Evidence-based Kernels: Fundamental Units of Behavioral Influence

This paper describes evidence-based kernels, fundamental units of behavioral influence that appear to underlie effective prevention and treatment for children, adults, and families. A kernel is a behavior–influence procedure shown through experimental analysis to affect a specific behavior and that is indivisible in the sense that removing any of its components would render it inert. Existing evidence shows that a variety of kernels can influence behavior in context, and some evidence suggests that frequent use or sufficient use of some kernels may produce longer lasting behavioral shifts. The analysis of kernels could contribute to an empirically based theory of behavioral influence, augment existing prevention or treatment efforts, facilitate the dissemination of effective prevention and treatment practices, clarify the active ingredients in existing interventions, and contribute to efficiently developing interventions that are more effective. Kernels involve one or more of the following mechanisms of behavior influence: reinforcement, altering antecedents, changing verbal relational responding, or changing physiological states directly. The paper describes 52 of these kernels, and details practical, theoretical, and research implications, including calling for a national database of kernels that influence human behavior

Low-Molecular-Weight Cyclin E in Human Cancer: Cellular Consequences and Opportunities for Targeted Therapies

Cyclin E, a regulatory subunit of cyclin-dependent kinase 2 (CDK2), is central to the initiation of DNA replication at the G1/S checkpoint. Tight temporal control of cyclin E is essential to the coordination of cell-cycle processes and the maintenance of genome integrity. Overexpression of cyclin E in human tumors was first observed in the 1990s and led to the identification of oncogenic roles for deregulated cyclin E in experimental models. A decade later, low-molecular-weight cyclin E (LMW-E) isoforms were observed in aggressive tumor subtypes. Compared with full-length cyclin E, LMW-E hyperactivates CDK2 through increased complex stability and resistance to the endogenous inhibitors p21CIP1 and p27KIP1 LMW-E is predominantly generated by neutrophil elastase-mediated proteolytic cleavage, which eliminates the N-terminal cyclin E nuclear localization signal and promotes cyclin E's accumulation in the cytoplasm. Compared with full-length cyclin E, the aberrant localization and unique stereochemistry of LMW-E dramatically alters the substrate specificity and selectivity of CDK2, increasing tumorigenicity in experimental models. Cytoplasmic LMW-E, which can be assessed by IHC, is prognostic of poor survival and predicts resistance to standard therapies in patients with cancer. These patients may benefit from therapeutic modalities targeting the altered biochemistry of LMW-E or its associated vulnerabilities. Cancer Res; 78(19); 5481-91. ©2018 AACR

Mitochondrial metabolism in hibernation and daily torpor: a review.

Hibernation and daily torpor involve substantial decreases in body temperature and metabolic rate, allowing birds and mammals to cope with cold environments and/or limited food. Regulated suppression of mitochondrial metabolism probably contributes to energy savings: state 3 (phosphorylating) respiration is lower in liver mitochondria isolated from mammals in hibernation or daily torpor compared to normothermic controls, although data on state 4 (non-phosphorylating) respiration are equivocal. However, no suppression is seen in skeletal muscle, and there is little reliable data from other tissues. In both daily torpor and hibernation, liver state 3 substrate oxidation is suppressed, especially upstream of electron transport chain complex IV. In hibernation respiratory suppression is reversed quickly in arousal even when body temperature is very low, implying acute regulatory mechanisms, such as oxaloacetate inhibition of succinate dehydrogenase. Respiratory suppression depends on in vitro assay temperature (no suppression is evident below approximately 30 degrees C) and (at least in hibernation) dietary polyunsaturated fats, suggesting effects on inner mitochondrial membrane phospholipids. Proton leakiness of the inner mitochondrial membrane does not change in hibernation, but this also depends on dietary polyunsaturates. In contrast proton leak increases in daily torpor, perhaps limiting reactive oxygen species production