Aberrant CDK1 Activity in S Phase Induces Chromosomal Instability by Increasing Mitotic Microtubule Polymerisation Rates in Colorectal Cancer Cells

Whole chromosomal instability (W-CIN), one of the major hallmarks of human cancer, is defined as the perpetual gain or loss of whole chromosomes during mitosis leading to the development of heterogeneous karyotypes. W-CIN is associated with tumourigenesis, tumour progression, therapy resistance, and poor prognosis. Therefore, it is of great interest to elucidate the molecular mechanisms underlying W-CIN in order to understand genome instability driven tumorigenesis and tumour progression. Recently, our lab has shown that W-CIN is triggered by increased microtubule polymerisation rates during mitosis which promote the formation of lagging chromosomes in anaphase, a mitotic error frequently observed in cancer cells. The results presented in this study show that the concomitant loss of the transcription factors p53 and p73 increases mitotic microtubule polymerisation rates and, consequently, induces W-CIN. Reduced expression of CDKN1A, a target gene of p53 and p73 encoding for the CDK inhibitor p21CIP1, causes the mitotic defects observed upon p53/p73 depletion. Importantly, increased CDK1 activity, which is the result of loss of the p73/p53-p21CIP1 pathway, is responsible for the observed chromosome missegregation. Unexpectedly, increased microtubule polymerisation rates and W-CIN are the result of elevated CDK1 activity specifically during S phase and not during mitosis. This suggests that increased CDK1 activity might interfere with DNA replication which leads to subsequent mitotic chromosome missegregation. Accordingly, normal mitotic microtubule growth rates and chromosome segregation were restored by nucleoside supplementation or inhibition of CDC7, a kinase involved in the firing of DNA replication origins. These results indicate that replication stress and increased origin firing are indeed triggered by increased CDK1 activity. In line with this, inhibition of the kinase ATR, a negative regulator of CDK1 in S phase, also increases mitotic microtubule growth rates and the incidence of lagging chromosomes. In summary, this study shows that loss of the p73/p53-p21CIP1 tumour suppressor pathway in colorectal cancer cells causes abnormal microtubule polymerisation rates in mitosis and W-CIN by unleashing CDK1 activity during S phase of the cell cycle, which might trigger increased origin firing during DNA replication. Thus, the present study provides new insights into the mechanisms promoting the generation of chromosomal instability in human cancer cells.2022-04-1

The impact of different care dependencies on people’s willingness to provide informal care: a discrete choice experiment in Germany

Background: Informal care provided by family members, friends, or neighbors is a major pillar in the German long-term care system. As the number of care-dependent older adults grow, ensuring their future care still relies on the willingness of family members, friends, or neighbors to assume the role of an informal caregiver. This study aimed to investigate the impact on people’s willingness to provide informal care to a close relative with predominately cognitive compared to physical impairments. Methods: An online survey was distributed to the general population in Germany, which resulted in 260 participants. A discrete choice experiment was created to elicit and quantify people’s preferences. A conditional logit model was used to investigate preferences and marginal willingness-to-accept values were estimated for one hour of informal caregiving. Results:Increased care time per day (hours) and expected duration of caregiving were negatively valued by the participants and reduced willingness to care. Descriptions of the two care dependencies had a significant impact on participants’ decisions. Having to provide care to a close relative with cognitive impairments was slightly preferred over caring for a relative with physical impairments. Conclusions: Our study results show the impact of different factors on the willingness to provide informal care to a close relative. How far the preference weights as well as the high willingness-to-accept values for an hour of caregiving can be explained by the sociodemographic structure of our cohort needs to be investigated by further research. Participants slightly preferred caring for a close relative with cognitive impairments, which might be explained by fear or discomfort with providing personal care to a relative with physical impairments or feelings of sympathy and pity towards people with dementia. Future qualitative research designs can help understand these motivations

Vorteile und Herausforderungen bei der Kombination von Elektrospeicherheizungen mit PV-Anlagen

Die Kombination einer Elektrospeicherheizung (ESH) mit einer PV-Anlagen birgt mehrere Vorteile. Die natürliche Speicherfähigkeit der ESH kompensiert die tageszeitliche Verschiebung von PV-Einspeisung und Wärmebedarf. Die ESH wird in diesem Fall unabhängig von den Freigabezeiten auch tagsüber geladen, was einen Wärmekomfortgewinn für den Nutzer bewirkt. Der Eigenverbrauchsanteil der PV-Anlage wird durch den im Vergleich zum Strombedarf des Haushalts hohen Strombedarf der ESH deutlich erhöht. Dieser Aspekt ist vor allem für PV-Anlagen interessant, die eine niedrige Einspeisevergütung aufweisen oder aufgrund ihres Alters aus der Förderung herausfallen

The relationship of self-reported and device-based measures of physical activity and health-related quality of life in adolescents

"Background: Physical activity (PA) has benefcial efects on health and health-related quality of life (HRQoL), which is a protective factor of illness and mortality. The purpose of this examination was to investigate if self-reported and device-based measures of PA were related to HRQoL in adolescents. Methods: Participants (N=1565; 54.3% female; Mage=14.37 years, SDage=1.99) were recruited from 167 sample points across Germany. Adolescents self-reported their PA, supplemented by a 1-week examination of device-based PA using accelerometry. Additionally, they completed the multidimensional KIDSCREEN-27 to assess HRQoL. Results: Results showed that self-reported PA was correlated with overall HRQoL, Physical Well-Being, Psychological Well-Being, Social Support & Peers, and School Environment, whereas device-based PA was only correlated with Physi‑ cal as well as Psychological Well-Being. Further, self-reported PA signifcantly predicted all facets of HRQoL except for Autonomy and Parent Relations, whereas device-based PA solely heightened the amount of explained variance in the Physical Well-Being subscale. Conclusions: Findings demonstrate the importance of self-reported PA as it is related to almost all facets of HRQoL. Both measures of PA are not congruent in their relationship with HRQoL and thus implications have to be carefully considered. Future studies should investigate the direct efect of PA on HRQoL and health in a longitudinal approach to account for the causality of efects.

The relationship of self-reported and device-based measures of physical activity and health-related quality of life in adolescents

Background Physical activity (PA) has beneficial effects on health and health-related quality of life (HRQoL), which is a protective factor of illness and mortality. The purpose of this examination was to investigate if self-reported and device-based measures of PA were related to HRQoL in adolescents. Methods Participants (N = 1565; 54.3% female; Mage = 14.37 years, SDage = 1.99) were recruited from 167 sample points across Germany. Adolescents self-reported their PA, supplemented by a 1-week examination of device-based PA using accelerometry. Additionally, they completed the multidimensional KIDSCREEN-27 to assess HRQoL. Results Results showed that self-reported PA was correlated with overall HRQoL, Physical Well-Being, Psychological Well-Being, Social Support & Peers, and School Environment, whereas device-based PA was only correlated with Physical as well as Psychological Well-Being. Further, self-reported PA significantly predicted all facets of HRQoL except for Autonomy and Parent Relations, whereas device-based PA solely heightened the amount of explained variance in the Physical Well-Being subscale. Conclusions Findings demonstrate the importance of self-reported PA as it is related to almost all facets of HRQoL. Both measures of PA are not congruent in their relationship with HRQoL and thus implications have to be carefully considered. Future studies should investigate the direct effect of PA on HRQoL and health in a longitudinal approach to account for the causality of effects

Predestination of special educational assessments? An empirical study of expert opinions in the area of emotional and social development

Die vorliegende Arbeit untersucht 38 sonderpädagogische Gutachten aus dem Förderschwerpunkt Emotionale und soziale Entwicklung mit Fokus darauf, ob diese die wissenschaftlich gebräuchlichen Qualitätskriterien erfüllen, welche Bereiche untersucht werden, welche Merkmale für die Verfahrenseröffnung und Zuschreibung des Förderschwerpunktes herangezogen werden und anhand welcher Merkmale die Begründung für die Verfahrenseröffnung und die Zuschreibung erfolgt. Die Gutachten wurden in einem Mixed-Methods-Design aus quantitativer und qualitativer Inhaltsanalyse ausgewertet. Die Ergebnisse zeigen auf, dass die Gutachten nicht den wissenschaftlichen Qualitätsstandards entsprechen und im Prozess primär individuumsbezogene Merkmale, insbesondere das Verhalten des Kindes, berücksichtigt werden. (DIPF/Orig.)This study examined 38 expert opinions in the area of emotional and social development with a focus on whether they meet the scientifically accepted quality criteria, which areas are investigated, which characteristics are considered for the initiation and the recommendation and based on which characteristics the rationale for the initiation and the recommendation is made. The expert opinions were analysed using a mixed-methods design involving quantitative and qualitative content analysis. The results indicate that the expert opinions do not meet scientific quality standards and primarily consider individual-related characteristics, particularly the child’s behaviour, in the process. (DIPF/Orig.