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101.
Jürgen Schnekenburger Ina-Alexandra Weber Daniela Hahn Igor Buchwalow Burkhard Krüger Elke Albrecht Wolfram Domschke Markus M. Lerch 《Cellular and molecular life sciences : CMLS》2009,66(15):2525-2537
The regulated secretion of pancreatic zymogens depends on a functional cytoskeleton and intracellular vesicle transport. To
study the dynamics of tubulin and its motor proteins dynein and kinesin during secretion in pancreatic acinar cells, we infused
rats with 0.1 μg/kg/h caerulein. Electron and fluorescence microscopy detected neither dynein nor kinesin at the apical secretory
pole, nor on the surface of mature zymogen granules. After 30 min of secretagogue stimulation, kinesin and the Golgi marker
protein 58 K were reallocated towards the apical plasma membrane and association of kinesin with tubulin was enhanced. Disruption
of acinar cell microtubules had no effect on initial caerulein-induced amylase release but completely blocked secretion during
a second stimulus. Our results suggest that mature zymogen granule exocytosis is independent of intact microtubules, kinesin
and dynein. However, microtubule-dependent mechanisms seem to be important for the replenishment of secretory vesicles by
redistribution of Golgi elements towards the apical cell pole.
J. Schnekenburger and I.-A. Weber have contributed equally to this work. 相似文献
102.
RA Scott V Lagou RP Welch E Wheeler ME Montasser J Luan R Mägi RJ Strawbridge E Rehnberg S Gustafsson S Kanoni LJ Rasmussen-Torvik L Yengo C Lecoeur D Shungin S Sanna C Sidore PC Johnson JW Jukema T Johnson A Mahajan N Verweij G Thorleifsson JJ Hottenga S Shah AV Smith B Sennblad C Gieger P Salo M Perola NJ Timpson DM Evans BS Pourcain Y Wu JS Andrews J Hui LF Bielak W Zhao M Horikoshi P Navarro A Isaacs JR O'Connell K Stirrups V Vitart C Hayward T Esko E Mihailov RM Fraser T Fall BF Voight 《Nature genetics》2012,44(9):991-1005
Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control. 相似文献
103.
Pasternack SM von Kügelgen I Al Aboud K Lee YA Rüschendorf F Voss K Hillmer AM Molderings GJ Franz T Ramirez A Nürnberg P Nöthen MM Betz RC 《Nature genetics》2008,40(3):329-334
Hypotrichosis simplex is a group of nonsyndromic human alopecias. We mapped an autosomal recessive form of this disorder to chromosome 13q14.11-13q21.33, and identified homozygous truncating mutations in P2RY5, which encodes an orphan G protein-coupled receptor. Furthermore, we identified oleoyl-L-alpha-lysophosphatidic acid (LPA), a bioactive lipid, as a ligand for P2Y5 in reporter gene and radioligand binding experiments. Homology and studies of signaling transduction pathways suggest that P2Y5 is a member of a subgroup of LPA receptors, which also includes LPA4 and LPA5. Our study is the first to implicate a G protein-coupled receptor as essential for and specific to the maintenance of human hair growth. This finding may provide opportunities for new therapeutic approaches to the treatment of hair loss in humans. 相似文献
104.
Lisa Seipold Hermann Altmeppen Tomas Koudelka Andreas Tholey Petr Kasparek Radislav Sedlacek Michaela Schweizer Julia Bär Marina Mikhaylova Markus Glatzel Paul Saftig 《Cellular and molecular life sciences : CMLS》2018,75(17):3251-3267
A disintegrin and metalloproteinase 10 (ADAM10) plays a major role in the ectodomain shedding of important surface molecules with physiological and pathological relevance including the amyloid precursor protein (APP), the cellular prion protein, and different cadherins. Despite its therapeutic potential, there is still a considerable lack of knowledge how this protease is regulated. We have previously identified tetraspanin15 (Tspan15) as a member of the TspanC8 family to specifically associate with ADAM10. Cell-based overexpression experiments revealed that this binding affected the maturation process and surface expression of the protease. Our current study shows that Tspan15 is abundantly expressed in mouse brain, where it specifically interacts with endogenous ADAM10. Tspan15 knockout mice did not reveal an overt phenotype but showed a pronounced decrease of the active and mature form of ADAM10, an effect which augmented with aging. The decreased expression of active ADAM10 correlated with an age-dependent reduced shedding of neuronal (N)-cadherin and the cellular prion protein. APP α-secretase cleavage and the expression of Notch-dependent genes were not affected by the loss of Tspan15, which is consistent with the hypothesis that different TspanC8s cause ADAM10 to preferentially cleave particular substrates. Analyzing spine morphology revealed no obvious differences between Tspan15 knockout and wild-type mice. However, Tspan15 expression was elevated in brains of an Alzheimer’s disease mouse model and of patients, suggesting that upregulation of Tspan15 expression reflects a cellular response in a disease state. In conclusion, our data show that Tspan15 and most likely also other members of the TspanC8 family are central modulators of ADAM10-mediated ectodomain shedding in vivo. 相似文献
105.
Eva C. Schwarz Christina Backes Arne Knörck Nicole Ludwig Petra Leidinger Cora Hoxha Gertrud Schwär Thomas Grossmann Sabine C. Müller Martin Hart Jan Haas Valentina Galata Isabelle Müller Tobias Fehlmann Hermann Eichler Andre Franke Benjamin Meder Eckart Meese Markus Hoth Andreas Keller 《Cellular and molecular life sciences : CMLS》2016,73(16):3169-3181
106.
Duy C Hurtz C Shojaee S Cerchietti L Geng H Swaminathan S Klemm L Kweon SM Nahar R Braig M Park E Kim YM Hofmann WK Herzog S Jumaa H Koeffler HP Yu JJ Heisterkamp N Graeber TG Wu H Ye BH Melnick A Müschen M 《Nature》2011,473(7347):384-388
Tyrosine kinase inhibitors (TKIs) are widely used to treat patients with leukaemia driven by BCR-ABL1 (ref. 1) and other oncogenic tyrosine kinases. Recent efforts have focused on developing more potent TKIs that also inhibit mutant tyrosine kinases. However, even effective TKIs typically fail to eradicate leukaemia-initiating cells (LICs), which often cause recurrence of leukaemia after initially successful treatment. Here we report the discovery of a novel mechanism of drug resistance, which is based on protective feedback signalling of leukaemia cells in response to treatment with TKI. We identify BCL6 as a central component of this drug-resistance pathway and demonstrate that targeted inhibition of BCL6 leads to eradication of drug-resistant and leukaemia-initiating subclones. 相似文献
107.
108.
Unprecedented Arctic ozone loss in 2011 总被引:7,自引:0,他引:7
Manney GL Santee ML Rex M Livesey NJ Pitts MC Veefkind P Nash ER Wohltmann I Lehmann R Froidevaux L Poole LR Schoeberl MR Haffner DP Davies J Dorokhov V Gernandt H Johnson B Kivi R Kyrö E Larsen N Levelt PF Makshtas A McElroy CT Nakajima H Parrondo MC Tarasick DW von der Gathen P Walker KA Zinoviev NS 《Nature》2011,478(7370):469-475
Chemical ozone destruction occurs over both polar regions in local winter-spring. In the Antarctic, essentially complete removal of lower-stratospheric ozone currently results in an ozone hole every year, whereas in the Arctic, ozone loss is highly variable and has until now been much more limited. Here we demonstrate that chemical ozone destruction over the Arctic in early 2011 was--for the first time in the observational record--comparable to that in the Antarctic ozone hole. Unusually long-lasting cold conditions in the Arctic lower stratosphere led to persistent enhancement in ozone-destroying forms of chlorine and to unprecedented ozone loss, which exceeded 80 per cent over 18-20 kilometres altitude. Our results show that Arctic ozone holes are possible even with temperatures much milder than those in the Antarctic. We cannot at present predict when such severe Arctic ozone depletion may be matched or exceeded. 相似文献
109.
Villeda SA Luo J Mosher KI Zou B Britschgi M Bieri G Stan TM Fainberg N Ding Z Eggel A Lucin KM Czirr E Park JS Couillard-Després S Aigner L Li G Peskind ER Kaye JA Quinn JF Galasko DR Xie XS Rando TA Wyss-Coray T 《Nature》2011,477(7362):90-94
In the central nervous system, ageing results in a precipitous decline in adult neural stem/progenitor cells and neurogenesis, with concomitant impairments in cognitive functions. Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise. Here, using heterochronic parabiosis we show that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. Accordingly, exposing a young mouse to an old systemic environment or to plasma from old mice decreased synaptic plasticity, and impaired contextual fear conditioning and spatial learning and memory. We identify chemokines--including CCL11 (also known as eotaxin)--the plasma levels of which correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and the levels of which are increased in the plasma and cerebrospinal fluid of healthy ageing humans. Lastly, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Together our data indicate that the decline in neurogenesis and cognitive impairments observed during ageing can be in part attributed to changes in blood-borne factors. 相似文献
110.