Time Scale Hierarchies in the Functional Organization of Complex Behaviors

Traditional approaches to cognitive modelling generally portray cognitive events in terms of ‘discrete’ states (point attractor dynamics) rather than in terms of processes, thereby neglecting the time structure of cognition. In contrast, more recent approaches explicitly address this temporal dimension, but typically provide no entry points into cognitive categorization of events and experiences. With the aim to incorporate both these aspects, we propose a framework for functional architectures. Our approach is grounded in the notion that arbitrary complex (human) behaviour is decomposable into functional modes (elementary units), which we conceptualize as low-dimensional dynamical objects (structured flows on manifolds). The ensemble of modes at an agent’s disposal constitutes his/her functional repertoire. The modes may be subjected to additional dynamics (termed operational signals), in particular, instantaneous inputs, and a mechanism that sequentially selects a mode so that it temporarily dominates the functional dynamics. The inputs and selection mechanisms act on faster and slower time scales then that inherent to the modes, respectively. The dynamics across the three time scales are coupled via feedback, rendering the entire architecture autonomous. We illustrate the functional architecture in the context of serial behaviour, namely cursive handwriting. Subsequently, we investigate the possibility of recovering the contributions of functional modes and operational signals from the output, which appears to be possible only when examining the output phase flow (i.e., not from trajectories in phase space or time)

The progestational and androgenic properties of medroxyprogesterone acetate: gene regulatory overlap with dihydrotestosterone in breast cancer cells

INTRODUCTION: Medroxyprogesterone acetate (MPA), the major progestin used for oral contraception and hormone replacement therapy, has been implicated in increased breast cancer risk. Is this risk due to its progestational or androgenic properties? To address this, we assessed the transcriptional effects of MPA as compared with those of progesterone and dihydrotestosterone (DHT) in human breast cancer cells. METHOD: A new progesterone receptor-negative, androgen receptor-positive human breast cancer cell line, designated Y-AR, was engineered and characterized. Transcription assays using a synthetic promoter/reporter construct, as well as endogenous gene expression profiling comparing progesterone, MPA and DHT, were performed in cells either lacking or containing progesterone receptor and/or androgen receptor. RESULTS: In progesterone receptor-positive cells, MPA was found to be an effective progestin through both progesterone receptor isoforms in transient transcription assays. Interestingly, DHT signaled through progesterone receptor type B. Expression profiling of endogenous progesterone receptor-regulated genes comparing progesterone and MPA suggested that although MPA may be a somewhat more potent progestin than progesterone, it is qualitatively similar to progesterone. To address effects of MPA through androgen receptor, expression profiling was performed comparing progesterone, MPA and DHT using Y-AR cells. These studies showed extensive gene regulatory overlap between DHT and MPA through androgen receptor and none with progesterone. Interestingly, there was no difference between pharmacological MPA and physiological MPA, suggesting that high-dose therapeutic MPA may be superfluous. CONCLUSION: Our comparison of the gene regulatory profiles of MPA and progesterone suggests that, for physiologic hormone replacement therapy, the actions of MPA do not mimic those of endogenous progesterone alone. Clinically, the complex pharmacology of MPA not only influences its side-effect profile; but it is also possible that the increased breast cancer risk and/or the therapeutic efficacy of MPA in cancer treatment is in part mediated by androgen receptor

Human aging in the post-GWAS era: further insights reveal potential regulatory variants

NoHuman aging involves a gradual decrease in cellular integrity that contributes to multiple complex disorders such as neurodegenerative disorders, cancer, diabetes, and cardiovascular diseases. Genome-wide association studies (GWAS) play a key role in discovering genetic variations that may contribute towards disease vulnerability. However, mostly disease-associated SNPs lie within non-coding part of the genome; majority of the variants are also present in linkage disequilibrium (LD) with the genome-wide significant SNPs (GWAS lead SNPs). Overall 600 SNPs were analyzed, out of which 291 returned RegulomeDB scores of 1-6. It was observed that just 4 out of those 291 SNPs show strong evidence of regulatory effects (RegulomeDB score < 3), while none of them includes any GWAS lead SNP. Nevertheless, this study demonstrates that by combining ENCODE project data along with GWAS reported information will provide important insights on the impact of a genetic variant-moving from GWAS towards understanding disease pathways. It is noteworthy that both genome-wide significant SNPs as well as the SNPs in LD must be considered for future studies; this may prove to be crucial in deciphering the potential regulatory elements involved in complex disorders and aging in particular