Pyruvate Kinase Activity Regulates Cystine Starvation Induced Ferroptosis through Malic Enzyme 1 in Pancreatic Cancer Cells.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with high mortality and limited efficacious therapeutic options. PDAC cells undergo metabolic alterations to survive within a nutrient-depleted tumor microenvironment. One critical metabolic shift in PDAC cells occurs through altered isoform expression of the glycolytic enzyme, pyruvate kinase (PK). Pancreatic cancer cells preferentially upregulate pyruvate kinase muscle isoform 2 isoform (PKM2). PKM2 expression reprograms many metabolic pathways, but little is known about its impact on cystine metabolism. Cystine metabolism is critical for supporting survival through its role in defense against ferroptosis, a non-apoptotic iron-dependent form of cell death characterized by unchecked lipid peroxidation. To improve our understanding of the role of PKM2 in cystine metabolism and ferroptosis in PDAC, we generated PKM2 knockout (KO) human PDAC cells. Fascinatingly, PKM2KO cells demonstrate a remarkable resistance to cystine starvation mediated ferroptosis. This resistance to ferroptosis is caused by decreased PK activity, rather than an isoform-specific effect. We further utilized stable isotope tracing to evaluate the impact of glucose and glutamine reprogramming in PKM2KO cells. PKM2KO cells depend on glutamine metabolism to support antioxidant defenses against lipid peroxidation, primarily by increased glutamine flux through the malate aspartate shuttle and utilization of ME1 to produce NADPH. Ferroptosis can be synergistically induced by the combination of PKM2 activation and inhibition of the cystine/glutamate antiporter in vitro. Proof-of-concept in vivo experiments demonstrate the efficacy of this mechanism as a novel treatment strategy for PDAC.

The Development of Preschoolers' Living Kinds Concept: A Longitudinal Study.

Given limitations in the integrative scope of past research, basic questions about the organization and development of preschoolers' living kinds concept remain open to debate. This study was designed to address past limitations through use of a longitudinal design, extensive stimulus set, and alternate indices of understanding. Thirty-five English-speaking 3-year-olds from middle-class families in Albuquerque, NM participated in four testing sessions over 1 year. Indices of understanding included statements that preschoolers generated about various living and nonliving objects, biological properties they attributed to the objects, and their characterization of objects as "alive" or not. Results reveal a multifaceted picture of developmental change in preschoolers' living kinds concept involving both the construction and elaboration of a core biological understanding.

Susceptible to distraction: children lack top-down control over spatial attention capture.

Considerable evidence has indicated that adults can exert top-down control to avoid distraction by salient-but-irrelevant stimuli. However, relatively little research has explored how this ability develops across the lifespan. In the present study, we therefore assessed how well children can control the capture of spatial attention. Children (M age = 4.2 years) and adults (M age = 21.5 years) searched for target "spaceships" of a specific color while trying to ignore salient precues that either matched or mismatched the target spaceship color. The results demonstrated that children are, in fact, more vulnerable to capture by irrelevant stimuli than are adults, even after accounting for children's overall cognitive slowing.