sessions, suggesting that the effect of testosterone that we observed for judgments of women's faces was not due to a general response bias. Collectively, these findings suggest that changes in testosterone levels contribute to the strength of men's reported attraction to femininity in women's faces and complement previous findings showing that testosterone modulates men's interest in sexual stimuli. 相似文献
137.
Tanabe K Liu Z Patel S Doble BW Li L Cras-Méneur C Martinez SC Welling CM White MF Bernal-Mizrachi E Woodgett JR Permutt MA 《PLoS biology》2008,6(2):e37
Despite treatment with agents that enhance beta-cell function and insulin action, reduction in beta-cell mass is relentless in patients with insulin resistance and type 2 diabetes mellitus. Insulin resistance is characterized by impaired signaling through the insulin/insulin receptor/insulin receptor substrate/PI-3K/Akt pathway, leading to elevation of negatively regulated substrates such as glycogen synthase kinase-3beta (Gsk-3beta). When elevated, this enzyme has antiproliferative and proapoptotic properties. In these studies, we designed experiments to determine the contribution of Gsk-3beta to regulation of beta-cell mass in two mouse models of insulin resistance. Mice lacking one allele of the insulin receptor (Ir+/-) exhibit insulin resistance and a doubling of beta-cell mass. Crossing these mice with those having haploinsufficiency for Gsk-3beta (Gsk-3beta+/-) reduced insulin resistance by augmenting whole-body glucose disposal, and significantly reduced beta-cell mass. In the second model, mice missing two alleles of the insulin receptor substrate 2 (Irs2-/-), like the Ir+/- mice, are insulin resistant, but develop profound beta-cell loss, resulting in early diabetes. We found that islets from these mice had a 4-fold elevation of Gsk-3beta activity associated with a marked reduction of beta-cell proliferation and increased apoptosis. Irs2-/- mice crossed with Gsk-3beta+/- mice preserved beta-cell mass by reversing the negative effects on proliferation and apoptosis, preventing onset of diabetes. Previous studies had shown that islets of Irs2-/- mice had increased cyclin-dependent kinase inhibitor p27(kip1) that was limiting for beta-cell replication, and reduced Pdx1 levels associated with increased cell death. Preservation of beta-cell mass in Gsk-3beta+/- Irs2-/- mice was accompanied by suppressed p27(kip1) levels and increased Pdx1 levels. To separate peripheral versus beta-cell-specific effects of reduction of Gsk3beta activity on preservation of beta-cell mass, mice homozygous for a floxed Gsk-3beta allele (Gsk-3(F/F)) were then crossed with rat insulin promoter-Cre (RIP-Cre) mice to produce beta-cell-specific knockout of Gsk-3beta (betaGsk-3beta-/-). Like Gsk-3beta+/- mice, betaGsk-3beta-/- mice also prevented the diabetes of the Irs2-/- mice. The results of these studies now define a new, negatively regulated substrate of the insulin signaling pathway specifically within beta-cells that when elevated, can impair replication and increase apoptosis, resulting in loss of beta-cells and diabetes. These results thus form the rationale for developing agents to inhibit this enzyme in obese insulin-resistant individuals to preserve beta-cells and prevent diabetes onset. 相似文献
138.
Health organizations worldwide recommend that adults and children minimize intakes of excess energy and salty, sweet, and fatty foods (all of which are highly preferred tastes) and eat diets richer in whole grains, low- and non- fat dairy products, legumes, fish, lean meat, fruits, and vegetables (many of which taste bitter). Despite such recommendations and the well-established benefits of these foods to human health, adults are not complying, nor are their children. A primary reason for this difficulty is... 相似文献
139.
Wade JB Welling PA Donowitz M Shenolikar S Weinman EJ 《American journal of physiology. Cell physiology》2001,280(1):C192-C198
Na(+)/H(+) exchanger regulatory factor (NHERF) and NHERF2 are PDZ motif proteins that mediate the inhibitory effect of cAMP on Na(+)/H(+) exchanger 3 (NHE3) by facilitating the formation of a multiprotein signaling complex. With the use of antibodies specific for NHERF and NHERF2, immunocytochemical analysis of rat kidney was undertaken to determine the nephron distribution of both proteins and their colocalization with other transporters and with ezrin. NHERF was most abundant in apical membrane of proximal tubule cells, where it colocalized with ezrin and NHE3. NHERF2 was detected in the glomerulus and in other renal vascular structures. In addition, NHERF2 was strongly expressed in collecting duct principal cells, where it colocalized with ROMK. These results indicate a striking difference in the nephron distribution of NHERF and NHERF2 and suggests NHERF is most likely to be the relevant biological regulator of NHE3 in the proximal tubule, while NHERF2 may interact with ROMK or other targets in the collecting duct. The finding that NHERF isoforms occur in different cell types suggests that NHERF and NHERF2 may subserve different functions in the kidney. 相似文献
140.
Functional embryonic cardiomyocytes after disruption of the L-type alpha1C (Cav1.2) calcium channel gene in the mouse 总被引:1,自引:0,他引:1
Seisenberger C Specht V Welling A Platzer J Pfeifer A Kühbandner S Striessnig J Klugbauer N Feil R Hofmann F 《The Journal of biological chemistry》2000,275(50):39193-39199
The L-type alpha(1C) (Ca(v)1.2) calcium channel is the major calcium entry pathway in cardiac and smooth muscle. We inactivated the Ca(v)1.2 gene in two independent mouse lines that had indistinguishable phenotypes. Homozygous knockout embryos (Ca(v)1. 2-/-) died before day 14.5 postcoitum (p.c.). At day 12.5 p.c., the embryonic heart contracted with identical frequency in wild type (+/+), heterozygous (+/-), and homozygous (-/-) Ca(v)1.2 embryos. Beating of isolated embryonic cardiomyocytes depended on extracellular calcium and was blocked by 1 microm nisoldipine. In (+/+), (+/-), and (-/-) cardiomyocytes, an L-type Ba(2+) inward current (I(Ba)) was present that was stimulated by Bay K 8644 in all genotypes. At a holding potential of -80 mV, nisoldipine blocked I(Ba) of day 12.5 p.c. (+/+) and (+/-) cells with two IC(50) values of approximately 0.1 and approximately 1 microm. Inhibition of I(Ba) of (-/-) cardiomyocytes was monophasic with an IC(50) of approximately 1 microm. The low affinity I(Ba) was also present in cardiomyocytes of homozygous alpha(1D) (Ca(v)1.3) knockout embryos at day 12.5 p.c. These results indicate that, up to day 14 p.c., contraction of murine embryonic hearts requires an unidentified, low affinity L-type like calcium channel. 相似文献