No interrelation of motor planning and executive functions across young ages

The present study examined the developmental trajectories of motor planning and executive functioning in children. To this end, we tested 217 participants with three motor tasks, measuring anticipatory planning abilities (i.e., the bar-transport-task, the sword-rotation-task and the grasp-height-task), and three cognitive tasks, measuring executive functions (i.e., the Tower-of-Hanoi-task, the Mosaic-task, and the D2-attention-endurance-task). Children were aged between 3 and 10 years and were separated into age groups by 1-year bins, resulting in a total of eight groups of children and an additional group of adults. Results suggested (1) a positive developmental trajectory for each of the sub-tests, with better task performance as children get older; (2) that the performance in the separate tasks was not correlated across participants in the different age groups; and (3) that there was no relationship between performance in the motor tasks and in the cognitive tasks used in the present study when controlling for age. These results suggest that both, motor planning and executive functions are rather heterogeneous domains of cognitive functioning with fewer interdependencies than often suggested

Characterization of the stem cell system of the acoel Isodiametra pulchra

Background: Tissue plasticity and a substantial regeneration capacity based on stem cells are the hallmark of several invertebrate groups such as sponges, cnidarians and Platyhelminthes. Traditionally, Acoela were seen as an early branching clade within the Platyhelminthes, but became recently positioned at the base of the Bilateria. However, little is known on how the stem cell system in this new phylum is organized. In this study, we wanted to examine if Acoela possess a neoblast-like stem cell system that is responsible for development, growth, homeostasis and regeneration. Results: We established enduring laboratory cultures of the acoel Isodiametra pulchra (Acoela, Acoelomorpha) and implemented in situ hybridization and RNA interference (RNAi) for this species. We used BrdU labelling, morphology, ultrastructure and molecular tools to illuminate the morphology, distribution and plasticity of acoel stem cells under different developmental conditions. We demonstrate that neoblasts are the only proliferating cells which are solely mesodermally located within the organism. By means of in situ hybridisation and protein localisation we could demonstrate that the piwi-like gene ipiwi1 is expressed in testes, ovaries as well as in a subpopulation of somatic stem cells. In addition, we show that germ cell progenitors are present in freshly hatched worms, suggesting an embryonic formation of the germline. We identified a potent stem cell system that is responsible for development, homeostasis, regeneration and regrowth upon starvation. Conclusions: We introduce the acoel Isodiametra pulchra as potential new model organism, suitable to address developmental questions in this understudied phylum. We show that neoblasts in I. pulchra are crucial for tissue homeostasis, development and regeneration. Notably, epidermal cells were found to be renewed exclusively from parenchymally located stem cells, a situation known only from rhabditophoran flatworms so far. For further comparison, it will be important to analyse the stem cell systems of other key-positioned understudied taxa

Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma, or leukemia

Background: Until today, adult and pediatric clinical trials investigating single-agent or combinatorial HDAC inhibitors including vorinostat in solid tumors have largely failed to demonstrate efficacy. These results may in part be explained by data from preclinical models showing significant activity only at higher concentrations compared to those achieved with current dosing regimens. In the current pediatric trial, we applied an intra-patient dose escalation design. The purpose of this trial was to determine a safe dose recommendation (SDR) of single-agent vorinostat for intra-patient dose escalation, pharmacokinetic analyses (PK), and activity evaluation in children (3-18 years) with relapsed or therapy-refractory malignancies. Results: A phase I intra-patient dose (de)escalation was performed until individual maximum tolerated dose (MTD). The starting dose was 180 mg/m(2)/day with weekly dose escalations of 50 mg/m(2) until DLT/maximum dose. After MTD determination, patients seamlessly continued in phase II with disease assessments every 3 months. PK and plasma cytokine profiles were determined. Fifty of 52 patients received treatment. n = 27/50 (54%) completed the intra-patient (de)escalation and entered phase II. An SDR of 130 mg/m(2)/day was determined (maximum, 580 mg/m(2)/day). n = 46/50 (92%) patients experienced treatment-related AEs which were mostly reversible and included thrombocytopenia, fatigue, nausea, diarrhea, anemia, and vomiting. n = 6/50 (12%) had treatment-related SAEs. No treatment-related deaths occurred. Higher dose levels resulted in higher C-max. Five patients achieved prolonged disease control (> 12 months) and showed a higher C-max (> 270 ng/mL) and MTDs. Best overall response (combining PR and SD, no CR observed) rate in phase II was 6/27 (22%) with a median PFS and OS of 5.3 and 22.4 months. Low levels of baseline cytokine expression were significantly correlated with favorable outcome. Conclusion: An SDR of 130 mg/m(2)/day for individual dose escalation was determined. Higher drug exposure was associated with responses and long-term disease stabilization with manageable toxicity. Patients with low expression of plasma cytokine levels at baseline were able to tolerate higher doses of vorinostat and benefited from treatment. Baseline cytokine profile is a promising potential predictive biomarker

Drug sensitivity profiling of 3D tumor tissue cultures in the pediatric precision oncology program INFORM

The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75–78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET, and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs

Drug sensitivity profiling of 3D tumor tissue cultures in the pediatric precision oncology program INFORM

The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75-78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET, and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs.Peer reviewe

Regionale Standards: Ausgabe 2019

Die "Regionalen Standards" gehen zurück auf die Initiative eines gemeinsamen Arbeitskreises, bestehend aus Vertretern des Statistischen Bundesamtes, der Arbeitsgemeinschaft Sozialwissenschaftlicher Institute e.V. (ASI) und des ADM Arbeitskreis Deutscher Markt- und Sozialforschungsinstitute e.V. Sie stellen ein Angebot für die Forschung in der Bundesrepublik Deutschland dar. Die "Regionalen Standards" beschreiben Gebietsabgrenzungen und Instrumente zur Typisierung von Regionen, wie sie in der Bundesrepublik Deutschland von der amtlichen Statistik und/oder der Markt- und Sozialforschung in gewisser Regelmäßigkeit eingesetzt werden. Zusätzlich werden Datensätze aus unterschiedlichen Quellen vorgestellt, die für die Regionalisierung von Bevölkerungsumfragen genutzt werden können und für die Forschung (teils jedoch mit Einschränkungen) zur Verfügung stehen

Regionale Standards: Ausgabe 2013

"Die 'Regionalen Standards' gehen zurück auf die Initiative eines gemeinsamen Arbeitskreises, bestehend aus Vertretern des Statistischen Bundesamtes, der Arbeitsgemeinschaft Sozialwissenschaftlicher Institute e.V. (ASI) und des ADM Arbeitskreis Deutscher Markt- und Sozialforschungsinstitute e.V. Sie stellen ein Angebot für die Forschung in der Bundesrepublik Deutschland dar. Die 'Regionalen Standards' beschreiben Gebietsabgrenzungen und Instrumente zur Typisierung von Regionen, wie sie in der Bundesrepublik Deutschland von der amtlichen Statistik und/oder der Markt- und Sozialforschung in gewisser Regelmäßigkeit eingesetzt werden. Zusätzlich werden Datensätze aus unterschiedlichen Quellen vorgestellt, die für die Regionalisierung von Bevölkerungsumfragen genutzt werden können und für die Forschung (teils jedoch mit Einschränkungen) zur Verfügung stehen. Ergänzt werden die 'Regionalen Standards' durch eine jährlich aktualisierte Tabellenanalyse aus dem Mikrozensus, zu beziehen über die Internetseiten www.destatis.de, www.gesis.org und www.adm-ev.de." (Autorenreferat

Plus- and Minus-End Directed Microtubule Motors Bind Simultaneously to Herpes Simplex Virus Capsids Using Different Inner Tegument Structures

Many viruses depend on host microtubule motors to reach their destined intracellular location. Viral particles of neurotropic alphaherpesviruses such as herpes simplex virus 1 (HSV1) show bidirectional transport towards the cell center as well as the periphery, indicating that they utilize microtubule motors of opposing directionality. To understand the mechanisms of specific motor recruitment, it is necessary to characterize the molecular composition of such motile viral structures. We have generated HSV1 capsids with different surface features without impairing their overall architecture, and show that in a mammalian cell-free system the microtubule motors dynein and kinesin-1 and the dynein cofactor dynactin could interact directly with capsids independent of other host factors. The capsid composition and surface was analyzed with respect to 23 structural proteins that are potentially exposed to the cytosol during virus assembly or cell entry. Many of these proteins belong to the tegument, the hallmark of all herpesviruses located between the capsid and the viral envelope. Using immunoblots, quantitative mass spectrometry and quantitative immunoelectron microscopy, we show that capsids exposing inner tegument proteins such as pUS3, pUL36, pUL37, ICP0, pUL14, pUL16, and pUL21 recruited dynein, dynactin, kinesin-1 and kinesin-2. In contrast, neither untegumented capsids exposing VP5, VP26, pUL17 and pUL25 nor capsids covered by outer tegument proteins such as vhs, pUL11, ICP4, ICP34.5, VP11/12, VP13/14, VP16, VP22 or pUS11 bound microtubule motors. Our data suggest that HSV1 uses different structural features of the inner tegument to recruit dynein or kinesin-1. Individual capsids simultaneously accommodated motors of opposing directionality as well as several copies of the same motor. Thus, these associated motors either engage in a tug-of-war or their activities are coordinately regulated to achieve net transport either to the nucleus during cell entry or to cytoplasmic membranes for envelopment during assembly

Material- und Verfahrensentwicklung zur industriellen Umsetzung großflächiger endlosfaserverstärkter Bauteile aus aPA6 - am Beispiel von 2D-Flechtbauteilen

Traditionelle Thermoplaste können im HD-T-RTM Verfahren auf Grund der hohen Verarbeitungsviskosität und der hohen Temperaturen nicht verwendet werden. Ein vielversprechender Ansatz stellt die in-situ Polymerisation des Monomers Caprolactam zu Polyamid 6 (aPA6) dar. Bisher befinden sich Fertigungsprozesse zur Herstellung endlosfaserverstärkter Kunststoffe auf der Basis von aPA6 nicht im industriellen Einsatz aufgrund komplexer chemischer Vorgänge des Werkstoffsystems, deren sicherer Beherrschung sowie der aufwändigen Anlagen- und Werkzeugtechnik. Ziel der vorliegenden Arbeit ist die Schaffung einer Grundlage zur industriellen Umsetzung der anionischen Lactampolymerisation von PA6 zu endlosfaserverstärkten großflächigen Bauteilen nach der HD-RTM-Verfahrenstechnik. Dazu wird ein neues hochinnovatives Verfahrenskonzept basierend auf der reaktiven Spritzgusstechnik (rSG) mit einem dafür kompatiblen Faser-Matrixsystem eruiert und entwickelt. Durch die Material- und Verfahrensentwicklung wird die Realisierbarkeit des neuen Verfahrenskonzeptes am Beispiel der 2D-Flechtbauteile dargestellt. Das Potential zur industriellen Umsetzung erfolgt abschließend durch die Prozesscharakterisierung