Effects of schedule segmentation on pausing and escape in the transitions between favorable and unfavorable schedules of reinforcement

Simple schedules of reinforcement typically are preferred to chained schedules of equal duration. In the current study, pigeons served in six experiments designed to test whether the juxtaposition of simple and chained schedules would engender the disruption in behavior typically observed in the transition from favorable to unfavorable conditions of reinforcement. In one set of experiments, a multiple schedule was employed in which a simple schedule alternated irregularly with a chained schedule. Whether fixed-ratio or fixed-interval schedules were employed, only half the subjects paused for an extended duration in the simple-to-chain transition, and this occurred only when the first segment of the chained schedule was short. When the option to turn off the stimuli correlated with the schedule in effect (escape) was available at the start of each component, escape occurred infrequently and inconsistently across pigeons. In another set of experiments, a (rich) schedule ending in a large reinforcer was juxtaposed with a (lean) schedule ending in a small reinforcer. In addition, either the rich or lean schedule was segmented across conditions. Inconsistent results were obtained when fixed-ratio schedules were employed; however, when fixed-interval schedules were employed, pausing was extended in the rich-to-lean transition and this effect was attenuated by segmenting the rich schedule and enhanced by segmenting the lean schedule. When the option to escape was available, escape was more frequent (or constituted a larger percentage of the session) in the rich-to-lean transition when simple schedules operated. Segmenting the lean schedule had inconsistent effects on escape. The fact that the predicted results were obtained only when fixed-interval schedules differed in reinforcer magnitude and schedule segmentation is attributed to two factors. First, perhaps it was only in this experiment that the difference in favorability across schedules was sufficient to produce noticeable disruptions in behavior. Second, response patterns suggest that the pigeons failed to respond differentially across the simple and chained fixed-ratio schedules. The results of the present study together with previous findings suggest the potential for basic research to contribute to the identification and manipulation of variables that control problem behavior in institutional settings and in everyday situations

Association of Candidate Genes with Phenotypic Traits Relevant to Anorexia Nervosa

This analysis is a follow-up to an earlier investigation of 182 genes selected as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN). As those initial case-control results revealed no statistically significant differences in single nucleotide polymorphisms, herein we investigate alternative phenotypes associated with AN. In 1762 females using regression analyses we examined: (1) lowest illness-related attained body mass index; (2) age at menarche; (3) drive for thinness; (4) body dissatisfaction; (5) trait anxiety; (6) concern over mistakes; and (7) the anticipatory worry and pessimism vs. uninhibited optimism subscale of the harm avoidance scale. After controlling for multiple comparisons, no statistically significant results emerged. Although results must be viewed in the context of limitations of statistical power, the approach illustrates a means of potentially identifying genetic variants conferring susceptibility to AN because less complex phenotypes associated with AN are more proximal to the genotype and may be influenced by fewer genes

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Overexpression of the RNA binding protein HuR impairs tumor growth in triple negative breast cancer associated with deficient angiogenesis

Interactions between RNA binding proteins (RBPs) and genes are not well understood, especially in regulation of angiogenesis. The RBP HuR binds to the AU-rich (ARE) regions of labile mRNAs, facilitating their translation into protein and has been hypothesized to be a tumor-maintenance gene. Elevated levels of cytoplasmic HuR directly correlate with increased invasiveness and poor prognosis for many cancers, including those of the breast. HuR controls the expression of multiple genes involved in angiogenesis including VEGFα, HIF1α and thrombospondin 1 (TSP1). We investigated the role of HuR in estrogen receptor negative (ER−) breast cancer. MDA-MB-231 cells with higher levels of HuR have alterations in cell cycle kinetics and faster growth. Unexpectedly, HuR overexpression significantly interfered with tumor growth in orthotopic mouse models. The putative mechanism seems to be an anti-angiogenetic effect by increasing expression of TSP1 but also surprisingly, downregulating VEGF, a target which HuR normally increases. Our findings reveal that HuR may be regulating a cluster of genes involved in blood vessel formation which controls tumor angiogenesis. An approach of modulating HuR levels may overcome limitations associated with monotherapies targeting tumor vessel formation