Myocardial hypertrophy is an adaptation to increased hemodynamic demands. An increase in heart tissue must be matched by a corresponding expansion of the coronary vasculature to maintain and adequate supply of oxygen and nutrients for the heart. The physiological mechanisms that underlie the coordination of angiogenesis and cardiomyocyte growth are unknown. We report that induction of myocardial angiogenesis promotes cardiomyocyte growth and cardiac hypertrophy through a novel NO-dependent mechanism. We used transgenic, conditional overexpression of placental growth factor (PlGF) in murine cardiac tissues to stimulate myocardial angiogenesis and increase endothelial-derived NO release. NO production, in turn, induced myocardial hypertrophy by promoting proteasomal degradation of regulator of G protein signaling type 4 (RGS4), thus relieving the repression of the Gβγ/PI3Kγ/AKT/mTORC1 pathway that stimulates cardiomyocyte growth. This hypertrophic response was prevented by concomitant transgenic expression of RGS4 in cardiomyocytes. NOS inhibitor L-NAME also significantly attenuated RGS4 degradation, and reduced activation of AKT/mTORC1 signaling and induction of myocardial hypertrophy in PlGF transgenic mice, while conditional cardiac-specific PlGF expression in eNOS knockout mice did not induce myocardial hypertrophy. These findings describe a novel NO/RGS4/Gβγ/PI3Kγ/AKT mechanism that couples cardiac vessel growth with myocyte growth and heart size. IntroductionRecent studies have increased appreciation for the relationship between cardiomyocyte growth and angiogenesis and its contribution to molecular regulation of the myocardial hypertrophic response. Myocardial hypertrophy, secondary to increased hemodynamic demands, requires commensurate growth of the coronary vasculature to provide adequate oxygen and nutrients to the increasing cardiac mass; lack of coordination between the myocyte-driven hypertrophic response and the production of angiogenic growth factors hallmarks the transition to heart failure (1). Although vascular endothelium controls a plethora of biological events contributing to cardiovascular homeostasis, including regulation of vascular tone, thrombosis, and myocardial stiffness, little is known about the effect of endothelial signaling on cardiomyocyte growth, regulation of myocardial hypertrophy, and heart size. Our previous observation that a NOS inhibitor, N G -nitro-l-arginine methyl ester (L-NAME), partially prevented angiogenesis-driven myocardial hypertrophy (2) suggests that endothelium-dependent NO production might be responsible for the hypertrophic effect on cardiomyocytes and the increase in heart size.Because there are no known mechanisms that link NO to stimulation of cardiomyocyte hypertrophy, we designed the present study to fill this gap. In cardiomyocytes, G protein-mediated hypertrophic signaling is negatively modulated by regulators of G protein signaling (RGS proteins). Among more than 20 RGS proteins, RGS subtype 4, a GTPase-activating protein for heterotrimeric Gq and ...

As one of the most widespread drugs of abuse, nicotine has long been known to impact the brain, particularly with respect to addiction. However, the regional effects of nicotine on the concentrations and kinetics of amino acid neurotransmitters and some energetically related neurochemicals have been little studied. In this investigation, acute effects of nicotine were measured by 1 H-observed/ 13 C-edited nuclear magnetic resonance spectroscopy method in extracts obtained from nicotine-naïve, freely moving rats given 0.7 mg/kg nicotine or saline, with [1-13 C] glucose to track metabolism. Nicotine was observed to exert significant effects on the concentrations of N-acetylaspartate and GABA, particularly in the striatum. Nicotine decreased brain glucose oxidation, glutamate-glutamine neurotransmitter cycling, and GABA synthesis regionally, including in the parietal and occipital cortices and the striatum. The olfactory bulb showed kinetics that differed markedly from those observed in the rest of the brain. Independently of nicotine, the concentration of glutamate was found to be correlated significantly with levels of N-acetylaspartate and GABA, suggesting a potential interplay of energetics and excitatory and inhibitory neurotransmission. In summary, the study revealed that the neurochemicals were most affected in the cortex and striatum of the rat brain after acute nicotine treatment.

Glioblastoma is a highly malignant and incurable brain tumor characterized by intrinsic and adaptive resistance to immunotherapies. However, how glioma cells induce tumor immunosuppression and escape immunosurveillance remains poorly understood. Here, we find upregulation of cancer-intrinsic Chitinase-3-like-1 (CHI3L1) signaling modulating an immunosuppressive microenvironment by reprogramming tumor-associated macrophages (TAMs). Mechanistically, CHI3L1 binding with Galectin-3 (Gal3) selectively promotes TAM migration and infiltration with a protumor M2-like but not an antitumor M1-like phenotype in vitro and in vivo, governed by a transcriptional program of NFκB/CEBPβ in the CHI3L1/Gal3-PI3K/AKT/mTOR axis. Conversely, Galectin-3-binding protein (Gal3BP) negatively regulates this process by competing with Gal3 to bind CHI3L1.Administration of a Gal3BP mimetic peptide in syngeneic glioblastoma mouse models reverses immune suppression and attenuates tumor progression. These results shed light on the role of CHI3L1 protein complexes in immune evasion by glioblastoma and as a potential immunotherapeutic target for this devastating disease.

Breast cancer stem cells (BCSCs) are essential for cancer growth, metastasis and recurrence. The regulatory mechanisms of BCSC interactions with the vascular niche within the tumor microenvironment (TME) and their self-renewal are currently under extensive investigation. We have demonstrated the existence of an arteriolar niche in the TME of human BC tissues. Intriguingly, BCSCs tend to be enriched within the arteriolar niche in human estrogen receptor positive (ER+) BC and bi-directionally interact with arteriolar endothelial cells (ECs). Mechanistically, this interaction is driven by the lysophosphatidic acid (LPA)/protein kinase D (PKD-1) signaling pathway, which promotes both arteriolar differentiation of ECs and self-renewal of CSCs likely via differential regulation of CD36 transcription. This study indicates that CSCs may enjoy blood perfusion to maintain their stemness features. Targeting the LPA/PKD-1 -CD36 signaling pathway may have therapeutic potential to curb tumor progression by disrupting the arteriolar niche and effectively eliminating CSCs.

Using joint actuators to drive the skeletal movements is a common practice in character animation, but the resultant torque patterns are often unnatural or infeasible for real humans to achieve. On the other hand, physiologicallybased models explicitly simulate muscles and tendons and thus produce more human-like movements and torque patterns. This paper introduces a technique to transform an optimal control problem formulated in the muscleactuation space to an equivalent problem in the joint-actuation space, such that the solutions to both problems have the same optimal value. By solving the equivalent problem in the joint-actuation space, we can generate humanlike motions comparable to those generated by musculotendon models, while retaining the benefit of simple modeling and fast computation offered by joint-actuation models. Our method transforms constant bounds on muscle activations to nonlinear, state-dependent torque limits in the joint-actuation space. In addition, the metabolic energy function on muscle activations is transformed to a nonlinear function of joint torques, joint configuration and joint velocity. Our technique can also benefit policy optimization using deep reinforcement learning approach, by providing a more anatomically realistic action space for the agent to explore during the learning process. We take the advantage of the physiologically-based simulator, OpenSim, to provide training data for learning the torque limits and the metabolic energy function. Once trained, the same torque limits and the energy function can be applied to drastically different motor tasks formulated as either trajectory optimization or policy learning.