排序方式: 共有116条查询结果,搜索用时 265 毫秒
11.
Hauber E van Gasselt S Ivanov B Werner S Head JW Neukum G Jaumann R Greeley R Mitchell KL Muller P;HRSC Co-Investigator Team 《Nature》2005,434(7031):356-361
The majority of volcanic products on Mars are thought to be mafic and effusive. Explosive eruptions of basic to ultrabasic chemistry are expected to be common, but evidence for them is rare and mostly confined to very old surface features. Here we present new image and topographic data from the High Resolution Stereo Camera that reveal previously unknown traces of an explosive eruption at 30 degrees N and 149 degrees E on the northwestern flank of the shield volcano Hecates Tholus. The eruption created a large, 10-km-diameter caldera approximately 350 million years ago. We interpret these observations to mean that large-scale explosive volcanism on Mars was not confined to the planet's early evolution. We also show that glacial deposits partly fill the caldera and an adjacent depression. Their age, derived from crater counts, is about 5 to 24 million years. Climate models predict that near-surface ice is not stable at mid-latitudes today, assuming a thermo-dynamic steady state. Therefore, the discovery of very young glacial features at Hecates Tholus suggests recent climate changes. We show that the absolute ages of these very recent glacial deposits correspond very well to a period of increased obliquity of the planet's rotational axis. 相似文献
12.
Evidence from the Mars Express High Resolution Stereo Camera for a frozen sea close to Mars' equator
Murray JB Muller JP Neukum G Werner SC van Gasselt S Hauber E Markiewicz WJ Head JW Foing BH Page D Mitchell KL Portyankina G;HRSC Co-Investigator Team 《Nature》2005,434(7031):352-356
It is thought that the Cerberus Fossae fissures on Mars were the source of both lava and water floods two to ten million years ago. Evidence for the resulting lava plains has been identified in eastern Elysium, but seas and lakes from these fissures and previous water flooding events were presumed to have evaporated and sublimed away. Here we present High Resolution Stereo Camera images from the European Space Agency Mars Express spacecraft that indicate that such lakes may still exist. We infer that the evidence is consistent with a frozen body of water, with surface pack-ice, around 5 degrees north latitude and 150 degrees east longitude in southern Elysium. The frozen lake measures about 800 x 900 km in lateral extent and may be up to 45 metres deep--similar in size and depth to the North Sea. From crater counts, we determined its age to be 5 +/- 2 million years old. If our interpretation is confirmed, this is a place that might preserve evidence of primitive life, if it has ever developed on Mars. 相似文献
13.
Illing PT Vivian JP Dudek NL Kostenko L Chen Z Bharadwaj M Miles JJ Kjer-Nielsen L Gras S Williamson NA Burrows SR Purcell AW Rossjohn J McCluskey J 《Nature》2012,486(7404):554-558
Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T?cells. HLA polymorphisms mostly map to the antigen-binding cleft, thereby diversifying the repertoire of self-derived and pathogen-derived peptide antigens selected by different HLA allotypes. A growing number of immunologically based drug reactions, including abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Stevens-Johnson syndrome (SJS), are associated with specific HLA alleles. However, little is known about the underlying mechanisms of these associations, including AHS, a prototypical HLA-associated drug reaction occurring exclusively in individuals with the common histocompatibility allele HLA-B*57:01, and with a relative risk of more than 1,000 (refs?6, 7). We show that unmodified abacavir binds non-covalently to HLA-B*57:01, lying across the bottom of the antigen-binding cleft and reaching into the F-pocket, where a carboxy-terminal tryptophan typically anchors peptides bound to HLA-B*57:01. Abacavir binds with exquisite specificity to HLA-B*57:01, changing the shape and chemistry of the antigen-binding cleft, thereby altering the repertoire of endogenous peptides that can bind HLA-B*57:01. In this way, abacavir guides the selection of new endogenous peptides, inducing a marked alteration in 'immunological self'. The resultant peptide-centric 'altered self' activates abacavir-specific T-cells, thereby driving polyclonal CD8 T-cell activation and a systemic reaction manifesting as AHS. We also show that carbamazepine, a widely used anti-epileptic drug associated with hypersensitivity reactions in HLA-B*15:02 individuals, binds to this allotype, producing alterations in the repertoire of presented self peptides. Our findings simultaneously highlight the importance of HLA polymorphism in the evolution of pharmacogenomics and provide a general mechanism for some of the growing number of HLA-linked hypersensitivities that involve small-molecule drugs. 相似文献
14.
Schmeisser MJ Ey E Wegener S Bockmann J Stempel AV Kuebler A Janssen AL Udvardi PT Shiban E Spilker C Balschun D Skryabin BV Dieck St Smalla KH Montag D Leblond CS Faure P Torquet N Le Sourd AM Toro R Grabrucker AM Shoichet SA Schmitz D Kreutz MR Bourgeron T Gundelfinger ED Boeckers TM 《Nature》2012,486(7402):256-260
Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour. Mutations in synaptic proteins such as neuroligins, neurexins, GKAPs/SAPAPs and ProSAPs/Shanks were identified in patients with autism spectrum disorder, but the causative mechanisms remain largely unknown. ProSAPs/Shanks build large homo- and heteromeric protein complexes at excitatory synapses and organize the complex protein machinery of the postsynaptic density in a laminar fashion. Here we demonstrate that genetic deletion of ProSAP1/Shank2 results in an early, brain-region-specific upregulation of ionotropic glutamate receptors at the synapse and increased levels of ProSAP2/Shank3. Moreover, ProSAP1/Shank2(-/-) mutants exhibit fewer dendritic spines and show reduced basal synaptic transmission, a reduced frequency of miniature excitatory postsynaptic currents and enhanced N-methyl-d-aspartate receptor-mediated excitatory currents at the physiological level. Mutants are extremely hyperactive and display profound autistic-like behavioural alterations including repetitive grooming as well as abnormalities in vocal and social behaviours. By comparing the data on ProSAP1/Shank2(-/-) mutants with ProSAP2/Shank3αβ(-/-) mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype. 相似文献
15.
Global variation in copy number in the human genome 总被引:3,自引:0,他引:3
Redon R Ishikawa S Fitch KR Feuk L Perry GH Andrews TD Fiegler H Shapero MH Carson AR Chen W Cho EK Dallaire S Freeman JL González JR Gratacòs M Huang J Kalaitzopoulos D Komura D MacDonald JR Marshall CR Mei R Montgomery L Nishimura K Okamura K Shen F Somerville MJ Tchinda J Valsesia A Woodwark C Yang F Zhang J Zerjal T Zhang J Armengol L Conrad DF Estivill X Tyler-Smith C Carter NP Aburatani H Lee C Jones KW Scherer SW Hurles ME 《Nature》2006,444(7118):444-454
Copy number variation (CNV) of DNA sequences is functionally significant but has yet to be fully ascertained. We have constructed a first-generation CNV map of the human genome through the study of 270 individuals from four populations with ancestry in Europe, Africa or Asia (the HapMap collection). DNA from these individuals was screened for CNV using two complementary technologies: single-nucleotide polymorphism (SNP) genotyping arrays, and clone-based comparative genomic hybridization. A total of 1,447 copy number variable regions (CNVRs), which can encompass overlapping or adjacent gains or losses, covering 360 megabases (12% of the genome) were identified in these populations. These CNVRs contained hundreds of genes, disease loci, functional elements and segmental duplications. Notably, the CNVRs encompassed more nucleotide content per genome than SNPs, underscoring the importance of CNV in genetic diversity and evolution. The data obtained delineate linkage disequilibrium patterns for many CNVs, and reveal marked variation in copy number among populations. We also demonstrate the utility of this resource for genetic disease studies. 相似文献
16.
Induction of an illusory shadow person 总被引:1,自引:0,他引:1
Stimulation of a site on the brain's left hemisphere prompts the creepy feeling that somebody is close by. The strange sensation that somebody is nearby when no one is actually present has been described by psychiatric and neurological patients, as well as by healthy subjects, but it is not understood how the illusion is triggered by the brain. Here we describe the repeated induction of this sensation in a patient who was undergoing presurgical evaluation for epilepsy treatment, as a result of focal electrical stimulation of the left temporoparietal junction: the illusory person closely 'shadowed' changes in the patient's body position and posture. These perceptions may have been due to a disturbance in the multisensory processing of body and self at the temporoparietal junction. 相似文献
17.
Boxiao Wang Stephanie Thurmond Rong Hai Jikui Song 《Cellular and molecular life sciences : CMLS》2018,75(10):1723-1736
Zika virus (ZIKV) belongs to the positive-sense single-stranded RNA-containing Flaviviridae family. Its recent outbreak and association with human diseases (e.g. neurological disorders) have raised global health concerns, and an urgency to develop a therapeutic strategy against ZIKV infection. However, there is no currently approved antiviral against ZIKV. Here we present a comprehensive overview on recent progress in structure–function investigation of ZIKV NS5 protein, the largest non-structural protein of ZIKV, which is responsible for replication of the viral genome, RNA capping and suppression of host interferon responses. Structural comparison of the N-terminal methyltransferase domain and C-terminal RNA-dependent RNA polymerase domain of ZIKV NS5 with their counterparts from related viruses provides mechanistic insights into ZIKV NS5-mediated RNA replication, and identifies residues critical for its enzymatic activities. Finally, a collection of recently identified small molecule inhibitors against ZIKV NS5 or its closely related flavivirus homologues are also discussed. 相似文献
18.
Mailman MD Feolo M Jin Y Kimura M Tryka K Bagoutdinov R Hao L Kiang A Paschall J Phan L Popova N Pretel S Ziyabari L Lee M Shao Y Wang ZY Sirotkin K Ward M Kholodov M Zbicz K Beck J Kimelman M Shevelev S Preuss D Yaschenko E Graeff A Ostell J Sherry ST 《Nature genetics》2007,39(10):1181-1186
The National Center for Biotechnology Information has created the dbGaP public repository for individual-level phenotype, exposure, genotype and sequence data and the associations between them. dbGaP assigns stable, unique identifiers to studies and subsets of information from those studies, including documents, individual phenotypic variables, tables of trait data, sets of genotype data, computed phenotype-genotype associations, and groups of study subjects who have given similar consents for use of their data. 相似文献
19.
Albert Lee Stephanie L. Rayner Serene S. L. Gwee Alana De Luca Hamideh Shahheydari Vinod Sundaramoorthy Audrey Ragagnin Marco Morsch Rowan Radford Jasmin Galper Sarah Freckleton Bingyang Shi Adam K. Walker Emily K. Don Nicholas J. Cole Shu Yang Kelly L. Williams Justin J. Yerbury Ian P. Blair Julie D. Atkin Mark P. Molloy Roger S. Chung 《Cellular and molecular life sciences : CMLS》2018,75(2):335-354
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that have common molecular and pathogenic characteristics, such as aberrant accumulation and ubiquitylation of TDP-43; however, the mechanisms that drive this process remain poorly understood. We have recently identified CCNF mutations in familial and sporadic ALS and FTD patients. CCNF encodes cyclin F, a component of an E3 ubiquitin–protein ligase (SCFcyclin F) complex that is responsible for ubiquitylating proteins for degradation by the ubiquitin–proteasome system. In this study, we examined the ALS/FTD-causing p.Ser621Gly (p.S621G) mutation in cyclin F and its effect upon downstream Lys48-specific ubiquitylation in transfected Neuro-2A and SH-SY5Y cells. Expression of mutant cyclin FS621G caused increased Lys48-specific ubiquitylation of proteins in neuronal cells compared to cyclin FWT. Proteomic analysis of immunoprecipitated Lys48-ubiquitylated proteins from mutant cyclin FS621G-expressing cells identified proteins that clustered within the autophagy pathway, including sequestosome-1 (p62/SQSTM1), heat shock proteins, and chaperonin complex components. Examination of autophagy markers p62, LC3, and lysosome-associated membrane protein 2 (Lamp2) in cells expressing mutant cyclin FS621G revealed defects in the autophagy pathway specifically resulting in impairment in autophagosomal–lysosome fusion. This finding highlights a potential mechanism by which cyclin F interacts with p62, the receptor responsible for transporting ubiquitylated substrates for autophagic degradation. These findings demonstrate that ALS/FTD-causing mutant cyclin FS621G disrupts Lys48-specific ubiquitylation, leading to accumulation of substrates and defects in the autophagic machinery. This study also demonstrates that a single missense mutation in cyclin F causes hyper-ubiquitylation of proteins that can indirectly impair the autophagy degradation pathway, which is implicated in ALS pathogenesis. 相似文献
20.
Marthe-Susanna Wegner Nina Schömel Lisa Gruber Stephanie Beatrice Örtel Matti Aleksi Kjellberg Peter Mattjus Jennifer Kurz Sandra Trautmann Bing Peng Martin Wegner Manuel Kaulich Robert Ahrends Gerd Geisslinger Sabine Grösch 《Cellular and molecular life sciences : CMLS》2018,75(18):3393-3410
The UDP-glucose ceramide glucosyltransferase (UGCG) is a key enzyme in the synthesis of glycosylated sphingolipids, since this enzyme generates the precursor for all complex glycosphingolipids (GSL), the GlcCer. The UGCG has been associated with several cancer-related processes such as maintaining cancer stem cell properties or multidrug resistance induction. The precise mechanisms underlying these processes are unknown. Here, we investigated the molecular mechanisms occurring after UGCG overexpression in breast cancer cells. We observed alterations of several cellular properties such as morphological changes, which enhanced proliferation and doxorubicin resistance in UGCG overexpressing MCF-7 cells. These cellular effects seem to be mediated by an altered composition of glycosphingolipid-enriched microdomains (GEMs), especially an accumulation of globotriaosylceramide (Gb3) and glucosylceramide (GlcCer), which leads to an activation of Akt and ERK1/2. The induction of the Akt and ERK1/2 signaling pathway results in an increased gene expression of multidrug resistance protein 1 (MDR1) and anti-apoptotic genes and a decrease of pro-apoptotic gene expression. Inhibition of the protein kinase C (PKC) and phosphoinositide 3 kinase (PI3K) reduced MDR1 gene expression. This study discloses how changes in UGCG expression impact several cellular signaling pathways in breast cancer cells resulting in enhanced proliferation and multidrug resistance. 相似文献