排序方式: 共有62条查询结果,搜索用时 15 毫秒
51.
W Zhou EA Otto A Cluckey R Airik TW Hurd M Chaki K Diaz FP Lach GR Bennett HY Gee AK Ghosh S Natarajan S Thongthip U Veturi SJ Allen S Janssen G Ramaswami J Dixon F Burkhalter M Spoendlin H Moch MJ Mihatsch J Verine R Reade H Soliman M Godin D Kiss G Monga G Mazzucco K Amann F Artunc RC Newland T Wiech S Zschiedrich TB Huber A Friedl GG Slaats JA Joles R Goldschmeding J Washburn RH Giles S Levy A Smogorzewska F Hildebrandt 《Nature genetics》2012,44(8):910-915
Chronic kidney disease (CKD) represents a major health burden. Its central feature of renal fibrosis is not well understood. By exome sequencing, we identified mutations in FAN1 as a cause of karyomegalic interstitial nephritis (KIN), a disorder that serves as a model for renal fibrosis. Renal histology in KIN is indistinguishable from that of nephronophthisis, except for the presence of karyomegaly. The FAN1 protein has nuclease activity and acts in DNA interstrand cross-link (ICL) repair within the Fanconi anemia DNA damage response (DDR) pathway. We show that cells from individuals with FAN1 mutations have sensitivity to the ICL-inducing agent mitomycin C but do not exhibit chromosome breakage or cell cycle arrest after diepoxybutane treatment, unlike cells from individuals with Fanconi anemia. We complemented ICL sensitivity with wild-type FAN1 but not with cDNA having mutations found in individuals with KIN. Depletion of fan1 in zebrafish caused increased DDR, apoptosis and kidney cysts. Our findings implicate susceptibility to environmental genotoxins and inadequate DNA repair as novel mechanisms contributing to renal fibrosis and CKD. 相似文献
52.
53.
Zusammenfassung Die chemisch verwandten Rauwolfia-Alkaloide Raunescin, Isoraunescin, Deserpidin, Rescinnamin und Reserpin verursachen einen
starken Abfall des Noradrenalingehaltes des Rattenherzens, wenn sie intraperitoneal in einer Dosis von 5 mg/kg gegeben werden.
Der Adrenalingehalt wird nicht deutlich oder einheitlich ver?ndert. α-Yohimbin, das chemisch zu einer andern Gruppe geh?rt,
hat keine Wirkung auf den Noradrenalingehalt des Herzens.
This work was supported by a grant from the U. S. Public Health Service (H-2205) and by funds from the Eugene Higgins Trust. 相似文献
This work was supported by a grant from the U. S. Public Health Service (H-2205) and by funds from the Eugene Higgins Trust. 相似文献
54.
Mohammed FF Smookler DS Taylor SE Fingleton B Kassiri Z Sanchez OH English JL Matrisian LM Au B Yeh WC Khokha R 《Nature genetics》2004,36(9):969-977
Tumor-necrosis factor (TNF), a pleiotropic cytokine, triggers physiological and pathological responses in several organs. Here we show that deletion of the mouse gene Timp3 resulted in an increase in TNF-alpha converting enzyme activity, constitutive release of TNF and activation of TNF signaling in the liver. The increase in TNF in Timp3(-/-) mice culminated in hepatic lymphocyte infiltration and necrosis, features that are also seen in chronic active hepatitis in humans. This pathology was prevented when deletion of Timp3 was combined with Tnfrsf1a deficiency. In a liver regeneration model that requires TNF signaling, Timp3(-/-) mice succumbed to liver failure. Hepatocytes from Timp3(-/-) mice completed the cell cycle but then underwent cell death owing to sustained activation of TNF. This hepatocyte cell death was completely rescued by a neutralizing antibody to TNF. Dysregulation of TNF occurred specifically in Timp3(-/-), and not Timp1(-/-) mice. These data indicate that TIMP3 is a crucial innate negative regulator of TNF in both tissue homeostasis and tissue response to injury. 相似文献
55.
Mutations in a novel gene,NPHP3, cause adolescent nephronophthisis,tapeto-retinal degeneration and hepatic fibrosis 总被引:12,自引:0,他引:12
Olbrich H Fliegauf M Hoefele J Kispert A Otto E Volz A Wolf MT Sasmaz G Trauer U Reinhardt R Sudbrak R Antignac C Gretz N Walz G Schermer B Benzing T Hildebrandt F Omran H 《Nature genetics》2003,34(4):455-459
Nephronophthisis (NPHP), a group of autosomal recessive cystic kidney disorders, is the most common genetic cause of progressive renal failure in children and young adults. NPHP may be associated with Leber congenital amaurosis, tapeto-retinal degeneration, cerebellar ataxia, cone-shaped epiphyses, congenital oculomotor apraxia and hepatic fibrosis. Loci associated with an infantile type of NPHP on 9q22-q31 (NPHP2), juvenile types of NPHP on chromosomes 2q12-q13 (NPHP1) and 1p36 (NPHP4) and an adolescent type of NPHP on 3q21-q22 (NPHP3) have been mapped. NPHP1 and NPHP4 have been identified, and interaction of the respective encoded proteins nephrocystin and nephrocystin-4 has been shown. Here we report the identification of NPHP3, encoding a novel 1,330-amino acid protein that interacts with nephrocystin. We describe mutations in NPHP3 in families with isolated NPHP and in families with NPHP with associated hepatic fibrosis or tapeto-retinal degeneration. We show that the mouse ortholog Nphp3 is expressed in the node, kidney tubules, retina, respiratory epithelium, liver, biliary tract and neural tissues. In addition, we show that a homozygous missense mutation in Nphp3 is probably responsible for the polycystic kidney disease (pcy) mouse phenotype. Interventional studies in the pcy mouse have shown beneficial effects by modification of protein intake and administration of methylprednisolone, suggesting therapeutic strategies for treating individuals with NPHP3. 相似文献
56.
Greiner J Klose S Reinsch K Schmid HM Sari R Hartmann DH Kouveliotou C Rau A Palazzi E Straubmeier C Stecklum B Zharikov S Tovmassian G Bärnbantner O Ries C Jehin E Henden A Kaas AA Grav T Hjorth J Pedersen H Wijers RA Kaufer A Park HS Williams G Reimer O 《Nature》2003,426(6963):157-159
The association of a supernova with GRB030329 strongly supports the 'collapsar' model of gamma-ray bursts, where a relativistic jet forms after the progenitor star collapses. Such jets cannot be spatially resolved because gamma-ray bursts lie at cosmological distances; their existence is instead inferred from 'breaks' in the light curves of the afterglows, and from the theoretical desire to reduce the estimated total energy of the burst by proposing that most of it comes out in narrow beams. Temporal evolution of the polarization of the afterglows may provide independent evidence for the jet structure of the relativistic outflow. Small-level polarization ( approximately 1-3 per cent) has been reported for a few bursts, but its temporal evolution has yet to be established. Here we report polarimetric observations of the afterglow of GRB030329. We establish the polarization light curve, detect sustained polarization at the per cent level, and find significant variability. The data imply that the afterglow magnetic field has a small coherence length and is mostly random, probably generated by turbulence, in contrast with the picture arising from the high polarization detected in the prompt gamma-rays from GRB021206 (ref. 18). 相似文献
57.
Most mammals, with the exception of primates, have dichromatic vision and correspondingly limited colour perception. Ultraviolet vision was discovered in mammals only a decade ago, and in the few rodents and marsupials where it has been found, ultraviolet light is detected by an independent photoreceptor. Bats orient primarily by echolocation, but they also use vision. Here we show that a phyllostomid flower bat, Glossophaga soricina, is colour-blind but sensitive to ultraviolet light down to a wavelength of 310 nm. Behavioural experiments revealed a spectral-sensitivity function with maxima at 510 nm (green) and above 365 nm (ultraviolet). A test for colour vision was negative. Chromatic adaptation had the same threshold-elevating effects on ultraviolet and visible test lights, indicating that the same photoreceptor is responsible for both response peaks (ultraviolet and green). Thus, excitation of the beta-band of the visual pigment is the most likely cause of ultraviolet sensitivity. This is a mechanism for ultraviolet vision that has not previously been demonstrated in intact mammalian visual systems. 相似文献
58.
Sex and recombination are widespread, but explaining these phenomena has been one of the most difficult problems in evolutionary biology. Recombination is advantageous when different individuals in a population carry different advantageous alleles. By bringing together advantageous alleles onto the same chromosome, recombination speeds up the process of adaptation and opposes the fixation of harmful mutations by means of Muller's ratchet. Nevertheless, adaptive substitutions favour sex and recombination only if the rate of adaptive mutation is high, and Muller's ratchet operates only in small or asexual populations. Here, by tracking the fate of modifier alleles that alter the frequency of sex and recombination, we show that background selection against deleterious mutant alleles provides a stochastic advantage to sex and recombination that increases with population size. The advantage arises because, with low levels of recombination, selection at other loci severely reduces the effective population size and genetic variance in fitness at a focal locus (the Hill-Robertson effect), making a population less able to respond to selection and to rid itself of deleterious mutations. Sex and recombination reveal the hidden genetic variance in fitness by combining chromosomes of intermediate fitness to create chromosomes that are relatively free of (or are loaded with) deleterious mutations. This increase in genetic variance within finite populations improves the response to selection and generates a substantial advantage to sex and recombination that is fairly insensitive to the form of epistatic interactions between deleterious alleles. The mechanism supported by our results offers a robust and broadly applicable explanation for the evolutionary advantage of recombination and can explain the spread of costly sex. 相似文献
59.
60.
Hemmungswirkungen verschiedener Indophenole auf die Wasserstoff-peroxydzersetzung durch Blutkatalase
Otto Hoffmann-Ostenhof Elisabeth Biach Sepp Gierer 《Cellular and molecular life sciences : CMLS》1947,3(3):108-109
Summary Some indophenol derivatives inhibit strongly the activity of blood catalase. These effects were investigated quantitatively and compared with similar effects due to other oxidizing and reducing agents. 相似文献