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DNA damage in leukocytes after internal ex-vivo irradiation of blood with the α-emitter Ra-223
(2018)
Irradiation with high linear energy transfer α-emitters, like the clinically used Ra-223 dichloride, severely damages cells and induces complex DNA damage including closely spaced double-strand breaks (DSBs). As the hematopoietic system is an organ-at-risk for the treatment, knowledge about Ra-223-induced DNA damage in blood leukocytes is highly desirable. Therefore, 36 blood samples from six healthy volunteers were exposed ex-vivo (in solution) to different concentrations of Ra-223. Absorbed doses to the blood were calculated assuming local energy deposition of all α- and β-particles of the decay, ranging from 0 to 142 mGy. γ-H2AX + 53BP1 co-staining and analysis was performed in leukocytes isolated from the irradiated blood samples. For DNA damage quantification, leukocyte samples were screened for occurrence of α-induced DNA damage tracks and small γ-H2AX + 53BP1 DSB foci. This revealed a linear relationship between the frequency of α-induced γ-H2AX damage tracks and the absorbed dose to the blood, while the frequency of small γ-H2AX + 53BP1 DSB foci indicative of β-irradiation was similar to baseline values, being in agreement with a negligible β-contribution (3.7%) to the total absorbed dose to the blood. Our calibration curve will contribute to the biodosimetry of Ra-223-treated patients and early after incorporation of α-emitters.
Fibroblasts isolated from a skin biopsy of a healthy 46-year-old female were infected with Sendai virus containing the Yamanaka factors to produce transgene-free human induced pluripotent stem cells (iPSCs). CRISPR/Cas9 was used to generate isogenic cell lines with a gene dose-dependent deficiency of CDH13, a risk gene associated with neurodevelopmental and psychiatric disorders. Thereby, a heterozygous CDH13 knockout (CDH13\(^{+/-}\)) and a CDH13 null mutant (CDH13\(^{-/-}\)) iPSC line was obtained. All three lines showed expression of pluripotency-associated markers, the ability to differentiate into cells of the three germ layers in vitro, and a normal female karyotype.
Creativity, specifically divergent thinking, has been shown to benefit from unrestrained walking. Despite these findings, it is not clear if it is the lack of restriction that leads to the improvement. Our goal was to explore the effects of motor restrictions on divergent thinking for different movement states. In addition, we assessed whether spontaneous eye blinks, which are linked to motor execution, also predict performance. In experiment 1, we compared the performance in Guilford's alternate uses task (AUT) during walking vs. sitting, and analysed eye blink rates during both conditions. We found that AUT scores were higher during walking than sitting. Albeit eye blinks differed significantly between movement conditions (walking vs. sitting) and task phase (baseline vs. thinking vs. responding), they did not correlate with task performance. In experiment 2 and 3, participants either walked freely or in a restricted path, or sat freely or fixated on a screen. When the factor restriction was explicitly modulated, the effect of walking was reduced, while restriction showed a significant influence on the fluency scores. Importantly, we found a significant correlation between the rate of eye blinks and creativity scores between subjects, depending on the restriction condition. Our study shows a movement state-independent effect of restriction on divergent thinking. In other words, similar to unrestrained walking, unrestrained sitting also improves divergent thinking. Importantly, we discuss a mechanistic explanation of the effect of restriction on divergent thinking based on the increased size of the focus of attention and the consequent bias towards flexibility.