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  • Elsevier (CrossRef)  (94)
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  • 1
    Language: English
    In: Trends in Neurosciences, October 2015, Vol.38(10), pp.659-668
    Description: Several recent genome-wide association studies (GWAS) in patients with neurodegenerative disorders have shed new light on the brain immune system, suggesting that it plays a pivotal role in disease pathogenesis. Mononuclear phagocytes are blatantly involved in Alzheimer's disease (AD) of the central nervous system (CNS), but the specific functions of resident microglia, perivascular or meningeal macrophages, and circulating myeloid cells have not yet been fully resolved. Next-generation sequencing, high-throughput immune profiling technologies, and novel genetic tools have recently revolutionized the characterization of innate immune responses during AD. These studies advocate selective and non-redundant roles for myeloid subsets, which could be a target for novel disease-modifying therapies in AD. Myeloid cells differ in their kinetics (long-lived versus short-lived) and localization. This should be taken into account when targeting myeloid cells during neurodegenerative diseases. Microglia are recruited to and cluster around newly formed Aβ plaques, indicating that they are not directly involved in the initial stages of amyloid plaque formation. Microglia are phagocytic cells in the brain equipped with several receptors that play a role in the clearance of Aβ. Downregulation of these immune-receptors results in compromised phagocytotic capacity of microglia. Morphological alterations such as dystrophic (senescent) microglia have been observed in the aged human and AD brain. Emerging data suggest that microglia deteriorate with age and are dysfunctional during AD.
    Keywords: Microglia ; Yolk Sac ; Neurodegeneration ; Cx3cr1 ; Macrophage ; Alzheimer'S Disease ; Medicine ; Anatomy & Physiology
    ISSN: 0166-2236
    E-ISSN: 1878-108X
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  • 2
    Language: English
    In: LITHOS, 2011, Vol.126(3), pp.388-401
    Description: The trace element composition of rutile and Zr-in-rutile temperatures were determined for ultra-high temperature (UHT) metamorphic rocks from the Epembe Unit of the Epupa Complex in NW-Namibia. Ortho- and paragneisses record Mesoproterozoic peak metamorphic UHT conditions of 970 ± 40 °C at 9.5 ± 2 kbar, as estimated from conventional thermobarometry and constraints from pseudosection modeling. Rutile exhibits superchondritic concentrations of V, Zr, Nb, Hf, Ta, Th and U while rare earth elements (REE) are far less enriched. Zr and Hf correlate positively with two distinct trends. Nb and Ta as well as Cr and V show a positive correlation although with less clear trends. Only Hf correlates with Zr, suggesting a decoupling of Zr and Hf from the other high field-strength elements (HFSE) probably during retrogression. In general, the non-homogeneous HFSE distribution in rutile indicates that equilibrium trace element distribution achieved during UHT peak metamorphic conditions was either almost completely erased or had never been achieved as a common feature of all rutile grains. The retrograde metamorphic evolution of the UHT rocks is interpreted to be responsible for trace element redistribution under equilibrium conditions restricted to small domains. This has affected the trace element composition of the rutile grains investigated here thereby disturbing their UHT signature, which may cause problems for provenance studies involving such ‘disturbed’ grains. A systematic comparison of all available Zr-in-rutile thermometer calibrations shows that beside of one, all give similar temperature estimates for the studied samples. No systematic differences regarding the Zr content were observed between rutile grains in different textural positions (i.e. matrix grains, those shielded by host minerals or post-peak grains). However, calculations revealed a broad range of temperatures between 〈 400 °C and 〉 1000 °C. The large spread of calculated temperatures is interpreted to result from intergrain diffusion and trace element exchange by fluid-mediated recrystallization during the retrograde metamorphic evolution. This interpretation is supported by the presence of extensively formed retrograde reaction textures involving hydrous phases such as cordierite and biotite in the studied samples. In addition, tiny (≤ 5 μm) Zr-silica-rich phase separations which occur either homogeneously or heterogeneously distributed in single rutile grains may cause intergrain Zr variations. ► Three Zr-in-rutile calibrations give similar results independent of a P-correction. ► Re-equilibration of rutile during retrogression is likely =〉 loss of UHT information. ► Single rutile grains contain Zr-rich domains (here interpreted as exsolutions). ► Rutile trace element analysis shows a decoupling of Zr and Hf from the other HFSE. ► Protolithic signature of rutile might get lost during the metamorphic evolution.
    Keywords: Rutile Trace Element Composition ; La-Icp-MS ; Epupa Complex ; Uht Granulites ; Zr-in-Rutile Thermometry ; Engineering ; Geology
    ISSN: 0024-4937
    E-ISSN: 1872-6143
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  • 3
    Language: English
    In: Gondwana Research, August 2015, Vol.28(1), pp.1-25
    Description: The study of subduction-related high-pressure- and ultra-high-pressure metamorphic rocks exposed in orogenic belts is critical for unraveling the tectonothermal evolution of an orogen. The South Tianshan Orogen of the southwestern Central Asian Orogenic Belt, one of the world's largest accretionary orogens, contains several Paleozoic (ultra-)high-pressure ((U)HP) metamorphic terranes. (U)HP eclogites, blueschists and associated (U)HP metasedimentary rocks of continental and oceanic origin were reported from two localities in the Northern Tianshan (NTS) of Kazakhstan and Kyrgyzstan, namely from the Ordovician Aktyuz and Makbal metamorphic terranes. Furthermore Lower Carboniferous (U)HP eclogites and blueschists of oceanic origin are located in the Southern Tianshan Accretionary Complex (STAC) of southern Kyrgyzstan (Atbashi) and northwestern China (Akeyazi). The continentally-derived Aktyuz eclogite is considered to have experienced a continuous clockwise prograde P–T path with peak metamorphic conditions of ca. 1.6–2.1 GPa at 610–670 °C, corresponding to a burial depth of about 70 km. A peak metamorphic Lu–Hf garnet isochron age of 474 ± 2 Ma for the retrogressed eclogite of continental origin is in accordance with a Sm–Nd garnet isochron age of 462 ± 7 Ma interpreted as time of cooling and decompression of the metamorphic rock assemblage below 650 to 600 °C. Quantitative P–T pseudosection modeling for peripheral Makbal HP garnet amphibolites of continental origin also revealed a continuous clockwise P–T path with peak-metamorphic conditions of ca. 1.4 GPa at ca. 620 °C followed by an isothermal uplift to ca. 0.7 GPa. Furthermore, prograde P–T paths of oceanically-derived central Makbal high-pressure metabasic rocks revealed peak metamorphic conditions between 520 °C and 560 °C at 2.2 GPa to 2.5 GPa with subsequent isothermal decompressions. The metamorphic (P–T) evolution of a garnet–chloritoid–talc schist is exhibited by a P–T trajectory starting ca. 480 °C at 2.5 GPa, followed by peak pressures of ca. 2.85 GPa at 525 °C and peak temperatures of ca. 580 °C at 2.4 GPa. A Lu–Hf peak metamorphic age of 470.1 ± 2.5 Ma for a peripheral garnet amphibolite is in accordance with a garnet-growth Sm–Nd age of 475 ± 4 Ma of the UHP garnet–chloritoid–talc schist. Different and variable P–T paths show that former oceanic and continental crust at Makbal was subducted to different maximum depths (HP versus UHP conditions). The (U)HP metamorphism of oceanic and continental mafic rocks from the Aktyuz and Makbal metamorphic terranes is assumed to have occurred in a similar time frame of between 500 and 460 Ma. The proposed geodynamic model for the HP Aktyuz metamorphic terrane incorporates the deep northeast-directed subduction of NTS continental crust under the Ankrakhai block of Paleo-Kazakhstan subsequent to the closure of the Djalair–Naiman Basin. At Makbal the final consumption of the oceanic crust of the Terskey Ocean to the northeast was immediately followed by the deep subduction of a (thinned) passive continental margin of the Central Tianshan Arc Terrane (CTA). Both scenarios are in accordance with continental-type subduction geodynamics producing the subduction-related (U)HP rocks during continental–continental collision processes. The exhumation of detached oceanic material by channel flow may have been initiated by the transient subduction of oceanic and subsequent continental crust. The Lower Carboniferous (U)HP metamorphic terranes (Atbashi and Akeyazi) in the Southern Tianshan Accretionary Complex are mainly composed of metasediments which host some lenses and boudins of oceanically-derived blueschists and eclogites. Most eclogites, blueschists and metasediments have experienced peak high-pressure metamorphism (480–580 °C at 1.4–2.1 GPa), while some slices display UHP-conditions (2.7–3.3 GPa at 570–630 °C). Multi-point Lu–Hf and Sm–Nd isochrons from several eclogite and blueschist samples from the Atbashi and Akeyazi metamorphic terranes revealed consistent ages of ca. 320–315 Ma for the peak of metamorphism, thereby confirming that (U)HP metamorphism occurred during a single subduction event. The highly variable peak metamorphic conditions displayed by the (U)HP rocks imply that metamorphism of the metasediments and the various metabasic rocks occurred in different depths of the subduction zone. (U)HP metabasites and metasediments exhibit different P–T paths, which is consistent with the chaotic incorporation in a subduction channel resulting in the eventual exhumation as a mélange. This scenario is much in agreement with initial subduction of oceanic crust and accretionary wedge sediment removal by subduction erosion and thus is similar to accretionary-type subduction terranes, although, with higher peak P–T conditions than previously recorded. The absence of significant melting, in combination with the variable peak pressure metamorphic conditions and the intimate interlayering of high- and ultrahigh-pressure rocks, suggests that the (U)HP rocks were derived from varying depths within the subduction zone and then juxtaposed during exhumation in the subduction channel. This is in accordance with exhumation of the (U)HP rocks by channel flow.
    Keywords: South Tianshan Orogen ; (Ultra-)High-Pressure Metamorphism ; Geochronology ; Accretionary- and Continental-Type Subductions ; Channel Flow Exhumation ; Geology
    ISSN: 1342-937X
    E-ISSN: 1878-0571
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  • 4
    Language: English
    In: LITHOS, 01 September 2013, Vol.177, pp.207-225
    Description: The Makbal Complex in the western Tianshan Mountains of Kazakhstan and Kyrgyzstan consists of HP/UHP metasedimentary host rocks which enclose various HP mafic blocks or boudins. These mafic rocks comprise rare eclogites (sensu stricto and sensu lato), garnet amphibolites (retrograded eclogites) and a newly discovered glaucophanite (glaucophane–garnet–omphacite bearing rock). So far the Makbal Complex has been interpreted to predominantly consist of continental lithologies and the mafic rocks were considered as dismembered dikes intruding continental metasediments. This interpretation is mainly based on the geological relationship and bulk rock chemistry of the different rock types. It was further suggested that the continental lithologies of the Makbal Complex underwent eclogite-facies metamorphism in a former subduction zone. In the present study we combined conventional geothermometry, P–T pseudosection modeling and major and trace element whole rock geochemistry for different mafic samples (glaucophanite and eclogites (sensu lato)) in order to shed light on both the metamorphic evolution and the protoliths of the mafic HP rocks in the Makbal Complex. Prograde to peak-pressure clockwise P–T paths of glaucophanite and eclogites (sensu lato) were modeled using garnet isopleth thermobarometry. The results show that the glaucophanite and eclogite (sensu lato) samples experienced similar prograde P–T paths and slightly different peak metamorphic conditions at ~ 560 °C at 2.4 GPa for the former and between ~ 520 °C at 2.2 GPa and ~ 555 °C at ~ 2.5 GPa for the latter, corresponding to burial depths between 70 and 85 km. Whole rock major and trace element analyses and petrological evidence imply that the various rock types at the Makbal Complex most likely originated from different precursor rocks. Eclogites (sensu lato) are believed to represent strongly retrogressed former eclogite-facies rocks that had never been eclogites (sensu stricto, i.e. 〉 70 vol.% garnet and omphacite) due to an unfavorable alkali-poor bulk composition (Na O 〈 1 wt.%). The four high-pressure mafic samples investigated in this study originated from oceanic crust (Zr/Hf ratio of 33 to 35) which contradicts all previous studies suggesting a continental protolith for all mafic HP/UHP rocks at Makbal. The present study indicates that the mafic high-pressure rocks represent incoherent segments of exhumed oceanic crust. Juxtaposition of different mafic oceanic (this study) and continental rocks is suggested to be due to buoyancy-driven exhumation of the metasedimentary host rock in the subduction channel where dismembered fragments of the subducted oceanic crust were captured in different depths.
    Keywords: Makbal Hp/Uhp Complex ; Tianshan Mountains ; P–T Pseudosection ; Thermobarometry ; Garnet Isopleth Thermobarometry ; Engineering ; Geology
    ISSN: 0024-4937
    E-ISSN: 1872-6143
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  • 5
    Language: English
    In: Journal of Asian Earth Sciences, 22 October 2012, Vol.60, pp.174-187
    Description: ► Eclogites and blueschists coexist at the same peak metamorphic conditions. ► The peak metamorphic conditions were estimated at 540–565 °C and 21.8–23.1 kbar. ► Peak metamorphic mineral assemblages are in equilibrium with an aqueous fluid phase. ► Eclogite and blueschist stability is due to their different bulk-rock compositions. ► Prograde, retrograde and eclogite-facies blueschists occur in SW Tianshan. Carbonate-bearing eclogite and blueschist coexist in the same lithological sequence in the Tianshan (ultra-)high-pressure/low-temperature metamorphic belt, northwestern China. Both of them consist of the mineral assemblage garnet + omphacite + dolomite ± magnesite + phengite ± paragonite + epidote/clinozoisite + glaucophane ± barroisite/(Mg-)katophorite + rutile/titanite + pyrite. The eclogite has an omphacite content of 43 vol.% and a glaucophane content of 〈1 vol.%. In contrast, the blueschist has an omphacite content of 〈8 vol.% and a glaucophane content of 43 vol.%. The blueschist occurs as bands or interlayers in the eclogite. Lawsonite pseudomorphs of epidote/clinozoisite + paragonite assemblages in garnet are commonly observed in the eclogite and blueschist. High carbonate contents in oceanic metabasalts suggest that the precursor basaltic crust has undergone significant hydrothermal alteration prior to subduction. Mineral assemblages and textures show that the omphacite–carbonate-bearing blueschist and the carbonate-bearing eclogite underwent an identical metamorphic evolution. Phase equilibrium modeling in the TiNCaKFMASCHO system further indicates that both the carbonate-bearing eclogite and the omphacite-bearing blueschist equilibrated at peak metamorphic conditions of 540–565 °C and 21.8–23.1 kbar. Under these conditions calculated isopleths reveal the presence of a mainly aqueous fluid phase ( ⩽ 0.02) for the coexisting eclogite and omphacite-bearing blueschist. The stability of the high-pressure mineral assemblages in the eclogite and the omphacite-bearing blueschist is due to differences of the respective bulk-rock composition (the CaO content in particular). This study suggests that three different kinds of blueschist were formed during subduction and exhumation of the South Tianshan oceanic crust, including prograde blueschist formed prior to eclogitization, retrograde blueschist formed by rehydration of eclogite during exhumation in the subduction channel, and coexisting blueschist with eclogite under peak metamorphic conditions.
    Keywords: Eclogite ; Omphacite-Bearing Blueschist ; Coexistence ; Pseudosection ; Tianshan (Ultra-)High-Pressure/Low-Temperature Belt ; Environmental Sciences ; Geology
    ISSN: 1367-9120
    E-ISSN: 1878-5786
    Source: ScienceDirect Journals (Elsevier)
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  • 6
    Language: English
    In: Thrombosis Research, February 2016, Vol.138, pp.63-68
    Description: Novel (or non-vitamin K antagonist) oral anti-coagulants (NOACs) are antagonists of coagulation factors (F) Xa (rivaroxaban) or IIa (dabigatran), and their non-inferiority compared with vitamin K antagonists has been demonstrated in patients with non-valvular atrial fibrillation. However, it is still not fully understood if and how dabigatran and rivaroxaban impact platelet function. This observational study aimed to assess platelet function in patients receiving dabigatran or rivaroxaban. This was a single centre, observational study quantifying platelet aggregation in 90 patients treated with NOACs by multiple electrode aggregometry. The thrombin receptor activating peptide (TRAP)-induced platelet aggregation was significantly higher in 35 patients receiving dabigatran (d) compared with control (c) patients (d 108 ± 31 vs. c 85 ± 30 arbitrary units [AU]∗ min, p 〈 0.001). Patients receiving rivaroxaban (r) showed no differences compared with the control group (r 88 ± 32 vs. c 85 ± 30 AU ∗ min, p = 0.335). In intraindividual time courses of 16 patients, a significantly higher aggregation was found after the administration of dabigatran (before vs. after; 83 ± 29 vs. 100 ± 31 AU ∗ min, p = 0.009). In this observational study, the TRAP-induced platelet aggregation was enhanced in cardiovascular patients receiving dabigatran. This might be explained by a change in the expression profile of thrombin receptors on the surface of platelets. Rivaroxaban had no influence on platelet aggregation.
    Keywords: Dabigatran ; Rivaroxaban ; Platelet ; Aggregation ; Medicine
    ISSN: 0049-3848
    E-ISSN: 1879-2472
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  • 7
    Language: English
    In: Forensic Science International, 10 October 2012, Vol.222(1-3), pp.256-258
    Description: The HSP70 superfamily is a reliable biomarker for hyperthermia, hypothermia and hypoxia. The Enzyme-linked Immunosorbent Assay (ELISA) respectively immunohistochemically staining methods are the typically used techniques for the quantification of those proteins. As the costs for reagents and devices as well as the work schedule of these methods are immense it was the goal of our study to develop an easy and reliable method to quantify the concentration of specific proteins. We established a procedure to measure the relative concentration of proteins fixed on ROTI PVDF membranes via Western blot, calculating the relative protein concentration in dependency to the grey scale index of the normalized and digitalized pictures of the bands on the blots.
    Keywords: Quantification ; Protein ; Grey Scale ; Western Blot ; Hsp70 Superfamily ; Immune Detection ; Public Health
    ISSN: 0379-0738
    E-ISSN: 1872-6283
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  • 8
    Language: English
    In: Cell Chemical Biology, 18 May 2017, Vol.24(5), pp.605-613.e5
    Description: Protein synthesis plays an essential role in cell proliferation, differentiation, and survival. Inhibitors of eukaryotic translation have entered the clinic, establishing the translation machinery as a promising target for chemotherapy. A recently discovered, structurally unique marine sponge-derived brominated alkaloid, (−)-agelastatin A (AglA), possesses potent antitumor activity. Its underlying mechanism of action, however, has remained unknown. Using a systematic top-down approach, we show that AglA selectively inhibits protein synthesis. Using a high-throughput chemical footprinting method, we mapped the AglA-binding site to the ribosomal A site. A 3.5 Å crystal structure of the 80S eukaryotic ribosome from in complex with AglA was obtained, revealing multiple conformational changes of the nucleotide bases in the ribosome accompanying the binding of AglA. Together, these results have unraveled the mechanism of inhibition of eukaryotic translation by AglA at atomic level, paving the way for future structural modifications to develop AglA analogs into novel anticancer agents. The natural product AglA possesses promising antitumor activity. But its mechanism of action has remained a mystery. McClary et al. identified the A site of the ribosome as the molecular target of AglA, elucidating its molecular mechanism of action.
    Keywords: Ribosome ; Peptidyl Transferase Center ; Translation Elongation ; Brain Cancer ; Drug Design ; Molecular Docking ; Chemical Footprinting ; Rrna Seq ; Marine Alkaloid ; Agelastatin A ; Anatomy & Physiology
    ISSN: 2451-9456
    E-ISSN: 24519448
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  • 9
    Language: English
    In: Structure, 06 March 2018, Vol.26(3), pp.416-425.e4
    Description: Alkaloids isolated from the Amaryllidaceae plants have potential as therapeutics for treating human diseases. Haemanthamine has been studied as a novel anticancer agent due to its ability to overcome cancer cell resistance to apoptosis. Biochemical experiments have suggested that hemanthamine targets the ribosome. However, a structural characterization of its mechanism has been missing. Here we present the 3.1 Å resolution X-ray structure of haemanthamine bound to the 80S ribosome. This structure reveals that haemanthamine targets the A-site cleft on the large ribosomal subunit rearranging rRNA to halt the elongation phase of translation. Furthermore, we provide evidence that haemanthamine and other Amaryllidaceae alkaloids also inhibit specifically ribosome biogenesis, triggering nucleolar stress response and leading to p53 stabilization in cancer cells. Together with a computer-aided interpretation of existing structure-activity relationships of Amaryllidaceae alkaloids congeners, we provide a rationale for designing molecules with enhanced potencies and reduced toxicities. Pellegrino, Meyer et al. map at atomic resolution the binding site of the Amaryllidaceae alkaloid haemanthamine onto the eukaryotic 80S ribosome, and demonstrate that it inhibits ribosome biogenesis and activates a p53-dependent antitumor pathway in cancer cells. They provide a structure-based rationale for designing more potent and less cytotoxic molecules.
    Keywords: Haemanthamine ; Amaryllidaceae Alkaloids ; Ribosome ; X-Ray Crystallography ; Peptidyl Transferase Center ; Translation Elongation ; Ribosome Biogenesis ; Cancer ; P53 ; Nucleolar Stress Response ; Biology
    ISSN: 0969-2126
    E-ISSN: 1878-4186
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  • 10
    Language: English
    In: Methods, March 2011, Vol.53(3), pp.201-207
    Description: Aggregation of amyloid beta peptide into senile plaques and hyperphosphorylated tau protein into neurofibrillary tangles in the brain are the pathological hallmarks of Alzheimer’s disease. Despite over a century of research into these lesions, the exact relationship between pathology and neurotoxicity has yet to be fully elucidated. In order to study the formation of plaques and tangles and their effects on the brain, we have applied multiphoton in vivo imaging of transgenic mouse models of Alzheimer’s disease. This technique allows longitudinal imaging of pathological aggregation of proteins and the subsequent changes in surrounding neuropil neurodegeneration and recovery after therapeutic interventions.
    Keywords: Alzheimer ; Tau ; Plaque ; Multiphoton ; In Vivo Imaging ; Chemistry ; Anatomy & Physiology
    ISSN: 1046-2023
    E-ISSN: 1095-9130
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