Colorectal cancer (CRC) results from the accumulation of gene mutations and epigenetic alterations in colon epithelial cells, which promotes CRC formation through deregulating signaling pathways. One ...of the most commonly deregulated signaling pathways in CRC is the transforming growth factor β (TGF‐β) pathway. Importantly, the effects of TGF‐β signaling inactivation in CRC are modified by concurrent mutations in the tumor cell, and these concurrent mutations determine the ultimate biological effects of impaired TGF‐β signaling in the tumor. However, many of the mutations that cooperate with the deregulated TGF‐β signaling pathway in CRC remain unknown. Therefore, we sought to identify candidate driver genes that promote the formation of CRC in the setting of TGF‐β signaling inactivation. We performed a forward genetic screen in mice carrying conditionally inactivated alleles of the TGF‐β receptor, type II (Tgfbr2) using Sleeping Beauty (SB) transposon mediated mutagenesis. We used TAPDANCE and Gene‐centric statistical methods to identify common insertion sites (CIS) and, thus, candidate tumor suppressor genes and oncogenes within the tumor genome. CIS analysis of multiple neoplasms from these mice identified many candidate Tgfbr2 cooperating genes and the Wnt/β‐catenin, Hippo and MAPK pathways as the most commonly affected pathways. Importantly, the majority of candidate genes were also found to be mutated in human CRC. The SB transposon system provides an unbiased method to identify Tgfbr2 cooperating genes in mouse CRC that are functionally relevant and that may provide further insight into the pathogenesis of human CRC.
What's new?
Many of the genes and pathways that functionally cooperate with deregulated TGF‐β signaling to drive colorectal cancer (CRC) are unknown. Using the Sleeping Beauty mouse model, the authors discovered functionally‐relevant candidate pathways and driver genes that mediate CRC formation in vivo in the setting of TGF‐β receptor inactivation. Most of these genes are novel and the majority were also found to be mutated in human CRCs, demonstrating the relevance of the findings to human primary cancer. The identification of these factors advances our understanding of the molecular pathogenesis of CRC and provides insight into possible treatment options for CRC patients.
DO CONDITIONAL REINFORCERS COUNT? Davison, Michael; Baum, William M.
Journal of the experimental analysis of behavior,
11/2006, Letnik:
86, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Six pigeons were trained on a procedure in which seven components arranged different food‐delivery ratios on concurrent variable‐interval schedules each session. The components were unsignaled, ...lasted for 10 food deliveries, and occurred in random order with a 60‐s blackout between components. The schedules were arranged using a switching‐key procedure in which two responses on a center key changed the schedules and associated stimuli on two side keys. In Experiment 1, over five conditions, an increasing proportion of food deliveries accompanied by a magazine light was replaced with the presentation of the magazine light only. Local analyses of preference showed preference pulses toward the alternative that had just produced either a food‐plus‐magazine‐light or magazine‐light‐only presentation, but pulses after food deliveries were always greater than those after magazine lights. Increasing proportions of magazine lights did not change the size of preference pulses after food or magazine‐light presentations. Experiment 2 investigated the effects of correlations between food ratios and magazine‐light ratios: In Condition 6, magazine‐light ratios in components were inversely correlated (−1.0) with food ratios, and in Condition 7, magazine‐light ratios were uncorrelated with food ratios. In Conditions 8 and 9, pecks also produced occasional 2.5‐s flashes of a green keylight. In Condition 8, food and magazine‐light ratios were correlated 1.0 whereas food and green‐key ratios were correlated −1.0. In Condition 9, food and green‐key ratios were correlated 1.0 whereas food and magazine‐light ratios were correlated −1.0. Preference pulses toward alternatives after magazine lights and green keys depended on the correlation between these event ratios and the food ratios: If the ratios were correlated +1.0, positive preference pulses resulted; if the correlation was −1.0, preference pulses were negative. These results suggest that the Law of Effect has more to do with events signaling consequences than with strengthening responses.
Six pigeons were trained in sessions composed of seven components, each arranged with a different concurrent‐schedule reinforcer ratio. These components occurred in an irregular order with equal ...frequency, separated by 10‐s blackouts. No signals differentiated the different reinforcer ratios. Conditions lasted 50 sessions, and data were collected from the last 35 sessions. In Part 1, the arranged overall reinforcer rate was 2.22 reinforcers per minute. Over conditions, number of reinforcers per component was varied from 4 to 12. In Part 2, the overall reinforcer rate was six per minute, with both 4 and 12 reinforcers per component. Within components, log response‐allocation ratios adjusted rapidly as more reinforcers were delivered in the component, and the slope of the choice relation (sensitivity) leveled off at moderately high levels after only about eight reinforcers. When the carryover from previous components was taken into account, the number of reinforcers in the components appeared to have no systematic effect on the speed at which behavior changed after a component started. Consequently, sensitivity values at each reinforcer delivery were superimposable. However, adjustment to changing reinforcer ratios was faster, and reached greater sensitivity values, when overall reinforcer rate was higher. Within a component, each successive reinforcer from the same alternative (“confirming”) had a smaller effect than the one before, but single reinforcers from the other alternative (“disconfirming”) always had a large effect. Choice in the prior component carried over into the next component, and its effects could be discerned even after five or six reinforcers into the next component. A local model of performance change as a function of both reinforcement and nonreinforcement is suggested.
Four pigeons were trained in a procedure in which concurrent‐schedule food ratios changed unpredictably across seven unsignaled components after 10 food deliveries. Additional green‐key stimulus ...presentations also occurred on the two alternatives, sometimes in the same ratio as the component food ratio, and sometimes in the inverse ratio. In eight experimental conditions, we varied the contingencies surrounding these additional stimuli: In two conditions, stimulus onset and offset were noncontingent; in another two, stimulus onset was noncontingent, and offset was response contingent. In four conditions, both stimulus onset and offset were contingent, and in two of these conditions the stimulus was simultaneously paired with food delivery. Sensitivity to component food ratios was significantly higher when stimulus onset was response contingent compared to when it was noncontingent. Choice changes following food delivery were similar in all eight conditions. Choice changes following stimuli were smaller than those following food, and directionally were completely determined by the food‐ratio:stimulus‐ratio correlation, not by the stimulus contingency nor by whether the stimulus was paired with food or not. These results support the idea that conditional reinforcers may best be viewed as signals for next‐food location rather than as stimuli that have acquired hedonic value, at least when the signals are differential with respect to future conditions.
Molar and molecular views of behavior imply different approaches to data analysis. The molecular view privileges moment‐to‐moment analyses, whereas the molar view supports analysis of more and less ...extended activities. In concurrent performance, the molar view supports study of both extended patterns of choice and more local patterns of visiting the choice alternatives. Analysis of the present data illustrated the usefulness of investigating order at various levels of extendedness. Seven different reinforcer ratios were presented within each session, without cues to identify them, and pigeons pecked at two response keys that delivered food on variable‐interval schedules. Choice changed rapidly within components as reinforcers were delivered and, following each reinforcer, shifted toward the alternative that produced it. If several reinforcers were delivered consecutively by one alternative, choice favored that alternative, but shifted more slowly with each new reinforcer. A discontinuation of such a series of reinforcers by the delivery of a reinforcer by the other alternative resulted in a large shift of choice toward that alternative. These effects were illuminated by analysis of visits to the two alternatives. Changes in visit length occurred primarily in the first postreinforcer visit to the repeatedly reinforced alternative. All other visits tended to be brief and equal. Performance showed multiple signs of moving in the direction of a fix‐and‐sample pattern that characterized steady‐state performance in earlier experiments with many sessions of maintaining each schedule pair. The analyses of extended and local patterns illustrate the flexibility of a molar view of behavior.
Pigeons were trained in a procedure in which sessions included seven four‐ or 10‐reinforcer components, each providing a different reinforcer ratio that ranged from 27:1 to 1:27. The components were ...arranged in random order, and no signals differentiated the component reinforcer ratios. Each condition lasted 50 sessions, and the data from the last 35 sessions were analyzed. Previous results using 10‐s blackouts between components showed some carryover of preference from one component to the next, and this effect was investigated in Experiment 1 by varying blackout duration from 1 s to 120 s. The amount of carryover decreased monotonically as the blackout duration was lengthened. Preference also decreased between reinforcers within components, suggesting that preference change during blackout might follow the same function as preference change between reinforcers. Experiment 2 was designed to measure preference change between components more directly and to relate this to preference change during blackout. In two conditions a 60‐s blackout occurred between components, and in two other conditions a 60‐s period of unsignaled extinction occurred between components. Preference during the extinction period progressively fell toward indifference, and the level of preference following extinction was much the same as that following blackout. Although these results are consistent with Davison and Baum's (2000) theory of the effects of reinforcers on local preference, other findings suggest that theory is incomplete: After a sequence of reinforcers from one alternative, some residual preference remained after 60 s of extinction or blackout, indicating the possibility of an additional longer term accumulation of reinforcer effects than originally suggested.
Six pigeons were trained on concurrent variable‐interval schedules. Sessions consisted of seven components, each lasting 10 reinforcers, with the conditions of reinforcement differing between ...components. The component sequence was randomly selected without replacement. In Experiment 1, the concurrent‐schedule reinforcer ratios in components were all equal to 1.0, but across components reinforcer‐magnitude ratios varied from 1:7 through 7:1. Three different overall reinforcer rates were arranged across conditions. In Experiment 2, the reinforcer‐rate ratios varied across components from 27:1 to 1:27, and the reinforcer‐magnitude ratios for each alternative were changed across conditions from 1:7 to 7:1. The results of Experiment 1 replicated the results for changing reinforcer‐rate ratios across components reported by Davison and Baum (2000, 2002): Sensitivity to reinforcer‐magnitude ratios increased with increasing numbers of reinforcers in components. Sensitivity to magnitude ratio, however, fell short of sensitivity to reinforcer‐rate ratio. The degree of carryover from component to component depended on the reinforcer rate. Larger reinforcers produced larger and longer postreinforcer preference pulses than did smaller reinforcers. Similar results were found in Experiment 2, except that sensitivity to reinforcer magnitude was considerably higher and was greater for magnitudes that differed more from one another. Visit durations following reinforcers measured either as number of responses emitted or time spent responding before a changeover were longer following larger than following smaller reinforcers, and were longer following sequences of same reinforcers than following other sequences. The results add to the growing body of research that informs model building at local levels.
Modeling the dynamics of choice Baum, William M.; Davison, Michael
Behavioural processes,
06/2009, Letnik:
81, Številka:
2
Journal Article
Recenzirano
A simple linear-operator model both describes and predicts the dynamics of choice that may underlie the matching relation. We measured inter-food choice within components of a schedule that presented ...seven different pairs of concurrent variable-interval schedules for 12 food deliveries each with no signals indicating which pair was in force. This measure of local choice was accurately described and predicted as obtained reinforcer sequences shifted it to favor one alternative or the other. The effect of a changeover delay was reflected in one parameter, the asymptote, whereas the effect of a difference in overall rate of food delivery was reflected in the other parameter, rate of approach to the asymptote. The model takes choice as a primary dependent variable, not derived by comparison between alternatives—an approach that agrees with the molar view of behaviour.
LOCAL EFFECTS OF DELAYED FOOD Davison, Michael; Baum, William M.
Journal of the experimental analysis of behavior,
03/2007, Letnik:
87, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Five pigeons were trained on a procedure in which seven concurrent variable‐interval schedules arranged seven different food‐rate ratios in random sequence in each session. Each of these components ...lasted for 10 response‐produced food deliveries, and components were separated by 10‐s blackouts. We varied delays to food (signaled by blackout) between the two response alternatives in an experiment with three phases: In Phase 1, the delay on one alternative was 0 s, and the other was varied between 0 and 8 s; in Phase 2, both delays were equal and were varied from 0 to 4 s; in Phase 3, the two delays summed to 8 s, and each was varied from 1 to 7 s. The results showed that increasing delay affected local choice, measured by a pulse in preference, in the same way as decreasing magnitude, but we found also that increasing the delay at the other alternative increased local preference. This result casts doubt on the traditional view that a reinforcer strengthens a response depending only on the reinforcer's value discounted by any response‐reinforcer delay. The results suggest that food guides, rather than strengthens, behavior.
N-(2-Mercaptoethyl)picolylamine (MEPAH) was studied as a potentially biologically relevant ligand for the "fac-M(CO)(3)(+)" core (M = Re, (99)Tc, (99m)Tc). To this end, the complex Re(CO)(3)(MEPA) ...was synthesized. The reaction of MEPAH with fac-Re(CO)(3)(MeCN)(3)(+) took place over the course of seconds, showing the high affinity possessed by this ligand for the "fac-Re(CO)(3)(+)" core. A single-crystal X-ray diffraction study was performed confirming the nature of Re(CO)(3)(MEPA), a rare mononuclear rhenium(I) thiolate complex. Additional exploration into derivatization of the ligand backbone has afforded the analogous N-ethyl complex, Re(CO)(3)(MEPA-NEt). The high affinity of the ligand for the metal coupled with the ease of its derivatization implies that utilization of this ligand system for the purposes of (99m)Tc-radiopharmaceutical development is promising.
PDF
