Publications by authors named "Julia Kühn"

27 Publications

  • Page 1 of 1

Vitamin D Status of Mice Deficient in Scavenger Receptor Class B Type 1, Cluster Determinant 36 and ATP-Binding Cassette Proteins G5/G8.

Nutrients 2020 Jul 22;12(8). Epub 2020 Jul 22.

Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Von-Danckelmann-Platz 2, 06120 Halle (Saale), Germany.

Classical lipid transporters are suggested to modulate cellular vitamin D uptake. This study investigated the vitamin D levels in serum and tissues of mice deficient in SR-B1 (Srb1), CD36 (Cd36) and ABC-G5/G8 (Abcg5/g8) and compared them with corresponding wild-type (WT) mice. All mice received triple-deuterated vitamin D (vitamin D-d) for six weeks. All knockout mice vs. WT mice showed specific alterations in their vitamin D concentrations. Srb1 mice had higher levels of vitamin D-d in the serum, adipose tissue, kidney and heart, whereas liver levels of vitamin D-d remained unaffected. Additionally, Srb1 mice had lower levels of deuterated 25-hydroxyvitamin D (25(OH)D-d) in the serum, liver and kidney compared to WT mice. In contrast, Cd36 and WT mice did not differ in the serum and tissue levels of vitamin D-d, but Cd36 vs. WT mice were characterized by lower levels of 25(OH)D-d in the serum, liver and kidney. Finally, Abcg5/g8 mice tended to have higher levels of vitamin D-d in the serum and liver. Major alterations in Abcg5/g8 mice were notably higher levels of 25(OH)D-d in the serum and kidney, accompanied by a higher hepatic mRNA abundance of hydroxylase. To conclude, the current data emphasize the significant role of lipid transporters in the uptake, tissue distribution and activation of vitamin D.
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http://dx.doi.org/10.3390/nu12082169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469065PMC
July 2020

Markers Indicating Body Vitamin D Stores and Responses of Liver and Adipose Tissues to Changes in Vitamin D Intake in Male Mice.

Nutrients 2020 May 13;12(5). Epub 2020 May 13.

Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Von-Danckelmann-Platz 2, 06120 Halle (Saale), Germany.

Circulating 25-hydroxyvitamin D (25(OH)D) is regarded as the most reliable biomarker of vitamin D status. However, limited data exist concerning the suitability of 25(OH)D as an indicator of body vitamin D stores and the ability of adipose tissue to mobilize vitamin D. In the first study, in which male mice received different vitamin D doses for three weeks, we found strong linear response relationships between vitamin D intake and levels of vitamin D in the plasma ( < 0.001), liver ( < 0.001) and adipose tissues ( < 0.001), and strong positive correlations between plasma and tissue stores of vitamin D ( < 0.001). Plasma levels of 25(OH)D and 24,25-dihydroxyvitamin D (24,25(OH)D) showed weak or no correlations with tissue vitamin D stores. Data from a second study demonstrate a strong and rapid response of plasma 25(OH)D in vitamin D-treated mice with a low vitamin D status. Additionally, mice fed a vitamin D-free diet showed a strong and rapid decline in vitamin D in the liver, whereas the decline in different adipose tissues was distinctly lower than that in the liver. To conclude, tissue stores of vitamin D were best reflected by plasma vitamin D. In contrast to the liver, adipose tissues responded less sensitively to an absence of vitamin D intake.
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http://dx.doi.org/10.3390/nu12051391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284563PMC
May 2020

Ablation of spinal cord estrogen receptor α-expressing interneurons reduces chemically induced modalities of pain and itch.

J Comp Neurol 2020 Jul 6;528(10):1629-1643. Epub 2020 Jan 6.

Department of Anatomy, University of California, San Francisco, California.

Estrogens are presumed to underlie, at least in part, the greater pain sensitivity and chronic pain prevalence that women experience compared to men. Although previous studies revealed populations of estrogen receptor-expressing neurons in primary afferents and in superficial dorsal horn neurons, there is little to no information as to the contribution of these neurons to the generation of acute and chronic pain. Here we molecularly characterized neurons in the mouse superficial spinal cord dorsal horn that express estrogen receptor α (ERα) and explored the behavioral consequences of their ablation. We found that spinal ERα-positive neurons are largely excitatory interneurons and many coexpress substance P, a marker for a discrete subset of nociceptive, excitatory interneurons. After viral, caspase-mediated ablation of spinal ERα-expressing cells, we observed a significant decrease in the first phase of the formalin test, but in male mice only. ERα-expressing neuron-ablation also reduced pruritogen-induced scratching in both male and female mice. There were no ablation-related changes in mechanical or heat withdrawal thresholds or in capsaicin-induced nocifensive behavior. In chronic pain models, we found no change in Complete Freund's adjuvant-induced thermal or mechanical hypersensitivity, or in partial sciatic nerve injury-induced mechanical allodynia. We conclude that ERα labels a subpopulation of excitatory interneurons that are specifically involved in chemically evoked persistent pain and pruritogen-induced itch.
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http://dx.doi.org/10.1002/cne.24847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317200PMC
July 2020

Inhibition of Niemann-Pick C1-like protein 1 by ezetimibe reduces uptake of deuterium-labeled vitamin D in mice.

J Steroid Biochem Mol Biol 2020 03 1;197:105504. Epub 2019 Nov 1.

Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Germany; Competence Cluster of Cardiovascular Health and Nutrition (nutriCARD), Halle-Jena-Leipzig, Germany. Electronic address:

For a long time, orally ingested vitamin D was assumed to enter the body exclusively via simple passive diffusion. Recent data from in vitro experiments have described Niemann-Pick C1-like protein 1 (Npc1l1) as an important sterol transporter for vitamin D absorption. However, short-term applications of ezetimibe, which inhibits Npc1l1, were not associated with reduced vitamin D uptake in animals and humans. The current study aimed to elucidate the effect of long-term inhibition of Npc1l1 by ezetimibe on the uptake and storage of orally administered triple deuterated vitamin D (vitamin D-d). Therefore, 30 male wild-type mice were randomly assigned into three groups and received diets with 25 μg/kg of vitamin D-d that contained 0 (control group), 50 or 100 mg/kg ezetimibe for six weeks. Mice fed diets with 50 or 100 mg/kg ezetimibe had lower circulating levels of cholesterol than control mice (-12 %, -15 %, P < 0.01). In contrast, the concentrations of 7-dehydrocholesterol in serum (P < 0.001) and liver (P < 0.05) were higher in mice treated with ezetimibe than in control mice, indicating an increased sterol synthesis to compensate for cholesterol reduction. Long-term application of ezetimibe significantly reduced the concentrations of vitamin D-d in the serum and tissues of mice. The magnitude of vitamin D reduction was comparable between the two ezetimibe groups. In comparison to the control group, mice treated with ezetimibe had lower concentrations of deuterated vitamin D compared with the control group in serum (62 %, P < 0.001), liver (79 %, P < 0.001), kidney (54 %, P < 0.001), adipose tissues (55 %, P < 0.001) and muscle (41 %, P < 0.001). Surprisingly, the serum concentration of deuterated 25-hydroxyvitamin D was higher in the group fed 100 mg/kg ezetimibe than in the control group (P < 0.05). The protein expression of the vitamin D hydroxylases Cyp2r1, Cyp27a1, Cyp3a11, Cyp24a1 and Cyp2j3 in liver and Cyp27b1 and Cyp24a1 in kidney remained largely unaffected by ezetimibe. To conclude, Npc1l1 appears to be crucial for the uptake of orally ingested vitamin D because long-term inhibition of Npc1l1 by ezetimibe strongly reduced the levels of deuterium-labeled vitamin D in the body; the observed rise in deuterated 25-hydroxyvitamin D in serum of these mice can not be explained by the expression levels of the key enzymes involved in vitamin D hydroxylation.
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http://dx.doi.org/10.1016/j.jsbmb.2019.105504DOI Listing
March 2020

Intake of ergosterol increases the vitamin D concentrations in serum and liver of mice.

J Steroid Biochem Mol Biol 2019 11 25;194:105435. Epub 2019 Jul 25.

Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Von-Danckelmann-Platz 2, 06120, Halle (Saale), Germany; Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena-Leipzig, Germany. Electronic address:

Factors that can modify the bioavailability of orally administered vitamin D are not yet widely known. Ergosterol is a common fungal sterol found in food which has a chemical structure comparable to that of vitamin D. This study aimed to investigate the effect of ergosterol on vitamin D metabolism. Therefore, 36 male wild type-mice were randomly subdivided into three groups (n = 12) and received a diet containing 25 μg vitamin D and either 0 mg (control), 2 mg or 7 mg ergosterol per kg diet for 6 weeks. To elucidate the impact of ergosterol on hepatic hydroxylation of vitamin D, human hepatoma cells (HepG2) were treated with different concentrations of ergosterol. Concentrations of vitamin D and 25-hydroxyvitamin D (25(OH)D) in cells, livers and kidneys of mice and additionally 24,25-dihydroxyvitamin D (24,25(OH)D) in serum were quantified by LC-MS/MS. The concentration of 1,25-dihydroxyvitamin D (1,25(OH)D) in serum was analyzed by commercially-available enzyme immuno assay. The concentrations of cholesterol and triglycerides were analyzed in livers of mice by photometric assays. Analyses revealed that mice receiving 7 mg/kg ergosterol with their diet had 1.3-, 1.7- and 1.5-times higher concentrations of vitamin D in serum, liver and kidney, respectively, than control mice (P < 0.05), whereas no significant effects were observed in mice fed 2 mg/kg ergosterol. The hydroxylation of vitamin D remained unaffected by dietary ergosterol, since the concentration of 25-hydroxyvitamin D in serum and tissues and the concentrations of 1,25(OH)D and 24,25(OH)D in serum were not different between the three groups of mice. The lipid concentrations in liver were also not affected by dietary ergosterol. Data from the cell culture studies showed that ergosterol did not influence the conversion of vitamin D to 25(OH)D. To conclude, ergosterol appears to be a modulator of vitamin D concentrations in the body of mice, without modulating the hydroxylation of vitamin D in liver.
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http://dx.doi.org/10.1016/j.jsbmb.2019.105435DOI Listing
November 2019

Feasibility of artificial light regimes to increase the vitamin D content in indoor-laid eggs.

Poult Sci 2019 Oct;98(10):5177-5187

Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany.

Vitamin D insufficiency is prevalent worldwide. Recently, we showed that exposure of laying hens to sunlight or artificial ultraviolet B (UVB) light is an efficient strategy to increase the vitamin D content in eggs. In the current study, using 2 different chicken genotypes and stocking densities, we addressed the question of whether different UVB-emitting regimes work under real indoor housing conditions in a floor system or in furnished cages. Here, we found a 3.7-fold increase in the egg vitamin D content in Lohmann Selected Leghorn hens and a 4.2-fold increase in Lohmann Brown hens after UVB exposure for 6 h/d. The data further reveal that UVB exposure under high stocking density is equally effective compared to that at low stocking density. The different light regimes were not associated with changes in the behavior of these animals. To conclude, artificial UVB-emitting light regimes are a practical strategy to increase the vitamin D content in indoor-laid eggs.
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http://dx.doi.org/10.3382/ps/pez234DOI Listing
October 2019

Primary Afferent-Derived BDNF Contributes Minimally to the Processing of Pain and Itch.

eNeuro 2018 Nov-Dec;5(6). Epub 2018 Dec 26.

Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158.

BDNF is a critical contributor to neuronal growth, development, learning, and memory. Although extensively studied in the brain, BDNF is also expressed by primary afferent sensory neurons in the peripheral nervous system. Unfortunately, anatomical and functional studies of primary afferent-derived BDNF have been limited by the availability of appropriate molecular tools. Here, we used targeted, inducible molecular approaches to characterize the expression pattern of primary afferent BDNF and the extent to which it contributes to a variety of pain and itch behaviors. Using a reporter mouse, we found that BDNF is expressed primarily by myelinated primary afferents and has limited overlap with the major peptidergic and non-peptidergic subclasses of nociceptors and pruritoceptors. We also observed extensive neuronal, but not glial, expression in the spinal cord dorsal horn. In addition, because BDNF null mice are not viable and even Cre-mediated deletion of BDNF from sensory neurons could have developmental consequences, here we deleted BDNF selectively from sensory neurons, in the adult, using an advillin-Cre-ER line crossed to floxed BDNF mice. We found that BDNF deletion in the adult altered few itch or acute and chronic pain behaviors, beyond sexually dimorphic phenotypes in the tail immersion, histamine, and formalin tests. Based on the anatomical distribution of sensory neuron-derived BDNF and its limited contribution to pain and itch processing, we suggest that future studies of primary afferent-derived BDNF should examine behaviors evoked by activation of myelinated primary afferents.
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http://dx.doi.org/10.1523/ENEURO.0402-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325548PMC
March 2019

Cocoa and chocolate are sources of vitamin D.

Food Chem 2018 Dec 20;269:318-320. Epub 2018 Jun 20.

Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Germany; Competence Cluster of Cardiovascular Health and Nutrition (nutriCARD), Halle-Jena-Leipzig, Germany. Electronic address:

Cocoa beans are susceptible to fungal contamination and often contain substantial amounts of ergosterol, the precursor to vitamin D. We hypothesized that sun-drying the fermented cocoa beans might lead to the conversion of ergosterol to vitamin D. We quantified vitamin D in cocoa and cocoa-based foods by liquid chromatography-tandem mass spectrometry. Here, we show that cocoa beans from different growing regions contain vitamin D. Particularly high vitamin D content was found in cocoa powder and butter. Among the chocolates, dark chocolate had the highest vitamin D content (ranging from 1.90 to 5.48 µg/100 g), white chocolate had the lowest vitamin D content (ranging from 0.19 to 1.91 µg/100 g), and chocolate nut spreads had a comparatively low vitamin D content, with an average of 0.15 µg/100 g. Thus, cocoa and chocolate are clearly a dietary source of vitamin D, therefore, it is necessary to update food composition databases.
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http://dx.doi.org/10.1016/j.foodchem.2018.06.098DOI Listing
December 2018

Prevalence of vitamin D insufficiency and evidence for disease prevention in the older population.

Z Gerontol Geriatr 2018 Jul 17;51(5):567-572. Epub 2018 Apr 17.

Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Von-Danckelmann-Platz 2, 06120, Halle (Saale), Germany.

The prevalence of vitamin D insufficiency, usually assessed by the analysis of circulating 25-hydroxyvitamin D (25[OH])D), is very high in the aging German population. An important factor that reduces endogenous vitamin D synthesis in older persons is physical inactivity or care-dependency that limits the time spent outside. Additionally, it has been suggested that the age-dependent decline in the glomerular filtration rate is associated with a reduced production of bioactive calcitriol. As this phenomenon is not detectable by the assessment of 25(OH)D, it is necessary to analyze the level of parathyroid hormone as a marker of calcitriol function. Because 25(OH)D levels are highly correlated with an active and healthy life style, data from epidemiological studies are not necessarily suitable to elucidate the role of vitamin D in disease prevention. Recently published meta-analyses of randomized controlled trials (RCTs) showed moderate effects of vitamin D supplementation on fracture risk and found that vitamin D was more effective when administered in combination with calcium. The role of vitamin D in the prevention of falls and frailty remains unclear. Much evidence has demonstrated the beneficial effects of vitamin D on respiratory tract infections and asthma, which are very relevant health issues in the older population. To conclude, vitamin D, particularly combined with calcium, has moderately beneficial effects on the skeletal system and is useful for the prevention of respiratory tract infections.
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http://dx.doi.org/10.1007/s00391-018-1390-zDOI Listing
July 2018

Impact of chocolate liquor on vascular lesions in apoE-knockout mice.

Clin Sci (Lond) 2017 10 12;131(20):2549-2560. Epub 2017 Oct 12.

Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Germany

Cocoa polyphenols are thought to reduce the risk of cardiovascular diseases. Thus, cocoa-containing foods may have significant health benefits. Here, we studied the impact of chocolate liquor on vascular lesion development and plaque composition in a mouse model of atherosclerosis. Apolipoprotein E (apoE)-knockout mice were assigned to two groups and fed a Western diet that contained 250 g/kg of either chocolate liquor or a polyphenol-free isoenergetic control paste for 16 weeks. In addition to fat, protein, and fibers, the chocolate liquor contained 2 g/kg of polyphenols. Compared with the control group, mice fed the chocolate liquor had larger plaque areas in the descending aorta and aortic root, which were attributed to a higher mass of vascular smooth muscle cells (VSMCs) and collagen. Vascular lipid deposits and calcification areas did not differ between the two groups. The aortic tissue level of interleukin-6 (IL-6) mRNA was 5-fold higher in the mice fed chocolate liquor than in the control mice. Chocolate-fed mice exhibited an increased hepatic saturated to polyunsaturated fatty acid ratio than the controls. Although the chocolate liquor contained 14 µg/kg of vitamin D, the chocolate liquor-fed mice did not have measurable 25-hydroxyvitamin D in the serum. These mice even showed a 25% reduction in the level of 25-hydroxyvitamin D compared with the control mice. Overall, present data may contribute to our understanding how chocolate constituents can impact vascular lesion development.
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http://dx.doi.org/10.1042/CS20170279DOI Listing
October 2017

Neuronal aromatase expression in pain processing regions of the medullary and spinal cord dorsal horn.

J Comp Neurol 2017 Nov 24;525(16):3414-3428. Epub 2017 Jul 24.

Department of Anatomy, University of California, San Francisco, San Francisco, California.

In both acute and chronic pain conditions, women tend to be more sensitive than men. This sex difference may be regulated by estrogens, such as estradiol, that are synthesized in the spinal cord and brainstem and act locally to influence pain processing. To identify a potential cellular source of local estrogen, here we examined the expression of aromatase, the enzyme that catalyzes the conversion of testosterone to estradiol. Our studies focused on primary afferent neurons and on their central targets in the spinal cord and medulla as well as in the nucleus of the solitary tract, the target of nodose ganglion-derived visceral afferents. Immunohistochemical staining in an aromatase reporter mouse revealed that many neurons in laminae I and V of the spinal cord dorsal horn and caudal spinal trigeminal nucleus and in the nucleus of the solitary tract express aromatase. The great majority of these cells also express inhibitory interneuron markers. We did not find sex differences in aromatase expression and neither the pattern nor the number of neurons changed in a sciatic nerve transection model of neuropathic pain or in the Complete Freund's adjuvant model of inflammatory pain. A few aromatase neurons express Fos after cheek injection of capsaicin, formalin, or chloroquine. In total, given their location, these aromatase neurons are poised to engage nociceptive circuits, whether it is through local estrogen synthesis or inhibitory neurotransmitter release.
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http://dx.doi.org/10.1002/cne.24269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174086PMC
November 2017

Functional Synaptic Integration of Forebrain GABAergic Precursors into the Adult Spinal Cord.

J Neurosci 2016 11;36(46):11634-11645

Department of Anatomy, University of California, San Francisco, California 94158, and

Spinal cord transplants of embryonic cortical GABAergic progenitor cells derived from the medial ganglionic eminence (MGE) can reverse mechanical hypersensitivity in the mouse models of peripheral nerve injury- and paclitaxel-induced neuropathic pain. Here, we used electrophysiology, immunohistochemistry, and electron microscopy to examine the extent to which MGE cells integrate into host circuitry and recapitulate endogenous inhibitory circuits. Whether the transplants were performed before or after nerve injury, the MGE cells developed into mature neurons and exhibited firing patterns characteristic of subpopulations of cortical and spinal cord inhibitory interneurons. Conversely, the transplanted cells preserved cortical morphological and neurochemical properties. We also observed a robust anatomical and functional synaptic integration of the transplanted cells into host circuitry in both injured and uninjured animals. The MGE cells were activated by primary afferents, including TRPV1-expressing nociceptors, and formed GABAergic, bicuculline-sensitive, synapses onto host neurons. Unexpectedly, MGE cells transplanted before injury prevented the development of mechanical hypersensitivity. Together, our findings provide direct confirmation of an extensive, functional synaptic integration of MGE cells into host spinal cord circuits. This integration underlies normalization of the dorsal horn inhibitory tone after injury and may be responsible for the prophylactic effect of preinjury transplants.

Significance Statement: Spinal cord transplants of embryonic cortical GABAergic interneuron progenitors from the medial ganglionic eminence (MGE), can overcome the mechanical hypersensitivity produced in different neuropathic pain models in adult mice. Here, we examined the properties of transplanted MGE cells and the extent to which they integrate into spinal cord circuitry. Using electrophysiology, immunohistochemistry, and electron microscopy, we demonstrate that MGE cells, whether transplanted before or after nerve injury, develop into inhibitory neurons, are activated by nociceptive primary afferents, and form GABA-A-mediated inhibitory synapses with the host. Unexpectedly, cells transplanted into naive spinal cord prevented the development of nerve-injury-induced mechanical hypersensitivity. These results illustrate the remarkable plasticity of adult spinal cord and the potential of cell-based therapies against neuropathic pain.
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http://dx.doi.org/10.1523/JNEUROSCI.2301-16.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125223PMC
November 2016

Oral intake of 7-dehydrocholesterol increases vitamin D concentrations in the liver and kidney.

J Steroid Biochem Mol Biol 2016 11 17;164:199-204. Epub 2015 Dec 17.

Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Von-Danckelmann-Platz 2, 06120 Halle (Saale), Germany. Electronic address:

Introduction: Due to the high prevalence of vitamin D deficiency, strategies are needed to improve vitamin D status. Food components can affect vitamin D metabolism and have to be considered when estimating the efficacy of vitamin D supplements. 7-dehydrocholesterol (7-DHC) occurs naturally in food, but its impact on vitamin D metabolism has not yet been examined.

Methods: Three groups of male C57BL/6 mice (n=12 per group) were placed on a diet that contained 0, 2.5 or 5mg 7-DHC per kg diet over a period of 6 weeks. Vitamin D and other sterols in the serum, skin, liver and kidney were quantified by LC-MS/MS. The relative mRNA abundance of hepatic genes encoding vitamin D hydroxylation enzymes and transporters was analyzed by real-time RT-PCR.

Results: We found a substantial dose-dependent increase of non-hydroxylated vitamin D in the liver and kidney of mice fed a diet containing 7-DHC. The vitamin D content in the liver was 2.80±0.61pmol/g, 7.34±4.28pmol/g and 12.9±3.58pmol/g in groups that received 0, 2.5 and 5mg/kg 7-DHC, respectively. In the kidney, the vitamin D content of these groups was 1.78±1.17pmol/g, 3.55±1.06 and 6.36±2.29pmol/g, respectively. The serum and tissue concentrations of 25-hydroxyvitamin D (25(OH)D) remained unaffected by 7-DHC. The relative mRNA data provided no plausible mechanism for the observed effects of 7-DHC on vitamin D. All groups of mice had similar concentrations of cholesterol, desmosterol and 7-DHC in their serum and tissues.

Conclusion: The current findings provide the first evidence that dietary 7-DHC seems to affect vitamin D metabolism. The underlying mechanism remains elusive and needs further investigation.
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http://dx.doi.org/10.1016/j.jsbmb.2015.12.017DOI Listing
November 2016

Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain.

Nat Neurosci 2016 Jan 7;19(1):94-101. Epub 2015 Dec 7.

Department of Anatomy, University of California San Francisco, San Francisco, California, USA.

Although microglia have been implicated in nerve injury-induced neuropathic pain, the manner by which injured sensory neurons engage microglia remains unclear. We found that peripheral nerve injury induced de novo expression of colony-stimulating factor 1 (CSF1) in injured sensory neurons. CSF1 was transported to the spinal cord, where it targeted the microglial CSF1 receptor (CSF1R). Cre-mediated sensory neuron deletion of Csf1 completely prevented nerve injury-induced mechanical hypersensitivity and reduced microglial activation and proliferation. In contrast, intrathecal injection of CSF1 induced mechanical hypersensitivity and microglial proliferation. Nerve injury also upregulated CSF1 in motoneurons, where it was required for ventral horn microglial activation and proliferation. Downstream of CSF1R, we found that the microglial membrane adaptor protein DAP12 was required for both nerve injury- and intrathecal CSF1-induced upregulation of pain-related microglial genes and the ensuing pain, but not for microglial proliferation. Thus, both CSF1 and DAP12 are potential targets for the pharmacotherapy of neuropathic pain.
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http://dx.doi.org/10.1038/nn.4189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703328PMC
January 2016

Drosophila muller f elements maintain a distinct set of genomic properties over 40 million years of evolution.

Authors:
Wilson Leung Christopher D Shaffer Laura K Reed Sheryl T Smith William Barshop William Dirkes Matthew Dothager Paul Lee Jeannette Wong David Xiong Han Yuan James E J Bedard Joshua F Machone Seantay D Patterson Amber L Price Bryce A Turner Srebrenka Robic Erin K Luippold Shannon R McCartha Tezin A Walji Chelsea A Walker Kenneth Saville Marita K Abrams Andrew R Armstrong William Armstrong Robert J Bailey Chelsea R Barberi Lauren R Beck Amanda L Blaker Christopher E Blunden Jordan P Brand Ethan J Brock Dana W Brooks Marie Brown Sarah C Butzler Eric M Clark Nicole B Clark Ashley A Collins Rebecca J Cotteleer Peterson R Cullimore Seth G Dawson Carter T Docking Sasha L Dorsett Grace A Dougherty Kaitlyn A Downey Andrew P Drake Erica K Earl Trevor G Floyd Joshua D Forsyth Jonathan D Foust Spencer L Franchi James F Geary Cynthia K Hanson Taylor S Harding Cameron B Harris Jonathan M Heckman Heather L Holderness Nicole A Howey Dontae A Jacobs Elizabeth S Jewell Maria Kaisler Elizabeth A Karaska James L Kehoe Hannah C Koaches Jessica Koehler Dana Koenig Alexander J Kujawski Jordan E Kus Jennifer A Lammers Rachel R Leads Emily C Leatherman Rachel N Lippert Gregory S Messenger Adam T Morrow Victoria Newcomb Haley J Plasman Stephanie J Potocny Michelle K Powers Rachel M Reem Jonathan P Rennhack Katherine R Reynolds Lyndsey A Reynolds Dong K Rhee Allyson B Rivard Adam J Ronk Meghan B Rooney Lainey S Rubin Luke R Salbert Rasleen K Saluja Taylor Schauder Allison R Schneiter Robert W Schulz Karl E Smith Sarah Spencer Bryant R Swanson Melissa A Tache Ashley A Tewilliager Amanda K Tilot Eve VanEck Matthew M Villerot Megan B Vylonis David T Watson Juliana A Wurzler Lauren M Wysocki Monica Yalamanchili Matthew A Zaborowicz Julia A Emerson Carlos Ortiz Frederic J Deuschle Lauren A DiLorenzo Katie L Goeller Christopher R Macchi Sarah E Muller Brittany D Pasierb Joseph E Sable Jessica M Tucci Marykathryn Tynon David A Dunbar Levent H Beken Alaina C Conturso Benjamin L Danner Gabriella A DeMichele Justin A Gonzales Maureen S Hammond Colleen V Kelley Elisabeth A Kelly Danielle Kulich Catherine M Mageeney Nikie L McCabe Alyssa M Newman Lindsay A Spaeder Richard A Tumminello Dennis Revie Jonathon M Benson Michael C Cristostomo Paolo A DaSilva Katherine S Harker Jenifer N Jarrell Luis A Jimenez Brandon M Katz William R Kennedy Kimberly S Kolibas Mark T LeBlanc Trung T Nguyen Daniel S Nicolas Melissa D Patao Shane M Patao Bryan J Rupley Bridget J Sessions Jennifer A Weaver Anya L Goodman Erica L Alvendia Shana M Baldassari Ashley S Brown Ian O Chase Maida Chen Scott Chiang Avery B Cromwell Ashley F Custer Tia M DiTommaso Jad El-Adaimi Nora C Goscinski Ryan A Grove Nestor Gutierrez Raechel S Harnoto Heather Hedeen Emily L Hong Barbara L Hopkins Vilma F Huerta Colin Khoshabian Kristin M LaForge Cassidy T Lee Benjamin M Lewis Anniken M Lydon Brian J Maniaci Ryan D Mitchell Elaine V Morlock William M Morris Priyanka Naik Nicole C Olson Jeannette M Osterloh Marcos A Perez Jonathan D Presley Matt J Randazzo Melanie K Regan Franca G Rossi Melanie A Smith Eugenia A Soliterman Ciani J Sparks Danny L Tran Tiffany Wan Anne A Welker Jeremy N Wong Aparna Sreenivasan Jim Youngblom Andrew Adams Justin Alldredge Ashley Bryant David Carranza Alyssa Cifelli Kevin Coulson Calise Debow Noelle Delacruz Charlene Emerson Cassandra Farrar Don Foret Edgar Garibay John Gooch Michelle Heslop Sukhjit Kaur Ambreen Khan Van Kim Travis Lamb Peter Lindbeck Gabi Lucas Elizabeth Macias Daniela Martiniuc Lissett Mayorga Joseph Medina Nelson Membreno Shady Messiah Lacey Neufeld San Francisco Nguyen Zachary Nichols George Odisho Daymon Peterson Laura Rodela Priscilla Rodriguez Vanessa Rodriguez Jorge Ruiz Will Sherrill Valeria Silva Jeri Sparks Geeta Statton Ashley Townsend Isabel Valdez Mary Waters Kyle Westphal Stacey Winkler Joannee Zumkehr Randall J DeJong Arlene J Hoogewerf Cheri M Ackerman Isaac O Armistead Lara Baatenburg Matthew J Borr Lindsay K Brouwer Brandon J Burkhart Kelsey T Bushhouse Lejla Cesko Tiffany Y Y Choi Heather Cohen Amanda M Damsteegt Jess M Darusz Cory M Dauphin Yelena P Davis Emily J Diekema Melissa Drewry Michelle E M Eisen Hayley M Faber Katherine J Faber Elizabeth Feenstra Isabella T Felzer-Kim Brandy L Hammond Jesse Hendriksma Milton R Herrold Julia A Hilbrands Emily J Howell Sarah A Jelgerhuis Timothy R Jelsema Benjamin K Johnson Kelly K Jones Anna Kim Ross D Kooienga Erika E Menyes Eric A Nollet Brittany E Plescher Lindsay Rios Jenny L Rose Allison J Schepers Geoff Scott Joshua R Smith Allison M Sterling Jenna C Tenney Chris Uitvlugt Rachel E VanDyken Marielle VanderVennen Samantha Vue Nighat P Kokan Kwabea Agbley Sampson K Boham Daniel Broomfield Kayla Chapman Ali Dobbe Ian Dobbe William Harrington Marwan Ibrahem Andre Kennedy Chad A Koplinsky Cassandra Kubricky Danielle Ladzekpo Claire Pattison Roman E Ramirez Lucia Wande Sarah Woehlke Matthew Wawersik Elizabeth Kiernan Jeffrey S Thompson Roxanne Banker Justina R Bartling Chinmoy I Bhatiya Anna L Boudoures Lena Christiansen Daniel S Fosselman Kristin M French Ishwar S Gill Jessen T Havill Jaelyn L Johnson Lauren J Keny John M Kerber Bethany M Klett Christina N Kufel Francis J May Jonathan P Mecoli Callie R Merry Lauren R Meyer Emily G Miller Gregory J Mullen Katherine C Palozola Jacob J Pfeil Jessica G Thomas Evan M Verbofsky Eric P Spana Anant Agarwalla Julia Chapman Ben Chlebina Insun Chong I N Falk John D Fitzgibbons Harrison Friedman Osagie Ighile Andrew J Kim Kristin A Knouse Faith Kung Danny Mammo Chun Leung Ng Vinayak S Nikam Diana Norton Philip Pham Jessica W Polk Shreya Prasad Helen Rankin Camille D Ratliff Victoria Scala Nicholas U Schwartz Jessica A Shuen Amy Xu Thomas Q Xu Yi Zhang Anne G Rosenwald Martin G Burg Stephanie J Adams Morgan Baker Bobbi Botsford Briana Brinkley Carter Brown Shadie Emiah Erica Enoch Chad Gier Alyson Greenwell Lindsay Hoogenboom Jordan E Matthews Mitchell McDonald Amanda Mercer Nicholaus Monsma Kristine Ostby Alen Ramic Devon Shallman Matthew Simon Eric Spencer Trisha Tomkins Pete Wendland Anna Wylie Michael J Wolyniak Gregory M Robertson Samuel I Smith Justin R DiAngelo Eric D Sassu Satish C Bhalla Karim A Sharif Tenzin Choeying Jason S Macias Fareed Sanusi Karvyn Torchon April E Bednarski Consuelo J Alvarez Kristen C Davis Carrie A Dunham Alaina J Grantham Amber N Hare Jennifer Schottler Zackary W Scott Gary A Kuleck Nicole S Yu Marian M Kaehler Jacob Jipp Paul J Overvoorde Elizabeth Shoop Olivia Cyrankowski Betsy Hoover Matt Kusner Devry Lin Tijana Martinov Jonathan Misch Garrett Salzman Holly Schiedermayer Michael Snavely Stephanie Zarrasola Susan Parrish Atlee Baker Alissa Beckett Carissa Belella Julie Bryant Turner Conrad Adam Fearnow Carolina Gomez Robert A Herbstsomer Sarah Hirsch Christen Johnson Melissa Jones Rita Kabaso Eric Lemmon Carolina Marques Dos Santos Vieira Darryl McFarland Christopher McLaughlin Abbie Morgan Sepo Musokotwane William Neutzling Jana Nietmann Christina Paluskievicz Jessica Penn Emily Peoples Caitlin Pozmanter Emily Reed Nichole Rigby Lasse Schmidt Micah Shelton Rebecca Shuford Tiara Tirasawasdichai Blair Undem Damian Urick Kayla Vondy Bryan Yarrington Todd T Eckdahl Jeffrey L Poet Alica B Allen John E Anderson Jason M Barnett Jordan S Baumgardner Adam D Brown Jordan E Carney Ramiro A Chavez Shelbi L Christgen Jordan S Christie Andrea N Clary Michel A Conn Kristen M Cooper Matt J Crowley Samuel T Crowley Jennifer S Doty Brian A Dow Curtis R Edwards Darcie D Elder John P Fanning Bridget M Janssen Anthony K Lambright Curtiss E Lane Austin B Limle Tammy Mazur Marly R McCracken Alexa M McDonough Amy D Melton Phillip J Minnick Adam E Musick William H Newhart Joseph W Noynaert Bradley J Ogden Michael W Sandusky Samantha M Schmuecker Anna L Shipman Anna L Smith Kristen M Thomsen Matthew R Unzicker William B Vernon Wesley W Winn Dustin S Woyski Xiao Zhu Chunguang Du Caitlin Ament Soham Aso Laura Simone Bisogno Jason Caronna Nadezhda Fefelova Lenin Lopez Lorraine Malkowitz Jonathan Marra Daniella Menillo Ifeanyi Obiorah Eric Nyabeta Onsarigo Shekerah Primus Mahdi Soos Archana Tare Ameer Zidan Christopher J Jones Todd Aronhalt James M Bellush Christa Burke Steve DeFazio Benjamin R Does Todd D Johnson Nicholas Keysock Nelson H Knudsen James Messler Kevin Myirski Jade Lea Rekai Ryan Michael Rempe Michael S Salgado Erica Stagaard Justin R Starcher Andrew W Waggoner Anastasia K Yemelyanova Amy T Hark Anne Bertolet Cyrus E Kuschner Kesley Parry Michael Quach Lindsey Shantzer Mary E Shaw Mary A Smith Omolara Glenn Portia Mason Charlotte Williams S Catherine Silver Key Tyneshia C P Henry Ashlee G Johnson Jackie X White Adam Haberman Sam Asinof Kelly Drumm Trip Freeburg Nadia Safa Darrin Schultz Yakov Shevin Petros Svoronos Tam Vuong Jules Wellinghoff Laura L M Hoopes Kim M Chau Alyssa Ward E Gloria C Regisford LaJerald Augustine Brionna Davis-Reyes Vivienne Echendu Jasmine Hales Sharon Ibarra Lauriaun Johnson Steven Ovu John M Braverman Thomas J Bahr Nicole M Caesar Christopher Campana Daniel W Cassidy Peter A Cognetti Johnathan D English Matthew C Fadus Cameron N Fick Philip J Freda Bryan M Hennessy Kelsey Hockenberger Jennifer K Jones Jessica E King Christopher R Knob Karen J Kraftmann Linghui Li Lena N Lupey Carl J Minniti Thomas F Minton Joseph V Moran Krishna Mudumbi Elizabeth C Nordman William J Puetz Lauren M Robinson Thomas J Rose Edward P Sweeney Ashley S Timko Don W Paetkau Heather L Eisler Megan E Aldrup Jessica M Bodenberg Mara G Cole Kelly M Deranek Megan DeShetler Rose M Dowd Alexandra K Eckardt Sharon C Ehret Jessica Fese Amanda D Garrett Anna Kammrath Michelle L Kappes Morgan R Light Anne C Meier Allison O'Rouke Mallory Perella Kimberley Ramsey Jennifer R Ramthun Mary T Reilly Deirdre Robinett Nadine L Rossi Mary Grace Schueler Emma Shoemaker Kristin M Starkey Ashley Vetor Abby Vrable Vidya Chandrasekaran Christopher Beck Kristen R Hatfield Douglas A Herrick Christopher B Khoury Charlotte Lea Christopher A Louie Shannon M Lowell Thomas J Reynolds Jeanine Schibler Alexandra H Scoma Maxwell T Smith-Gee Sarah Tuberty Christopher D Smith Jane E Lopilato Jeanette Hauke Jennifer A Roecklein-Canfield Maureen Corrielus Hannah Gilman Stephanie Intriago Amanda Maffa Sabya A Rauf Katrina Thistle Melissa Trieu Jenifer Winters Bib Yang Charles R Hauser Tariq Abusheikh Yara Ashrawi Pedro Benitez Lauren R Boudreaux Megan Bourland Miranda Chavez Samantha Cruz GiNell Elliott Jesse R Farek Sarah Flohr Amanda H Flores Chelsey Friedrichs Zach Fusco Zane Goodwin Eric Helmreich John Kiley John Mark Knepper Christine Langner Megan Martinez Carlos Mendoza Monal Naik Andrea Ochoa Nicolas Ragland England Raimey Sunil Rathore Evangelina Reza Griffin Sadovsky Marie-Isabelle B Seydoux Jonathan E Smith Anna K Unruh Vicente Velasquez Matthew W Wolski Yuying Gosser Shubha Govind Nicole Clarke-Medley Leslie Guadron Dawn Lau Alvin Lu Cheryl Mazzeo Mariam Meghdari Simon Ng Brad Pamnani Olivia Plante Yuki Kwan Wa Shum Roy Song Diana E Johnson Mai Abdelnabi Alexi Archambault Norma Chamma Shailly Gaur Deborah Hammett Adrese Kandahari Guzal Khayrullina Sonali Kumar Samantha Lawrence Nigel Madden Max Mandelbaum Heather Milnthorp Shiv Mohini Roshni Patel Sarah J Peacock Emily Perling Amber Quintana Michael Rahimi Kristen Ramirez Rishi Singhal Corinne Weeks Tiffany Wong Aubree T Gillis Zachary D Moore Christopher D Savell Reece Watson Stephanie F Mel Arjun A Anilkumar Paul Bilinski Rostislav Castillo Michael Closser Nathalia M Cruz Tiffany Dai Giancarlo F Garbagnati Lanor S Horton Dongyeon Kim Joyce H Lau James Z Liu Sandy D Mach Thu A Phan Yi Ren Kenneth E Stapleton Jean M Strelitz Ray Sunjed Joyce Stamm Morgan C Anderson Bethany Grace Bonifield Daniel Coomes Adam Dillman Elaine J Durchholz Antoinette E Fafara-Thompson Meleah J Gross Amber M Gygi Lesley E Jackson Amy Johnson Zuzana Kocsisova Joshua L Manghelli Kylie McNeil Michael Murillo Kierstin L Naylor Jessica Neely Emmy E Ogawa Ashley Rich Anna Rogers J Devin Spencer Kristina M Stemler Allison A Throm Matt Van Camp Katie Weihbrecht T Aaron Wiles Mallory A Williams Matthew Williams Kyle Zoll Cheryl Bailey Leming Zhou Darla M Balthaser Azita Bashiri Mindy E Bower Kayla A Florian Nazanin Ghavam Elizabeth S Greiner-Sosanko Helmet Karim Victor W Mullen Carly E Pelchen Paul M Yenerall Jiayu Zhang Michael R Rubin Suzette M Arias-Mejias Armando G Bermudez-Capo Gabriela V Bernal-Vega Mariela Colon-Vazquez Arelys Flores-Vazquez Mariela Gines-Rosario Ivan G Llavona-Cartagena Javier O Martinez-Rodriguez Lionel Ortiz-Fuentes Eliezer O Perez-Colomba Joseph Perez-Otero Elisandra Rivera Luke J Rodriguez-Giron Arnaldo J Santiago-Sanabria Andrea M Senquiz-Gonzalez Frank R Soto delValle Dorianmarie Vargas-Franco Karla I Velázquez-Soto Joan D Zambrana-Burgos Juan Carlos Martinez-Cruzado Lillyann Asencio-Zayas Kevin Babilonia-Figueroa Francis D Beauchamp-Pérez Juliana Belén-Rodríguez Luciann Bracero-Quiñones Andrea P Burgos-Bula Xavier A Collado-Méndez Luis R Colón-Cruz Ana I Correa-Muller Jonathan L Crooke-Rosado José M Cruz-García Marianna Defendini-Ávila Francheska M Delgado-Peraza Alex J Feliciano-Cancela Valerie M Gónzalez-Pérez Wilfried Guiblet Aldo Heredia-Negrón Jennifer Hernández-Muñiz Lourdes N Irizarry-González Ángel L Laboy-Corales Gabriela A Llaurador-Caraballo Frances Marín-Maldonado Ulises Marrero-Llerena Héctor A Martell-Martínez Idaliz M Martínez-Traverso Kiara N Medina-Ortega Sonya G Méndez-Castellanos Krizia C Menéndez-Serrano Carol I Morales-Caraballo Saryleine Ortiz-DeChoudens Patricia Ortiz-Ortiz Hendrick Pagán-Torres Diana Pérez-Afanador Enid M Quintana-Torres Edwin G Ramírez-Aponte Carolina Riascos-Cuero Michelle S Rivera-Llovet Ingrid T Rivera-Pagán Ramón E Rivera-Vicéns Fabiola Robles-Juarbe Lorraine Rodríguez-Bonilla Brian O Rodríguez-Echevarría Priscila M Rodríguez-García Abneris E Rodríguez-Laboy Susana Rodríguez-Santiago Michael L Rojas-Vargas Eva N Rubio-Marrero Albeliz Santiago-Colón Jorge L Santiago-Ortiz Carlos E Santos-Ramos Joseline Serrano-González Alina M Tamayo-Figueroa Edna P Tascón-Peñaranda José L Torres-Castillo Nelson A Valentín-Feliciano Yashira M Valentín-Feliciano Nadyan M Vargas-Barreto Miguel Vélez-Vázquez Luis R Vilanova-Vélez Cristina Zambrana-Echevarría Christy MacKinnon Hui-Min Chung Chris Kay Anthony Pinto Olga R Kopp Joshua Burkhardt Chris Harward Robert Allen Pavan Bhat Jimmy Hsiang-Chun Chang York Chen Christopher Chesley Dara Cohn David DuPuis Michael Fasano Nicholas Fazzio Katherine Gavinski Heran Gebreyesus Thomas Giarla Marcus Gostelow Rachel Greenstein Hashini Gunasinghe Casey Hanson Amanda Hay Tao Jian He Katie Homa Ruth Howe Jeff Howenstein Henry Huang Aaditya Khatri Young Lu Kim Olivia Knowles Sarah Kong Rebecca Krock Matt Kroll Julia Kuhn Matthew Kwong Brandon Lee Ryan Lee Kevin Levine Yedda Li Bo Liu Lucy Liu Max Liu Adam Lousararian Jimmy Ma Allyson Mallya Charlie Manchee Joseph Marcus Stephen McDaniel Michelle L Miller Jerome M Molleston Cristina Montero Diez Patrick Ng Natalie Ngai Hien Nguyen Andrew Nylander Jason Pollack Suchita Rastogi Himabindu Reddy Nathaniel Regenold Jon Sarezky Michael Schultz Jien Shim Tara Skorupa Kenneth Smith Sarah J Spencer Priya Srikanth Gabriel Stancu Andrew P Stein Marshall Strother Lisa Sudmeier Mengyang Sun Varun Sundaram Noor Tazudeen Alan Tseng Albert Tzeng Rohit Venkat Sandeep Venkataram Leah Waldman Tracy Wang Hao Yang Jack Y Yu Yin Zheng Mary L Preuss Angelica Garcia Matt Juergens Robert W Morris Alexis A Nagengast Julie Azarewicz Thomas J Carr Nicole Chichearo Mike Colgan Megan Donegan Bob Gardner Nik Kolba Janice L Krumm Stacey Lytle Laurell MacMillian Mary Miller Andrew Montgomery Alysha Moretti Brittney Offenbacker Mike Polen John Toth John Woytanowski Lisa Kadlec Justin Crawford Mary L Spratt Ashley L Adams Brianna K Barnard Martin N Cheramie Anne M Eime Kathryn L Golden Allyson P Hawkins Jessica E Hill Jessica A Kampmeier Cody D Kern Emily E Magnuson Ashley R Miller Cody M Morrow Julia C Peairs Gentry L Pickett Sarah A Popelka Alexis J Scott Emily J Teepe Katie A TerMeer Carmen A Watchinski Lucas A Watson Rachel E Weber Kate A Woodard Daron C Barnard Isaac Appiah Michelle M Giddens Gerard P McNeil Adeola Adebayo Kate Bagaeva Justina Chinwong Chrystel Dol Eunice George Kirk Haltaufderhyde Joanna Haye Manpreet Kaur Max Semon Dmitri Serjanov Anika Toorie Christopher Wilson Nicole C Riddle Jeremy Buhler Elaine R Mardis Sarah C R Elgin

G3 (Bethesda) 2015 Mar 4;5(5):719-40. Epub 2015 Mar 4.

Department of Biology, Washington University in St. Louis, St. Louis, MO 63130

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25-50%) than euchromatic reference regions (3-11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11-27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4-3.6 vs. 8.4-8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.
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http://dx.doi.org/10.1534/g3.114.015966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4426361PMC
March 2015

Non-linear increase of vitamin D content in eggs from chicks treated with increasing exposure times of ultraviolet light.

J Steroid Biochem Mol Biol 2015 Apr 27;148:7-13. Epub 2014 Oct 27.

Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Von-Danckelmann-Platz 2, Halle (Saale) 06120, Germany. Electronic address:

Vitamin D fortified food can help to reduce the prevalence for vitamin D deficiency. Previous data provided evidence that eggs from hens exposed to ultraviolet (UV) light contain large quantities of vitamin D. In the current study, we assessed the efficacy of vitamin D enrichment in eggs upon increasing daily UVB exposure times. We further addressed the question whether extended UVB irradiation affects the skin content of 7-dehydrocholesterol. To this end, 35 hens were assigned to 7 groups of 5 animals each and were exposed to UVB light (76μW/cm(2)) for 0, 15, 30, 60, 120, 180 and 300min per day, respectively. Eggs from the treatment groups were collected at baseline and after 2, 3 and 4 weeks of treatment, respectively. Skin samples were gained at the end of 4 weeks. Vitamin D metabolites were quantified by liquid chromatography-tandem mass spectrometry. The contents of vitamin D3 and 25(OH)D3 in egg yolk raised non-linear in response to increasing daily UVB exposure times. The vitamin D3 content did not reach a clear-cut plateau within the chosen UVB treatment times. A daily UVB exposure time of 300min resulted in vitamin D3 contents of 28.6μg/100g egg yolk dry matter. In contrast to vitamin D3, the 25(OH)D3 content in the egg yolk achieved a maximum upon an UVB irradiation time of 60min/d. The cutaneous 7-dehydrocholesterol contents were not altered in response to the chosen UVB irradiation times. In conclusion, the data show a distinct non-linear dose-response relationship of UVB exposure times on the total vitamin D content in eggs. This article is part of a special issue entitled '17th Vitamin D Workshop'.
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http://dx.doi.org/10.1016/j.jsbmb.2014.10.015DOI Listing
April 2015

Free-range farming: a natural alternative to produce vitamin D-enriched eggs.

Nutrition 2014 Apr 14;30(4):481-4. Epub 2013 Oct 14.

Institute of Agricultural and Nutritional Sciences, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany. Electronic address:

Objective: Food-based strategies need to be developed to improve the vitamin D status of individuals. Recent studies identified ultraviolet B irradiation as an efficient method to enrich mushrooms and eggs with vitamin D. The aim of this study was to determine whether free-range farming of hens could provide a valuable method to produce vitamin D-enriched eggs.

Methods: Laying hens were randomly assigned to three groups of 33 to 34 animals each, and were kept either indoors (indoor group), outdoors (outdoor group), or with an indoor/outdoor option (indoor/outdoor group) over 4 wk.

Results: The study shows that the vitamin D3 content of egg yolk was three- to fourfold higher in the groups that were exposed to sunlight (outdoor and indoor/outdoor groups) compared with the indoor group (P < 0.001). Egg yolk from the outdoor group revealed the highest vitamin D3 content, which averaged 14.3 μg/100 g dry matter (DM), followed by that from the indoor/outdoor group (11.3 μg/100 g DM). Yolk from indoor eggs contained only 3.8 μg vitamin D/100 g DM. The 25-hydroxyvitamin D (25[OH]D3) content of egg yolk was also influenced by sunlight exposure, although less pronounced than the vitamin D content (P < 0.05). In contrast, free-range eggs randomly acquired from supermarkets had relatively low vitamin D contents.

Conclusion: Free-range farming offers an efficient alternative to fortify eggs with vitamin D, provided that farming conditions are sufficiently attractive for hens to range outside.
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http://dx.doi.org/10.1016/j.nut.2013.10.002DOI Listing
April 2014

The prognostic effect of high diagnostic WT1 gene expression in pediatric AML depends on WT1 SNP rs16754 status: report from the Children's Oncology Group.

Pediatr Blood Cancer 2014 Jan 16;61(1):81-8. Epub 2013 Aug 16.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Pediatric Hematology/Oncology, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, Washington; Children's Oncology Group, Arcadia, California.

Background: WT1 is aberrantly over-expressed in most cases of AML. We recently demonstrated that WT1 SNP rs16754 correlates with favorable outcome and high diagnostic WT1 expression in childhood AML. We examined the clinical correlates of diagnostic WT1 expression within a contemporary COG trial and determined whether its prognostic impact differs between SNP+ and SNP- patients.

Procedure: WT1 mRNA expression was measured via qRT-PCR in diagnostic specimens obtained from 225 patients enrolled on COG-AAML03P1. Direct sequencing of WT1 exon 7 was performed to determine SNP rs16754 genotype. WT1 expression was correlated with disease characteristics, SNP status, and outcome.

Results: Patients were categorized into four groups (quartiles: Q1 through Q4) based on diagnostic WT1 expression for analysis. FLT3/ITD (P = 0.017) and WT1 mutations (P < 0.001) both occurred more frequently in patients with the highest WT1 expression. SNP rs16754 frequency did not vary significantly among the quartiles. When all patients were considered, survival outcomes were similar between quartiles. However, when only SNP- patients (n = 150) were analyzed, those with highest WT1 expression (Q4) had the poorest OS (51% vs. 72% for Q1-Q3, P = 0.006) and EFS (35% vs. 54% for Q1-Q3, P = 0.031). Among SNP+ patients (n = 75), survival did not vary significantly between WT1 expression quartiles.

Conclusion: Although WT1 expression was not prognostic when all patients were considered together, stratifying patients by SNP rs16754 genotype revealed significant differences in outcome. In SNP- patients, high WT1 expression predicted decreased survival in univariate, but not multivariate, analysis, due to a preponderance of high-risk cyto/molecular abnormalities in the highest expression quartile.
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http://dx.doi.org/10.1002/pbc.24700DOI Listing
January 2014

Ca++/CaMKII switches nociceptor-sensitizing stimuli into desensitizing stimuli.

J Neurochem 2012 Nov 28;123(4):589-601. Epub 2012 Sep 28.

Max Planck Institute for Molecular Genetics, Berlin, Germany.

Many extracellular factors sensitize nociceptors. Often they act simultaneously and/or sequentially on nociceptive neurons. We investigated if stimulation of the protein kinase C epsilon (PKCε) signaling pathway influences the signaling of a subsequent sensitizing stimulus. Central in activation of PKCs is their transient translocation to cellular membranes. We found in cultured nociceptive neurons that only a first stimulation of the PKCε signaling pathway resulted in PKCε translocation. We identified a novel inhibitory cascade to branch off upstream of PKCε, but downstream of Epac via IP3-induced calcium release. This signaling branch actively inhibited subsequent translocation and even attenuated ongoing translocation. A second 'sensitizing' stimulus was rerouted from the sensitizing to the inhibitory branch of the signaling cascade. Central for the rerouting was cytoplasmic calcium increase and CaMKII activation. Accordingly, in behavioral experiments, activation of calcium stores switched sensitizing substances into desensitizing substances in a CaMKII-dependent manner. This mechanism was also observed by in vivo C-fiber electrophysiology corroborating the peripheral location of the switch. Thus, we conclude that the net effect of signaling in nociceptors is defined by the context of the individual cell's signaling history.
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http://dx.doi.org/10.1111/j.1471-4159.2012.07920.xDOI Listing
November 2012

Prognostic implications of the IDH1 synonymous SNP rs11554137 in pediatric and adult AML: a report from the Children's Oncology Group and SWOG.

Blood 2011 Oct 26;118(17):4561-6. Epub 2011 Aug 26.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

IDH1 SNP rs11554137 was recently reported in association with poor prognosis in normal karyotype adult acute myeloid leukemia (AML). We aimed to determine the prevalence, clinical associations, and prognostic significance of SNP rs11554137 in unselected pediatric and adult AML patients. Diagnostic marrow specimens from 527 AML patients treated on the pediatric trial Children's Oncology Group-AAML03P1 (N = 253) or adult SWOG trials (N = 274) were analyzed for the presence of the SNP. SNP rs11554137 was present in 11% of all patients. SNP status had no prognostic impact on survival in pediatric patients. In adult AML, overall survival for SNP-positive patients was 10% versus 18% for SNP-negative patients (P = .44). Among the 142 adults who achieved complete remission, 5-year relapse-free survival was significantly worse for SNP-positive patients (0% vs 25%, P = .0014). However, among adults with normal cytogenetics, FLT3/ITD was present in 90% of SNP-positive patients versus 59% of SNP-negative patients (P = .0053). In multivariate analysis, adjusting for the effects of age, cytogenetics, and FLT3/ITD, the independent prognostic effect of SNP positivity was not statistically significant (hazard ratio = 1.72, P = .18). The clinical profile of SNP-positive patients suggests that SNP rs11554137 may have biologic effects that bear further investigation. The clinical trials in this study are registered at http://www.clinicaltrials.gov as #NCT000707174 and #NCT00899171.
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http://dx.doi.org/10.1182/blood-2011-04-348888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3208275PMC
October 2011

Estrogen destabilizes microtubules through an ion-conductivity-independent TRPV1 pathway.

J Neurochem 2011 Jun 13;117(6):995-1008. Epub 2011 May 13.

Department for Molecular Human Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.

Recently, we described estrogen and agonists of the G-protein coupled estrogen receptor GPR30 to induce protein kinase C (PKC)ε-dependent pain sensitization. PKCε phosphorylates the ion channel transient receptor potential, vanilloid subclass I (TRPV1) close to a novel microtubule-TRPV1 binding site. We now modeled the binding of tubulin to the TRPV1 C-terminus. The model suggests PKCε phosphorylation of TRPV1-S800 to abolish the tubulin-TRPV1 interaction. Indeed, in vitro PKCε phosphorylation of TRPV1 hindered tubulin-binding to TRPV1. In vivo, treatment of sensory neurons and F-11 cells with estrogen and the GPR30 agonist, G-1, resulted in microtubule destabilization and retraction of microtubules from filopodial structures. We found estrogen and G-1 to regulate the stability of the microtubular network via PKC phosphorylation of the PKCε-phosphorylation site TRPV1-S800. Microtubule disassembly was not, however, dependent on TRPV1 ion conductivity. TRPV1 knock-down in rats inverted the effect of the microtubule-modulating drugs, Taxol and Nocodazole, on estrogen-induced and PKCε-dependent mechanical pain sensitization. Thus, we suggest the C-terminus of TRPV1 to be a signaling intermediate downstream of estrogen and PKCε, regulating microtubule-stability and microtubule-dependent pain sensitization.
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http://dx.doi.org/10.1111/j.1471-4159.2011.07270.xDOI Listing
June 2011

WT1 synonymous single nucleotide polymorphism rs16754 correlates with higher mRNA expression and predicts significantly improved outcome in favorable-risk pediatric acute myeloid leukemia: a report from the children's oncology group.

J Clin Oncol 2011 Feb 28;29(6):704-11. Epub 2010 Dec 28.

Fred Hutchinson Cancer Research Center, D2-373, 1100 Fairview Ave N, Seattle, WA 98103, USA.

Purpose: To analyze the prevalence and clinical implications of Wilms' tumor 1 (WT1) single nucleotide polymorphism (SNP) rs16754 in the context of other prognostic markers in pediatric acute myeloid leukemia (AML).

Patients And Methods: Available diagnostic marrow specimens (n = 790) from 1,328 patients enrolled in three consecutive Children's Cancer Group/Children's Oncology Group trials were analyzed for the presence of SNP rs16754. SNP status was correlated with disease characteristics, WT1 expression level, and clinical outcome.

Results: SNP rs16754 was present in 229 (29%) of 790 patients. The SNP was significantly more common in Asian and Hispanic patients and less common in white patients (P < .001). SNP rs16754 was also less common in patients with inv(16) (P = .043) and more common in patients with -5/del(5q) (P = .047). WT1 expression levels were significantly higher in patients with rs16754 or with WT1 mutations compared with WT1 wild-type patients (P = .021). Five-year overall survival (OS) for patients with and without the SNP was 60% and 50%, respectively (P = .031). Prognostic assessment by risk group demonstrated that in patients with low-risk disease, OS for those with and without SNP rs16754 was 90% versus 64% (P < .001) with a corresponding disease-free survival of 72% versus 53% (P = .041).

Conclusion: The presence of SNP rs16754 was an independent predictor of improved OS; outcome differences were most pronounced in the low-risk subgroup. The high prevalence of WT1 SNP rs16754, and its correlation with improved outcome, identifies WT1 SNP rs16754 as a potentially important molecular marker of prognosis in pediatric AML.
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http://dx.doi.org/10.1200/JCO.2010.31.9327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056655PMC
February 2011

Importance of non-selective cation channel TRPV4 interaction with cytoskeleton and their reciprocal regulations in cultured cells.

PLoS One 2010 Jul 19;5(7):e11654. Epub 2010 Jul 19.

Signal Transduction in Pain and Mental Retardation, Department for Molecular Human Genetics Max Planck Institute for Molecular Genetics, Berlin, Germany.

Background: TRPV4 and the cellular cytoskeleton have each been reported to influence cellular mechanosensitive processes as well as the development of mechanical hyperalgesia. If and how TRPV4 interacts with the microtubule and actin cytoskeleton at a molecular and functional level is not known.

Methodology And Principal Findings: We investigated the interaction of TRPV4 with cytoskeletal components biochemically, cell biologically by observing morphological changes of DRG-neurons and DRG-neuron-derived F-11 cells, as well as functionally with calcium imaging. We find that TRPV4 physically interacts with tubulin, actin and neurofilament proteins as well as the nociceptive molecules PKCepsilon and CamKII. The C-terminus of TRPV4 is sufficient for the direct interaction with tubulin and actin, both with their soluble and their polymeric forms. Actin and tubulin compete for binding. The interaction with TRPV4 stabilizes microtubules even under depolymerizing conditions in vitro. Accordingly, in cellular systems TRPV4 colocalizes with actin and microtubules enriched structures at submembranous regions. Both expression and activation of TRPV4 induces striking morphological changes affecting lamellipodial, filopodial, growth cone, and neurite structures in non-neuronal cells, in DRG-neuron derived F11 cells, and also in IB4-positive DRG neurons. The functional interaction of TRPV4 and the cytoskeleton is mutual as Taxol, a microtubule stabilizer, reduces the Ca2+-influx via TRPV4.

Conclusions And Significance: TRPV4 acts as a regulator for both, the microtubule and the actin. In turn, we describe that microtubule dynamics are an important regulator of TRPV4 activity. TRPV4 forms a supra-molecular complex containing cytoskeletal proteins and regulatory kinases. Thereby it can integrate signaling of various intracellular second messengers and signaling cascades, as well as cytoskeletal dynamics. This study points out the existence of cross-talks between non-selective cation channels and cytoskeleton at multiple levels. These cross talks may help us to understand the molecular basis of the Taxol-induced neuropathic pain development commonly observed in cancer patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0011654PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2906515PMC
July 2010

Bovine and mouse SLO3 K+ channels: evolutionary divergence points to an RCK1 region of critical function.

J Biol Chem 2009 Aug 27;284(32):21589-98. Epub 2009 May 27.

Department of Anatomy and Neurobiology, Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

The slo3 gene encodes a K(+) channel found only in mammalian testis. This is in contrast to slo1, which is expressed in many tissues. Genes pertaining to male reproduction, especially those involved in sperm production, evolve morphologically and functionally much faster than their nonsexual counterparts. A comparison of SLO3 channel amino acid sequences from several species revealed a high degree of structural divergence relative to their SLO1 channel paralogues. To reveal any biophysical differences accompanying this rapid structural divergence, we analyzed the functional properties of SLO3 channels from two species, bovine and mouse. We observed several functional differences including voltage range of activation, kinetics, and pH sensitivity. Although SLO3 channel proteins from these two species lack conservation in many structural regions, we found that the first two of these three functional differences map to the same loop structure in their RCK1 (regulator of K(+) conductance 1) domain, which links the intermediate RCK1 subdomain to the C-terminal subdomain. We found that small structural changes in this region produce major changes in the voltage range of activation and kinetics. This rapidly evolving loop peptide shows the greatest length and sequence polymorphisms within RCK1 domains from many different species. In SLO3 channels this region may permit evolutionary changes that tune the gating properties in different species.
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http://dx.doi.org/10.1074/jbc.M109.015040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755883PMC
August 2009

GPR30 estrogen receptor agonists induce mechanical hyperalgesia in the rat.

Eur J Neurosci 2008 Apr 26;27(7):1700-9. Epub 2008 Mar 26.

Department for Molecular Human Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany.

We evaluated the signalling pathway by which estrogen acts in peripheral tissue to produce protein kinase Cepsilon (PKCepsilon)-dependent mechanical hyperalgesia. Specific agonists for the classical estrogen receptors (ER), ERalpha and ERbeta, did not result in activation of PKCepsilon in neurons of dissociated rat dorsal root ganglia. In contrast, G-1, a specific agonist of the recently identified G-protein-coupled estrogen receptor, GPR30, induced PKCepsilon translocation. Involvement of GPR30 and independence of ERalpha and ERbeta was confirmed using the GPR30 agonist and simultaneous ERalpha and ERbeta antagonist ICI 182,780 (fulvestrant). The GPR30 transcript could be amplified from dorsal root ganglia tissue. We found estrogen-induced as well as GPR30-agonist-induced PKCepsilon translocation to be restricted to the subgroup of nociceptive neurons positive for isolectin IB4 from Bandeiraea simplicifolia. Corroborating the cellular results, both GPR30 agonists, G-1 as well as ICI 182,780, resulted in the onset of PKCepsilon-dependent mechanical hyperalgesia if injected into paws of adult rats. We therefore suggest that estrogen acts acutely at GPR30 in nociceptors to produce mechanical hyperalgesia.
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http://dx.doi.org/10.1111/j.1460-9568.2008.06131.xDOI Listing
April 2008

Estrogen controls PKCepsilon-dependent mechanical hyperalgesia through direct action on nociceptive neurons.

Eur J Neurosci 2006 Jul 12;24(2):527-34. Epub 2006 Jul 12.

NIH Pain Center, UCSF, University of California, San Francisco, 521 Parnassus Avenue, PO-Box 0440, 94143, USA.

Protein kinase C epsilon (PKCepsilon) is an important intracellular signaling molecule in primary afferent nociceptors, implicated in acute and chronic inflammatory as well as neuropathic pain. In behavioral experiments inflammatory mediators produce PKCepsilon-dependent hyperalgesia only in male rats. The mechanism underlying this sexual dimorphism is unknown. We show that the hormone environment of female rats changes the nociceptive signaling in the peripheral sensory neuron. This change is maintained in culture also in the absence of a gender-simulating environment. Stimulation of beta(2)-adrenergic receptors (beta(2)-AR) leads to PKCepsilon activation in cultured dorsal root ganglia (DRG) neurons derived from male but not from female rats. Addition of estrogen to male DRG neurons produces a switch to the female phenotype, namely abrogation of beta(2)-AR-initiated activation of PKCepsilon. Estrogen interferes downstream of the beta(2)-AR with the signaling pathway leading from exchange protein activated by cAMP (Epac) to PKCepsilon. The interfering action is fast indicating a transcriptional-independent mechanism. Estrogen has a dual effect on PKCepsilon. If applied before beta(2)-AR or Epac stimulation, estrogen abrogates the activation of PKCepsilon. In contrast, estrogen applied alone leads to a brief translocation of PKCepsilon. Also in vivo the activity of estrogen depends on the stimulation context. In male rats, intradermal injection of an Epac activator or estrogen alone induces mechanical hyperalgesia through a PKCepsilon-dependent mechanism. In contrast, injection of estrogen preceding the activation of Epac completely abrogates the Epac-induced mechanical hyperalgesia. Our results suggest that gender differences in nociception do not reflect the use of generally different mechanisms. Instead, a common set of signaling pathways can be modulated by hormones.
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http://dx.doi.org/10.1111/j.1460-9568.2006.04913.xDOI Listing
July 2006