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  • 1
    Language: English
    In: Ecker, J., I. Oehme, R. Mazitschek, A. Korshunov, M. Kool, T. Hielscher, J. Kiss, et al. 2015. “Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma.” Acta Neuropathologica Communications 3 (1): 22. doi:10.1186/s40478-015-0201-7. http://dx.doi.org/10.1186/s40478-015-0201-7.
    Description: Introduction: Medulloblastoma (MB) is the most frequent malignant brain tumor in children. Four subgroups with distinct genetic, epigenetic and clinical characteristics have been identified. Survival remains particularly poor in patients with Group 3 tumors harbouring a MYC amplification. We herein explore the molecular mechanisms and translational implications of class I histone deacetylase (HDAC) inhibition in MYC driven MBs. Material and Methods Expression of HDACs in primary MB subgroups was compared to normal brain tissue. A panel of MB cell lines, including Group 3 MYC amplified cell lines, were used as model systems. Cells were treated with HDAC inhibitors (HDACi) selectively targeting class I or IIa HDACs. Depletion of HDAC2 was performed. Intracellular HDAC activity, cellular viability, metabolic activity, caspase activity, cell cycle progression, RNA and protein expression were analyzed. Results: HDAC2 was found to be overexpressed in MB subgroups with poor prognosis (SHH, Group 3 and Group 4) compared to normal brain and the WNT subgroup. Inhibition of the enzymatic activity of the class I HDACs reduced metabolic activity, cell number, and viability in contrast to inhibition of class IIa HDACs. Increased sensitivity to HDACi was specifically observed in MYC amplified cells. Depletion of HDAC2 increased H4 acetylation and induced cell death. Simulation of clinical pharmacokinetics showed time-dependent on target activity that correlated with binding kinetics of HDACi compounds. Conclusions: We conclude that HDAC2 is a valid drug target in patients with MYC amplified MB. HDACi should cover HDAC2 in their inhibitory profile and timing and dosing regimen in clinical trials should take binding kinetics of compounds into consideration. Electronic supplementary material The online version of this article (doi:10.1186/s40478-015-0201-7) contains supplementary material, which is available to authorized users.
    Keywords: Medulloblastoma ; Hdac ; Hdac Inhibitor ; Hdac2 ; Myc
    ISSN: 2051-5960
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  • 2
    Language: English
    In: BBA - Bioenergetics, June 2014, Vol.1837(6), pp.773-781
    Description: In this study we use a combination of absorption, fluorescence and low temperature single-molecule spectroscopy to elucidate the spectral properties, heterogeneities and dynamics of the chlorophyll (Chl ) molecules responsible for the fluorescence emission of photosystem II core complexes (PS II cc) from the cyanobacterium . At the ensemble level, the absorption and fluorescence spectra show a temperature dependence similar to plant PS II. We report emission spectra of single PS II cc for the first time; the spectra are dominated by zero-phonon lines (ZPLs) in the range between 680 and 705 nm. The single-molecule experiments show unambiguously that different emitters and not only the lowest energy trap contribute to the low temperature emission spectrum. The average emission spectrum obtained from more than hundred single complexes shows three main contributions that are in good agreement with the reported bands F685, F689 and F695. The intensity of F695 is found to be lower than in conventional ensemble spectroscopy. The reason for the deviation might be due to the accumulation of triplet states on the red-most chlorophylls (e.g. Chl29 in CP47) or on carotenoids close to these long-wavelength traps by the high excitation power used in the single-molecule experiments. The red-most emitter will not contribute to the fluorescence spectrum as long as it is in the triplet state. In addition, quenching of fluorescence by the triplet state may lead to a decrease of long-wavelength emission.
    Keywords: Photosystem II Core Complex ; Cp43 ; Cp47 ; Single-Molecule Spectroscopy ; Low Temperature Spectroscopy ; Fluorescence Quenching ; Chemistry
    ISSN: 0005-2728
    E-ISSN: 1879-2650
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  • 3
    Language: English
    In: The Journal of Infectious Diseases, 1 November 2011, Vol.204, pp.S850-S860
    Description: The antiviral protein tetherin/BST2/CD317/HM1.24 restricts cellular egress of human immunodeficiency virus (HIV) and of particles mimicking the Ebola virus (EBOV), a hemorrhagic fever virus. The HIV-1 viral protein U (Vpu) and the EBOV-glycoprotein (EBOV-GP) both inhibit tetherin. Here, we compared tetherin counteraction by EBOV-GP and Vpu. We found that EBOV-GP but not Vpu counteracted tetherin from different primate species, indicating that EBOV-GP and Vpu target tetherin differentially. Tetherin interacted with the GP2 subunit of EBOV-GP, which might encode the determinants for tetherin counteraction. Vpu reduced cell surface expression of tetherin while EBOV-GP did not, suggesting that both proteins employ different mechanisms to counteract tetherin. Finally, Marburg virus (MARV)-GP also inhibited tetherin and downregulated tetherin in a cell type-dependent fashion, indicating that tetherin antagonism depends on the cellular source of tetherin. Collectively, our results indicate that EBOV-GP counteracts tetherin by a novel mechanism and that tetherin inhibition is conserved between EBOV-GP and MARV-GP.
    Keywords: Biological sciences -- Biology -- Cytology -- HIV ; Biological sciences -- Biology -- Microbiology -- HIV ; Biological sciences -- Biology -- Microbiology -- HIV ; Biological sciences -- Biology -- Genetics -- HIV ; Biological sciences -- Biochemistry -- Biomolecules -- HIV ; Biological sciences -- Biology -- Genetics -- HIV ; Biological sciences -- Biology -- Microbiology -- HIV ; Biological sciences -- Biology -- Cytology -- HIV ; Biological sciences -- Biology -- Cytology -- HIV ; Physical sciences -- Chemistry -- Chemical compounds -- HIV
    ISSN: 00221899
    Source: Archival Journals (JSTOR)
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  • 4
    Language: English
    In: The Journal of Infectious Diseases, 1 November 2011, Vol.204, pp.S850-S860
    Description: The antiviral protein tetherin/BST2/CD317/HM1.24 restricts cellular egress of human immunodeficiency virus (HIV) and of particles mimicking the Ebola virus (EBOV), a hemorrhagic fever virus. The HIV-1 viral protein U (Vpu) and the EBOV-glycoprotein (EBOV-GP) both inhibit tetherin. Here, we compared tetherin counteraction by EBOV-GP and Vpu. We found that EBOV-GP but not Vpu counteracted tetherin from different primate species, indicating that EBOV-GP and Vpu target tetherin differentially. Tetherin interacted with the GP2 subunit of EBOV-GP, which might encode the determinants for tetherin counteraction. Vpu reduced cell surface expression of tetherin while EBOV-GP did not, suggesting that both proteins employ different mechanisms to counteract tetherin. Finally, Marburg virus (MARV)-GP also inhibited tetherin and downregulated tetherin in a cell type-dependent fashion, indicating that tetherin antagonism depends on the cellular source of tetherin. Collectively, our results indicate that EBOV-GP counteracts tetherin by a novel mechanism and that tetherin inhibition is conserved between EBOV-GP and MARV-GP.
    Keywords: Biological sciences -- Biology -- Cytology -- HIV ; Biological sciences -- Biology -- Microbiology -- HIV ; Biological sciences -- Biology -- Microbiology -- HIV ; Biological sciences -- Biology -- Genetics -- HIV ; Biological sciences -- Biochemistry -- Biomolecules -- HIV ; Biological sciences -- Biology -- Genetics -- HIV ; Biological sciences -- Biology -- Microbiology -- HIV ; Biological sciences -- Biology -- Cytology -- HIV ; Biological sciences -- Biology -- Cytology -- HIV ; Physical sciences -- Chemistry -- Chemical compounds -- HIV
    ISSN: 00221899
    Source: Archival Journals (JSTOR)
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  • 5
    Language: English
    In: European journal of nuclear medicine and molecular imaging, October 2015, Vol.42(11), pp.1739-1749
    Description: The aim of the study was to investigate DNA double strand break (DSB) formation and its correlation with the absorbed dose to the blood lymphocytes of patients undergoing their first peptide receptor radionuclide therapy (PRRT) with (177)Lu-labelled DOTATATE/DOTATOC. The study group comprised 16 patients receiving their first PRRT. At least six peripheral blood samples were obtained before, and between 0.5 h and 48 h after radionuclide administration. From the time-activity curves of the blood and the whole body, residence times for blood self-irradiation and whole-body irradiation were determined. Peripheral blood lymphocytes were isolated, fixed with ethanol and subjected to immunofluorescence staining for colocalizing γ-H2AX/53BP1 DSB-marking foci. The average number of DSB foci per cell per patient sample was determined as a function of the absorbed dose to the blood and compared with an in vitro calibration curve established in our laboratory with (131)I and (177)Lu. The average number of radiation-induced foci (RIF) per cell increased over the first 5 h after radionuclide administration and decreased thereafter. A linear fit from 0 to 5 h as a function of the absorbed dose to the blood agreed with our in vitro calibration curve. At later time-points the number of RIF decreased, indicating progression of DNA repair. Measurements of RIF and the absorbed dose to the blood after systemic administration of (177)Lu may be used to obtain data on the individual dose-response relationships in vivo. Individual patient data were characterized by a linear dose-dependent increase and an exponential decay function describing repair.
    Keywords: DNA Breaks, Double-Stranded -- Radiation Effects ; Lutetium -- Therapeutic Use ; Lymphocytes -- Metabolism ; Radiation Injuries -- Genetics ; Radioisotopes -- Therapeutic Use ; Receptors, Peptide -- Metabolism
    ISSN: 16197070
    E-ISSN: 1619-7089
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  • 6
    Language: English
    In: Journal of Thermal Biology, December 2016, Vol.62, pp.159-169
    Description: In 2010, approximately 14.9 million babies (11.1%) were born preterm. Because preterm infants suffer from an immature thermoregulatory system they have difficulty maintaining their core body temperature at a constant level. Therefore, it is essential to maintain their temperature at, ideally, around 37 °C. For this, mathematical models can provide detailed insight into heat transfer processes and body-environment interactions for clinical applications. A new multi-node mathematical model of the thermoregulatory system of newborn infants is presented. It comprises seven compartments, one spherical and six cylindrical, which represent the head, thorax, abdomen, arms and legs, respectively. The model is customizable, i.e. it meets individual characteristics of the neonate (e.g. gestational age, postnatal age, weight and length) which play an important role in heat transfer mechanisms. The model was validated during thermal neutrality and in a transient thermal environment. During thermal neutrality the model accurately predicted skin and core temperatures. The difference in mean core temperature between measurements and simulations averaged 0.25±0.21 °C and that of skin temperature averaged 0.36±0.36 °C. During transient thermal conditions, our approach simulated the thermoregulatory dynamics/responses. Here, for all infants, the mean absolute error between core temperatures averaged 0.12±0.11 °C and that of skin temperatures hovered around 0.30 °C. The mathematical model appears able to predict core and skin temperatures during thermal neutrality and in case of a transient thermal conditions.
    Keywords: Thermoregulation ; Physiological Processes ; Premature Infants ; Bioheat Model ; Computer Simulation ; Biology
    ISSN: 0306-4565
    E-ISSN: 1879-0992
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  • 7
    Language: English
    In: Biomedizinische Technik. Biomedical engineering, 01 December 2016, Vol.61(6), pp.631-643
    Description: Vital parameter monitoring of term and preterm infants during incubator care with self-adhesive electrodes or sensors directly positioned on the skin [e.g. photoplethysmography (PPG) for oxygen saturation or electrocardiography (ECG)] is an essential part of daily routine care in neonatal intensive care units. For various reasons, this kind of monitoring contains a lot of stress for the infants. Therefore, there is a need to measure vital parameters (for instance respiration, temperature, pulse, oxygen saturation) without mechanical or conductive contact. As a non-contact method of monitoring, we present an adapted version of camera-based photoplethysmography imaging (PPGI) according to neonatal requirements. Similar to classic PPG, the PPGI camera detects small temporal changes in the term and preterm infant's skin brightness due to the cardiovascular rhythm of dermal blood perfusion. We involved 10 preterm infants in a feasibility study [five males and five females; mean gestational age: 26 weeks (24-28 weeks); mean biological age: 35 days (8-41 days); mean weight at the time of investigation: 960 g (670-1290 g)]. The PPGI camera was placed directly above the incubators with the infant inside illuminated by an infrared light emitting diode (LED) array (850 nm). From each preterm infant, 5-min video sequences were recorded and analyzed post hoc. As the measurement scenario was kept as realistic as possible, the infants were not constrained in their movements in front of the camera. Movement intensities were assigned into five classes (1: no visible motion to 5: heavy struggling). PPGI was found to be significantly sensitive to movement artifacts. However, for movement classes 1-4, changes in blood perfusion according to the heart rate (HR) were recovered successfully (Pearson correlation: r=0.9759; r=0.765 if class 5 is included). The study was approved by the Ethics Committee of the Universal Hospital of the RWTH Aachen University, Aachen, Germany (EK 254/13).
    Keywords: Neonatology ; Electrocardiography -- Methods ; Heart Rate -- Physiology ; Photoplethysmography -- Methods
    ISSN: 00135585
    E-ISSN: 1862-278X
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  • 8
    In: Life Science Alliance, 2018, Vol.1(4)
    Description: This study identifies the cleavage sites of the endoribonuclease RNase E in the Rhodobacter sphaeroides transcriptome and demonstrates its effect on oxidative stress resistance and phototrophic growth. Bacteria adapt to changing environmental conditions by rapid changes in their transcriptome. This is achieved not only by adjusting rates of transcription but also by processing and degradation of RNAs. We applied TIER-Seq (transiently inactivating an endoribonuclease followed by RNA-Seq) for the transcriptome-wide identification of RNase E cleavage sites and of 5′ RNA ends, which are enriched when RNase E activity is reduced in Rhodobacter sphaeroides . These results reveal the importance of RNase E for the maturation and turnover of mRNAs, rRNAs, and sRNAs in this guanine-cytosine-rich α-proteobacterium, some of the latter have well-described functions in the oxidative stress response. In agreement with this, a role of RNase E in the oxidative stress response is demonstrated. A remarkably strong phenotype of a mutant with reduced RNase E activity was observed regarding the formation of photosynthetic complexes and phototrophic growth, whereas there was no effect on chemotrophic growth.
    Keywords: Research Article ; Research Articles ; 11 ; 16 ; 26
    ISSN: Life Science Alliance
    E-ISSN: 2575-1077
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  • 9
    Language: English
    In: Quaternary Science Reviews, 01 December 2017, Vol.177, pp.265-275
    Description: Most outlet glaciers of the Cordillera Darwin Icefield (CDI; Patagonia, 54°S) are currently transitioning from calving to land-based conditions. Whether this situation is unique to the modern climate or also occurred during the Holocene is entirely unknown. Here, we investigate the Holocene fluctuations of outlet glaciers from the northern flank of the CDI using a multi-proxy sedimentological and geochemical analysis of a 13.5 m long sediment core from Almirantazgo fjord. Our results demonstrate that sedimentation in Almirantazgo fjord started prior to 14,300 cal yr BP, with glacier-proximal deposits occurring until 13,500 cal yr BP. After 12,300 cal yr BP, most glaciers had retreated to land-locked locations and by 9800 cal yr BP, Almirantazgo fjord was a predominantly marine fjord environment with oceanographic conditions resembling the present-day setting. Our sediment record shows that during the first part of the Holocene, CDI glaciers were almost entirely land-based, with a possible re-advance at 7300–5700 cal yr BP. This is in clear contrast with the Neoglaciation, during which CDI glaciers rapidly re-advanced and shrank back several times, mostly in phase with the eastern outlet glaciers of the Southern Patagonian Icefield (SPI). Two significant meltwater events, indicative of rapid glacier retreat, were identified at 3250–2700 and 2000–1200 cal yr BP, based on an increase in grain-size mode and related inorganic geochemical parameters. This interpretation is additionally supported by concomitant decreases in organic carbon of marine origin and in Cl counts (salinity), reflecting higher terrestrial input to the fjord and freshening of the fjord waters. Overall, our record suggests that CDI outlet glaciers advanced in phase with eastern SPI glaciers during the Neoglaciation, and retreated far enough into their valleys twice to form large outwash plains. Our results also highlight the potential of fjord sediments to reconstruct glacier variability at high resolution on multi-millennial timescales.
    Keywords: Fjord Sediments ; Ice-Rafted Debris ; Meltwater ; Neoglaciation ; Holocene ; Sciences (General) ; Geology
    ISSN: 0277-3791
    E-ISSN: 1873-457X
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  • 10
    Language: English
    In: 2012
    Description: © The Author(s), 2012. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Climate of the Past 8 (2012): 519-534, doi:10.5194/cp-8-519-2012.
    Description: Glaciers are frequently used as indicators of climate change. However, the link between past glacier fluctuations and climate variability is still highly debated. Here, we investigate the mid- to late-Holocene fluctuations of Gualas Glacier, one of the northernmost outlet glaciers of the Northern Patagonian Icefield, using a multi-proxy sedimentological and geochemical analysis of a 15 m long fjord sediment core from Golfo Elefantes, Chile, and historical documents from early Spanish explorers. Our results show that the core can be sub-divided into three main lithological units that were deposited under very different hydrodynamic conditions. Between 5400 and 4180 cal yr BP and after 750 cal yr BP, sedimentation in Golfo Elefantes was characterized by the rapid deposition of fine silt, most likely transported by fluvio-glacial processes. By contrast, the sediment deposited between 4130 and 850 cal yr BP is composed of poorly sorted sand that is free of shells. This interval is particularly marked by high magnetic susceptibility values and Zr concentrations, and likely reflects a major advance of Gualas glacier towards Golfo Elefantes during the Neoglaciation. Several thin silt layers observed in the upper part of the core are interpreted as secondary fluctuations of Gualas glacier during the Little Ice Age, in agreement with historical and dendrochronological data. Our interpretation of the Golfo Elefantes glaciomarine sediment record in terms of fluctuations of Gualas glacier is in excellent agreement with the glacier chronology proposed for the Southern Patagonian Icefield, which is based on terrestrial (moraine) deposits. By comparing our results with independent proxy records of precipitation and sea surface temperature, we suggest that the fluctuations of Gualas glacier during the last 5400 yr were mainly driven by changes in precipitation in the North Patagonian Andes.
    Description: This research was supported by an EU FP6Marie Curie Outgoing Fellowship to S.B. Cruise NBP0505 wasfunded by the US National Science Foundation, Office of PolarPrograms grant number NSF/OPP 03-38137 to J. Anderson (RiceUniversity) and J. Smith Wellner (University of Houston). TheCimar-7 Program was supported by the Chilean National OceanographicCommittee (CONA, Grant C7F 01-10 to S. Pantoja).
    Source: AGRIS (Food and Agriculture Organization of the United Nations)
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