Influence factors for local comprehensibility of process models

The main aim of this study is to investigate human understanding of process models and to develop an improved understanding of its relevant influence factors. Aided by assumptions from cognitive psychology, this article attempts to address specific deductive reasoning difficulties based on process models. The authors developed a research model to capture the influence of two effects on the cognitive difficulty of reasoning tasks: (i) the presence of different control-flow patterns (such as conditional or parallel execution) in a process model and (ii) the interactivity of model elements. Based on solutions to 61 different reasoning tasks by 155 modelers, the results from this study indicate that the presence of certain control-flow patterns influences the cognitive difficulty of reasoning tasks. In particular, sequence is relatively easy, while loops in a model proved difficult. Modelers with higher process modeling knowledge performed better and rated subjective difficulty of loops lower than modelers with lower process modeling knowledge. The findings additionally support the prediction that interactivity between model elements is positively related to the cognitive difficulty of reasoning. Our research contributes to both academic literature on the comprehension of process models and practitioner literature focusing on cognitive difficulties when using process models

Kognitive Belastung als lokales Komplexitätsmaß in Geschäftsprozessmodellen

In unserem Beitrag [FL15] untersuchten wir die Verständlichkeit von Geschäftsprozessmodellen. Wir ließen Probanden Aufgaben zu Prozessmodellen lösen, in denen durch logisches Schlussfolgern Fragen zum Modell zu beantworten waren. Neben aus der Literatur bekannten Einflussfaktoren (z.B. Modellierungserfahrung) untersuchten wir, wie sich Metriken, die auf dem Begriff der kognitiven Belastung (cognitive load) aufbauen, auf die korrekte Beantwortung von Fragen auswirken. Unsere Ergebnisse erlauben eine neue Sicht auf Komplexitätsmetriken für Geschäftsprozessmodelle: Eine bisher kaum beachtete Variable wurde als relevanter Einflussfaktor für die Modellverständlichkeit erkannt - die Interaktivität zwischen Modellelementen. Diese kann durch die Zahl der Modellelemente, die zur Beantwortung einer Frage gemeinsam (in Verbindung zueinander) betrachtet werden müssen, operationalisiert werden

Osteocalcin signaling in myofibers is necessary and sufficient for optimum adaptation to exercise

Circulating levels of undercarboxylated and bioactive osteocalcin double during aerobic exercise at the time levels of insulin decrease. In contrast, circulating levels of osteocalcin plummet early during adulthood in mice, monkeys, and humans of both genders. Exploring these observations revealed that osteocalcin signaling in myofibers is necessary for adaptation to exercise by favoring uptake and catabolism of glucose and fatty acids, the main nutrients of myofibers. Osteocalcin signaling in myofibers also accounts for most of the exercise-induced release of interleukin-6, a myokine that promotes adaptation to exercise in part by driving the generation of bioactive osteocalcin. We further show that exogenous osteocalcin is sufficient to enhance the exercise capacity of young mice and to restore to 15-month-old mice the exercise capacity of 3-month-old mice. This study uncovers a bone-to-muscle feedforward endocrine axis that favors adaptation to exercise and can reverse the age-induced decline in exercise capacity

Human aneuploid cells depend on the RAF/MEK/ERK pathway for overcoming increased DNA damage

Aneuploidy is a hallmark of human cancer, yet the molecular mechanisms to cope with aneuploidy-induced cellular stresses remain largely unknown. Here, we induce chromosome mis-segregation in non-transformed RPE1-hTERT cells and derive multiple stable clones with various degrees of aneuploidy. We perform a systematic genomic, transcriptomic and proteomic profiling of 6 isogenic clones, using whole-exome DNA, mRNA and miRNA sequencing, as well as proteomics. Concomitantly, we functionally interrogate their cellular vulnerabilities, using genome-wide CRISPR/Cas9 and large-scale drug screens. Aneuploid clones activate the DNA damage response and are more resistant to further DNA damage induction. Aneuploid cells also exhibit elevated RAF/MEK/ERK pathway activity and are more sensitive to clinically-relevant drugs targeting this pathway, and in particular to CRAF inhibition. Importantly, CRAF and MEK inhibition sensitize aneuploid cells to DNA damage-inducing chemotherapies and to PARP inhibitors. We validate these results in human cancer cell lines. Moreover, resistance of cancer patients to olaparib is associated with high levels of RAF/MEK/ERK signaling, specifically in highly-aneuploid tumors. Overall, our study provides a comprehensive resource for genetically-matched karyotypically-stable cells of various aneuploidy states, and reveals a therapeutically-relevant cellular dependency of aneuploid cells

Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition

Selective targeting of aneuploid cells is an attractive strategy for cancer treatment(1). Here, we mapped the aneuploidy landscapes of ~1,000 human cancer cell lines, and analyzed genetic and chemical perturbation screens(2–9) to reveal aneuploidy-associated cellular vulnerabilities. We identified and validated an increased sensitivity of aneuploid cancer cells to genetic perturbation of core components of the spindle assembly checkpoint (SAC), which ensures the proper segregation of chromosomes during mitosis(10). Surprisingly, we also found aneuploid cancer cells to be less sensitive to short-term exposures to multiple SAC inhibitors. Indeed, aneuploid cancer cells became increasingly more sensitive to SAC inhibition (SACi) over time. Aneuploid cells exhibited aberrant spindle geometry and dynamics, and kept dividing in the presence of SACi, resulting in accumulating mitotic defects, and in unstable and less fit karyotypes. Therefore, although aneuploid cancer cells could overcome SACi more readily than diploid cells, their long-term proliferation was jeopardized. We identified a specific mitotic kinesin, KIF18A, whose activity was perturbed in aneuploid cancer cells. Aneuploid cancer cells were particularly vulnerable to KIF18A depletion, and KIF18A overexpression restored their response to SACi. Our study reveals a novel, therapeutically-relevant, synthetic lethal interaction between aneuploidy and the SAC

Osteocalcin is necessary and sufficient to maintain muscle mass in older mice

Objective: A decrease in muscle protein turnover and therefore in muscle mass is a hallmark of aging. Because the circulating levels of the bone-derived hormone osteocalcin decline steeply during aging in mice, monkeys and humans we asked here whether this hormone might regulate muscle mass as mice age. Methods: We examined muscle mass and strength in mice lacking osteocalcin (Ocn−/−) or its receptor in all cells (Gprc6a−/−) or specifically in myofibers (Gprc6aMck−/−) as well as in 9 month-old WT mice receiving exogenous osteocalcin for 28 days. We also examined protein synthesis in WT and Gprc6a−/− mouse myotubes treated with osteocalcin. Results: We show that osteocalcin signaling in myofibers is necessary to maintain muscle mass in older mice in part because it promotes protein synthesis in myotubes without affecting protein breakdown. We further show that treatment with exogenous osteocalcin for 28 days is sufficient to increase muscle mass of 9-month-old WT mice. Conclusion: This study uncovers that osteocalcin is necessary and sufficient to prevent age-related muscle loss in mice. Author Video: Author Video Watch what authors say about their articles Keywords: Osteocalcin, Muscle mass, Agin