| 1. |
- Breznau, Nate, et al.
(author)
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Observing many researchers using the same data and hypothesis reveals a hidden universe of uncertainty
- 2022
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In: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:44
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Journal article (peer-reviewed)abstract
- This study explores how researchers analytical choices affect the reliability of scientific findings. Most discussions of reliability problems in science focus on systematic biases. We broaden the lens to emphasize the idiosyncrasy of conscious and unconscious decisions that researchers make during data analysis. We coordinated 161 researchers in 73 research teams and observed their research decisions as they used the same data to independently test the same prominent social science hypothesis: that greater immigration reduces support for social policies among the public. In this typical case of social science research, research teams reported both widely diverging numerical findings and substantive conclusions despite identical start conditions. Researchers expertise, prior beliefs, and expectations barely predict the wide variation in research outcomes. More than 95% of the total variance in numerical results remains unexplained even after qualitative coding of all identifiable decisions in each teams workflow. This reveals a universe of uncertainty that remains hidden when considering a single study in isolation. The idiosyncratic nature of how researchers results and conclusions varied is a previously underappreciated explanation for why many scientific hypotheses remain contested. These results call for greater epistemic humility and clarity in reporting scientific findings.
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| 2. |
- Belova, Valentina, et al.
(author)
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Evidence for Anisotropic Electronic Coupling of Charge Transfer States in Weakly Interacting Organic Semiconductor Mixtures
- 2017
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In: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 139:25, s. 8474-8486
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Journal article (peer-reviewed)abstract
- We present a comprehensive investigation of the charge-transfer (CT) effect in weakly interacting organic semiconductor mixtures. The donor-acceptor pair diindenoperylene (DIP) and N,N′-bis(2-ethylhexyl)-1,7-dicyanoperylene-3,4/9,10-bis(dicarboxyimide) (PDIR-CN2) has been chosen as a model system. A wide range of experimental methods was used in order to characterize the structural, optical, electronic, and device properties of the intermolecular interactions. By detailed analysis, we demonstrate that the partial CT in this weakly interacting mixture does not have a strong effect on the ground state and does not generate a hybrid orbital. We also find a strong CT transition in light absorption as well as in photo- and electroluminescence. By using different layer sequences and compositions, we are able to distinguish electronic coupling in-plane vs out-of-plane and, thus, characterize the anisotropy of the CT state. Finally, we discuss the impact of CT exciton generation on charge-carrier transport and on the efficiency of photovoltaic devices.
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| 3. |
- Johard, Helena, et al.
(author)
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HCN Channel Activity Balances Quiescence and Proliferation in Neural Stem Cells and Is a Selective Target for Neuroprotection During Cancer Treatment
- 2020
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In: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 18:10, s. 1522-1533
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Journal article (peer-reviewed)abstract
- Children suffering from neurologic cancers undergoing chemotherapy and radiotherapy are at high risk of reduced neurocognitive abilities likely via damage to proliferating neural stem cells (NSC). Therefore, strategies to protect NSCs are needed. We argue that induced cell-cycle arrest/quiescence in NSCs during cancer treatment can represent such a strategy. Here, we show that hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels are dynamically expressed over the cell cycle in NSCs, depolarize the membrane potential, underlie spontaneous calcium oscillations and are required to maintain NSCs in the actively proliferating pool. Hyperpolarizing pharmacologic inhibition of HCN channels during exposure to ionizing radiation protects NSCs cells in neurogenic brain regions of young mice. In contrast, brain tumor-initiating cells, which also express HCN channels, remain proliferative during HCN inhibition.
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| 4. |
- Marwa, Karol J., et al.
(author)
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Cytochrome P450 single nucleotide polymorphisms in an indigenous Tanzanian population : a concern about the metabolism of artemisinin-based combinations
- 2014
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In: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 13, s. 420-
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Journal article (peer-reviewed)abstract
- Background: Artemisinin-based combinations currently recommended for treatment of uncomplicated Plasmodium falciparum malaria in many countries of sub-Saharan Africa are substrates of CYP enzymes. The cytochrome enzyme system is responsible for metabolism of about 80-90% of clinically used drugs. It is, therefore, important to obtain the pharmacogenetics of the population in the region with respect to these combinations and thereby enable practitioners to predict treatment outcomes. The aim of this study was to detect and determine allelic frequencies of CYP2C8*2, CYP2C8*3, CYP3A4*1B, CYP3A5*3 and CYP2B6*6 variant alleles in a Tanzanian indigenous population. Methods: Genomic DNA extraction from blood obtained from 256 participants who escorted patients at Karume Health Centre in Mwanza Tanzania, was carried out using the Gene JET (TM) Genomic DNA purification kit (Thermo Scientific). Genotyping for the cytochrome P450 variant alleles was performed using predesigned primers. Amplification was done by PCR while differentiation between alleles was done by restriction fragment length polymorphism (PCR-RFLP) (for CYP2C8*2, CYP2C8*3) and sequencing (for CYP2B6*6, CYP3A5*3 and CYP3A4*1B). Results: CYP2C8*2, CYP2C8*3, CYP3A5*3, CYP3A4*1B and CYP2B6*6 variant allelic frequencies were found to be 19,10,16,78 and 36% respectively. Conclusion: Prevalence of CYP2C8*2, CYP3A5*3, CYP3A4*1B and CYP2B6*6 mutations in a Tanzanian population/ subjects are common. The impact of these point mutations on the metabolism of anti-malarial drugs, particularly artemisinin-based combinations, and their potential drug-drug interactions (DDIs) needs to be further evaluated.
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| 5. |
- Namer, Barbara, et al.
(author)
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Changes in Ionic Conductance Signature of Nociceptive Neurons Underlying Fabry Disease Phenotype
- 2017
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In: Frontiers in Neurology. - : FRONTIERS MEDIA SA. - 1664-2295. ; 8
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Journal article (peer-reviewed)abstract
- The first symptom arising in many Fabry patients is neuropathic pain due to changes in small myelinated and unmyelinated fibers in the periphery, which is subsequently followed by a loss of sensory perception. Here we studied changes in the peripheral nervous system of Fabry patients and a Fabry mouse model induced by deletion of a-galactosidase A (Gla(-/0)). The skin innervation of Gla(-/0) mice resembles that of the human Fabry patients. In Fabry diseased humans and Gla(-/0) mice, we observed similar sensory abnormalities, which were also observed in nerve fiber recordings in both patients and mice. Electrophysiological recordings of cultured Gla(-/0) nociceptors revealed that the conductance of voltage-gated Na+ and Ca2+ currents was decreased in Gla(-/0) nociceptors, whereas the activation of voltage-gated K+ currents was at more depolarized potentials. Conclusively, we have observed that reduced sensory perception due to small-fiber degeneration coincides with altered electrophysiological properties of sensory neurons.
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| 6. |
- Niklasson, Mia, et al.
(author)
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Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses
- 2017
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In: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 77:7, s. 1741-1752
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Journal article (peer-reviewed)abstract
- Glioma-initiating cells (GIC) are considered the underlying cause of recurrences of aggressive glioblastomas, replenishing the tumor population and undermining the efficacy of conventional chemotherapy. Here we report the discovery that inhibiting T-type voltage-gated Ca2+ and KCa channels can effectively induce selective cell death of GIC and increase host survival in an orthotopic mouse model of human glioma. At present, the precise cellular pathways affected by the drugs affecting these channels are unknown. However, using cell-based assays and integrated proteomics, phosphoproteomics, and transcriptomics analyses, we identified the downstreamsignaling events these drugs affect. Changes in plasma membrane depolarization and elevated intracellular Na+, which compromised Na+-dependent nutrient transport, were documented. Deficits in nutrient deficit acted in turn to trigger the unfolded protein response and the amino acid response, leading ultimately to nutrient starvation and GIC cell death. Our results suggest new therapeutic targets to attack aggressive gliomas.
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| 7. |
- Stoppacher, Sara, et al.
(author)
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Modeling External Stimulation of Excitable Cells Using a Novel Light-Activated Organic Semiconductor Technology
- 2020
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In: Biomedical Informatics for Health and Care. - : IOS Press. - 9781643680842 - 9781643680859 ; , s. 9-16
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Conference paper (peer-reviewed)abstract
- Optoelectronic neurostimulation is a promising, minimally invasive treatment modality for neuronal damage, in particular for patients with traumatic brain injury. In this work, a newly developed optoelectronic device, a so-called photocap, based on light-activated organic semiconductor structures with high spatial and temporal resolution is investigated. To prove and verify the feasibility of this new technology, a mathematical model was developed, simulating the electrical response of excitable cells to photocap stimulation. In the first step, a comprehensive technical review of the device concept was performed, building the basis for setting up the simulation model. The simulations demonstrate that photocaps may serve as a stimulation device, triggering action potentials in neural or cardiac cells. Our first results show that the model serves as a perfect tool for evaluating and further developing this new technology, showing high potential for introducing new and innovative therapy methods in the field of optoelectronic cell stimulation.
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| 8. |
- Wiedorn, Max O., et al.
(author)
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Megahertz serial crystallography
- 2018
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In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9
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Journal article (peer-reviewed)abstract
- The new European X-ray Free-Electron Laser is the first X-ray free-electron laser capable of delivering X-ray pulses with a megahertz inter-pulse spacing, more than four orders of magnitude higher than previously possible. However, to date, it has been unclear whether it would indeed be possible to measure high-quality diffraction data at megahertz pulse repetition rates. Here, we show that high-quality structures can indeed be obtained using currently available operating conditions at the European XFEL. We present two complete data sets, one from the well-known model system lysozyme and the other from a so far unknown complex of a beta-lactamase from K. pneumoniae involved in antibiotic resistance. This result opens up megahertz serial femtosecond crystallography (SFX) as a tool for reliable structure determination, substrate screening and the efficient measurement of the evolution and dynamics of molecular structures using megahertz repetition rate pulses available at this new class of X-ray laser source.
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