Patients with human immunodeficiency virus (HIV) infection exhibit changes in sleep patterns, motor disorders, and cognitive dysfunction; these symptoms may be secondary to circadian rhythm abnormalities. Studies in mice have shown that intracerebral injection of an HIV protein, transactivator of transcription (Tat), alters the timing of circadian rhythms in a manner similar to light. Therefore, we tested the hypothesis that chronic Tat expression alters circadian rhythms, especially their entrainment to a light-dark (LD) cycle, by using transgenic mice in which Tat expression in the brain was induced via a doxycycline (DOX)-sensitive, glial fibrillary-associated, protein-restricted promoter. Because opiate substance abuse, which shares comorbidity with HIV infection, also disrupts sleep, a final experiment assessed the effects of morphine exposure on circadian rhythms in wild-type and Tat transgenic mice. Mice housed in cages equipped with running wheels were fed chow with or without DOX. Experiment 1 revealed a small but significant (P < 0.05) difference between groups in the phase angle of entrainment and a 15% decrease in the wheel running in the DOX group (P < 0.005). During exposure to constant darkness, DOX did not alter the endogenous period length of the circadian rhythm. Experiment 2 investigated the effect of DOX on circadian rhythms in wild-type and Tat(+) mice during exposure to a normal or phase-shifted LD cycle, or morphine treatment without any change in the LD cycle. Tat induction significantly decreased wheel running but did not affect entrainment to the normal or shifted LD cycle. Morphine decreased wheel running without altering the phase angle of entrainment, and the drug's effects were independent of Tat induction. In conclusion, these findings suggest that chronic brain expression of Tat decreases locomotor activity and the amplitude of circadian rhythms, but does not affect photic entrainment or reentrainment of the murine circadian pacemaker.

Our laboratory has recently demonstrated that low concentrations of ouabain increase blood pressure in rats associated with stimulation of Na-K ATPase activity and activation of the Src signaling cascade in NHE1-dependent manner. Proteomic analysis of human kidney proximal tubule cells (HKC11) suggested that the Angiotensin II type 1 receptor (AT1R) as an ouabain-associating protein. We hypothesize that ouabain-induced stimulation of Na-K ATPase activity is mediated through AT1R. To test this hypothesis, we examined the effect of ouabain on renal cell angiotensin II production, the effect of AT1R inhibition on ouabain-stimulated NKA activity, and the effect of ouabain on NKA-AT1R association. Ouabain increased plasma angiotensin II levels in rats treated with ouabain (1 μg/kg body wt./day) for 9 days and increased angiotensin II levels in cell culture media after 24 h treatment with ouabain in human (HKC11), mouse (MRPT), canine (MDCK) kidney cells, and human adrenal cells. Ouabain 10 pM stimulated NKA-mediated 86Rb uptake and phosphorylation of EGFR, Src, and ERK1/2. These effects were prevented by the AT1R receptor blocker candesartan. FRET and TIRF microscopy using Bodipy-labeled ouabain and mCherry-NKA or mCherry-AT1R demonstrated association of ouabain with AT1R and NKA. Further our FRET and TIRF studies demonstrated increased association between AT1R and NKA upon treatment with low dose ouabain. We conclude that ouabain stimulates NKA in renal proximal tubule cells through an angiotensin/AT1R-dependent mechanism and that this pathway contributes to cardiac glycoside associated hypertension.

A two-dimensional (2D) Weyl semimetal featuring a spin-polarized linear band dispersion and a nodal Fermi surface is a new topological phase of matter. It is a solidstate realization of Weyl fermions in an intrinsic 2D system. The nontrivial topology of 2D Weyl cones guarantees the existence of a new form of topologically protected boundary states, Fermi string edge states. In this work, we report the realization of a 2D Weyl semimetal in monolayer-thick epitaxial bismuthene grown on SnS(Se) substrate. The intrinsic band gap of bismuthene is eliminated by the space-inversionsymmetry-breaking substrate perturbations, resulting in a gapless spin-polarized Weyl band dispersion. The linear dispersion and spin polarization of the Weyl fermion states are observed in our spin and angle-resolved photoemission measurements. In addition, the scanning tunneling microscopy/spectroscopy reveals pronounced local density of states at the edge, suggesting the existence of Fermi string edge states. These results open the door for the experimental exploration of the exotic properties of Weyl fermion states in reduced dimensions.

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