Modeling Basal Ganglia for understanding Parkinsonian Reaching Movements

We present a computational model that highlights the role of basal ganglia (BG) in generating simple reaching movements. The model is cast within the reinforcement learning (RL) framework with the correspondence between RL components and neuroanatomy as follows: dopamine signal of substantia nigra pars compacta as the Temporal Difference error, striatum as the substrate for the Critic, and the motor cortex as the Actor. A key feature of this neurobiological interpretation is our hypothesis that the indirect pathway is the Explorer. Chaotic activity, originating from the indirect pathway part of the model, drives the wandering, exploratory movements of the arm. Thus the direct pathway subserves exploitation while the indirect pathway subserves exploration. The motor cortex becomes more and more independent of the corrective influence of BG, as training progresses. Reaching trajectories show diminishing variability with training. Reaching movements associated with Parkinson's disease (PD) are simulated by (a) reducing dopamine and (b) degrading the complexity of indirect pathway dynamics by switching it from chaotic to periodic behavior. Under the simulated PD conditions, the arm exhibits PD motor symptoms like tremor, bradykinesia and undershoot. The model echoes the notion that PD is a dynamical disease.Comment: Neural Computation, In Pres

Multiband theory of multi-exciton complexes in self-assembled quantum dots

We report on a multiband microscopic theory of many-exciton complexes in self-assembled quantum dots. The single particle states are obtained by three methods: single-band effective-mass approximation, the multiband $k\cdot p$ method, and the tight-binding method. The electronic structure calculations are coupled with strain calculations via Bir-Pikus Hamiltonian. The many-body wave functions of $N$ electrons and $N$ valence holes are expanded in the basis of Slater determinants. The Coulomb matrix elements are evaluated using statically screened interaction for the three different sets of single particle states and the correlated $N$-exciton states are obtained by the configuration interaction method. The theory is applied to the excitonic recombination spectrum in InAs/GaAs self-assembled quantum dots. The results of the single-band effective-mass approximation are successfully compared with those obtained by using the of $k\cdot p$ and tight-binding methods.Comment: 10 pages, 8 figure

Unified theory of phase separation and charge ordering in doped manganite perovskites

A unified theory is developed to explain various types of electronic collective behaviors in doped manganites R$_{1-x}$X$_x$MnO$_3$ (R = La, Pr,Nd etc. and X = Ca, Sr, Ba etc.). Starting from a realistic electronic model, we derive an effective Hamiltonianis by ultilizing the projection perturbation techniques and develop a spin-charge-orbital coherent state theory, in which the Jahn-Teller effect and the orbital degeneracy of e$_g$ electrons in Mn ions are taken into account. Physically, the experimentally observed charge ordering state and electronic phase separation are two macroscopic quantum phenomena with opposite physical mechanisms, and their physical origins are elucidated in this theory. Interplay of the Jahn-Teller effect, the lattice distortion as well as the double exchange mechanism leads to different magnetic structures and to different charge ordering patterns and phase separation.Comment: 10 ReVTEX pages with 4 figures attache

New variable separation approach: application to nonlinear diffusion equations

The concept of the derivative-dependent functional separable solution, as a generalization to the functional separable solution, is proposed. As an application, it is used to discuss the generalized nonlinear diffusion equations based on the generalized conditional symmetry approach. As a consequence, a complete list of canonical forms for such equations which admit the derivative-dependent functional separable solutions is obtained and some exact solutions to the resulting equations are described.Comment: 19 pages, 2 fig

The China miracle in a technological and socio-political framework—The role of institutions

China’s economy has grown at an average annual rate of around 9.5% in the past four decades, which is often hailed as the China Miracle. This paper proposes a new theoretical model to analyse the causes of China’s phenomenal growth in a technological and socio-political framework. In our new framework, the contemporary technology (T) determines what an economy can achieve; the objective (O) of the society has a fundamental impact on its economic growth; the performance (P) in implementing the social objective largely determines the growth rate of the economy; and the stability (S) of the society determines the sustainability of the economic growth. China’s institutions have played key roles in the TOPS framework to initiate and sustain China’s rapid growth in the past four decades. Socio-political changes caused by economic growth might affect the capacity of these institutions to promote economic growth in future

Relativistic quantum transport theory of hadronic matter: the coupled nucleon, delta and pion system

We derive the relativistic quantum transport equation for the pion distribution function based on an effective Lagrangian of the QHD-II model. The closed time-path Green's function technique, the semi-classical, quasi-particle and Born approximation are employed in the derivation. Both the mean field and collision term are derived from the same Lagrangian and presented analytically. The dynamical equation for the pions is consistent with that for the nucleons and deltas which we developed before. Thus, we obtain a relativistic transport model which describes the hadronic matter with $N$, $\Delta$ and $\pi$ degrees of freedom simultaneously. Within this approach, we investigate the medium effects on the pion dispersion relation as well as the pion absorption and pion production channels in cold nuclear matter. In contrast to the results of the non-relativistic model, the pion dispersion relation becomes harder at low momenta and softer at high momenta as compared to the free one, which is mainly caused by the relativistic kinetics. The theoretically predicted free $\pi N \to \Delta$ cross section is in agreement with the experimental data. Medium effects on the $\pi N \to \Delta$ cross section and momentum-dependent $\Delta$-decay width are shown to be substantial.Comment: 66 pages, Latex, 12 PostScript figures included; replaced by the revised version, to appear in Phys. Rev.

Role of Endoplasmic Reticulum Stress in α-TEA Mediated TRAIL/DR5 Death Receptor Dependent Apoptosis

Background -- α-TEA (RRR-α-tocopherol ether-linked acetic acid analog), a derivative of RRR-α-tocopherol (vitamin E) exhibits anticancer actions in vitro and in vivo in variety of cancer types. The objective of this study was to obtain additional insights into the mechanisms involved in α-TEA induced apoptosis in human breast cancer cells. Methodology/Principal Findings -- α-TEA induces endoplasmic reticulum (ER) stress as indicated by increased expression of CCAAT/enhancer binding protein homologous protein (CHOP) as well as by enhanced expression or activation of specific markers of ER stress such as glucose regulated protein (GRP78), phosphorylated alpha subunit of eukaryotic initiation factor 2 (peIF-2α), and spliced XBP-1 mRNA. Knockdown studies using siRNAs to TRAIL, DR5, JNK and CHOP as well as chemical inhibitors of ER stress and caspase-8 showed that: i) α-TEA activation of DR5/caspase-8 induces an ER stress mediated JNK/CHOP/DR5 positive amplification loop; ii) α-TEA downregulation of c-FLIP (L) protein levels is mediated by JNK/CHOP/DR5 loop via a JNK dependent Itch E3 ligase ubiquitination that further serves to enhance the JNK/CHOP/DR5 amplification loop by preventing c-FLIP's inhibition of caspase-8; and (iii) α-TEA downregulation of Bcl-2 is mediated by the ER stress dependent JNK/CHOP/DR5 signaling. Conclusion -- Taken together, ER stress plays an important role in α-TEA induced apoptosis by enhancing DR5/caspase-8 pro-apoptotic signaling and suppressing anti-apoptotic factors c-FLIP and Bcl-2 via ER stress mediated JNK/CHOP/DR5/caspase-8 signaling.The Clayton Foundation for Research, the National Institute of Environmental Health Sciences Center Grant ES007784, the Center for Molecular and Cellular Toxicology at the University of Texas at Austin and a NIEHS/NIH Toxicology Training Grant T32 ES07247. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Biological Sciences, School o

mTORC1-S6K Activation by Endotoxin Contributes to Cytokine Up-Regulation and Early Lethality in Animals

Background: mTORC1 (mammalian target of rapamycin complex 1) activation has been demonstrated in response to endotoxin challenge, but the mechanism and significance are unclear. We investigated the effect of mTORC1 suppression in an animal model of endotoxemia and in a cellular model of endotoxin signaling. Methodology/Principal Findings: Mice were treated with the mTORC1 inhibitor rapamycin or vehicle prior to lethal endotoxin challenge. Mortality and cytokine levels were assessed. Cultured macrophage-like cells were challenged with endotoxin with or without inhibitors of various pathways known to be upstream of mTORC1. Activated pathways, including downstream S6K pathway, were assessed by immunoblots. We found that mTORC1-S6K suppression by rapamycin delayed mortality of mice challenged with lethal endotoxin, and was associated with dampened circulating levels of VEGF, IL-1b, IFN-c and IL-5. Furthermore, in vitro cellular studies demonstrated that LPS (lipopolysaccharide) activation of mTORC1-S6K still occurs in the presence of PI3K-Akt inhibition alone, but can be suppressed by concurrent inhibition of PI3K-Akt and MEK-ERK pathways. Conclusions/Significance: We conclude that cellular activation of mTORC1-S6K contributes to cytokine up-regulation an

Probing reheating temperature of the universe with gravitational wave background

Thermal history of the universe after big-bang nucleosynthesis (BBN) is well understood both theoretically and observationally, and recent cosmological observations also begin to reveal the inflationary dynamics. However, the epoch between inflation and BBN is scarcely known. In this paper we show that the detection of the stochastic gravitational wave background around 1Hz provides useful information about thermal history well before BBN. In particular, the reheating temperature of the universe may be determined by future space-based laser interferometer experiments such as DECIGO and/or BBO if it is around 10^{6-9} GeV, depending on the tensor-to-scalar ratio $r$ and dilution factor $F$.Comment: 20 pages, 8 figure

Targeting cholesterol-rich microdomains to circumvent tamoxifen-resistant breast cancer

Adjuvant treatment with tamoxifen substantially improves survival of women with estrogen-receptor positive (ER+) tumors. Tamoxifen resistance (TAMR) limits clinical benefit. RRR alpha tocopherol ether-linked acetic acid analogue (alpha-TEA) is a small bioactive lipid with potent anticancer activity. We evaluated the ability of alpha-TEA in the presence of tamoxifen to circumvent TAMR in human breast cancer cell lines. Methods: Two genotypically matched sets of TAM-sensitive (TAMS) and TAM-resistant (TAMR) human breast cancer cell lines were assessed for signal-transduction events with Western blotting, apoptosis induction with Annexin V-FITC/PI assays, and characterization of cholesterol-rich microdomains with fluorescence staining. Critical involvement of selected mediators was determined by using RNA interference and chemical inhibitors. Results: Growth-factor receptors (total and phosphorylated forms of HER-1 and HER-2), their downstream prosurvival mediators pAkt, pmTOR, and pERK1/2, phosphorylated form of estrogen receptor-alpha (pER-alpha at Ser-167 and Ser-118, and cholesterol-rich lipid microdomains were highly amplified in TAMR cell lines and enhanced by treatment with TAM. alpha-TEA disrupted cholesterol-rich microdomains, acted cooperatively with TAM to reduce prosurvival mediators, and induced DR5-mediated mitochondria-dependent apoptosis via an endoplasmic reticulum stress-triggered pro-death pJNK/CHOP/DR5 amplification loop. Furthermore, methyl-beta-cyclodextrin (M beta CD), a chemical disruptor of cholesterol rich microdomains, acted cooperatively with TAM to reduce prosurvival mediators and to induce apoptosis. Conclusions: Data for the first time document that targeting cholesterol-rich lipid microdomains is a potential strategy to circumvent TAMR, and the combination of alpha-TEA + TAM can circumvent TAMR by suppression of prosurvival signaling via disruption of cholesterol-rich lipid microdomains and activation of apoptotic pathways via induction of endoplasmic reticulum stress.Clayton Foundation for ResearchCenter for Molecular and Cellular Toxicology at the University of TexasNIEHS/NIH T32 ES07247Nutritional Science