Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages

Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers

A graphene platform on silicon for the Internet of Everything

© 2018 IEEE. We have pioneered a platform technology able to harness the properties of graphene directly from silicon carbide on silicon substrates for integrated on-chip or in-package applications, ranging from sensing and nanophotonics to integrated energy storage. The graphene synthesis is transfer-free and site-selective, leading to straightforward wafer-level fabrication and yielding sufficient adhesion for subsequent processing. This approach among others can pave the way towards miniaturized energy sources in SiP systems for smart nodes of the Internet of Everything

Dopamine and its receptors play a role in the modulation of CCR5 expression in innate immune cells following exposure to Methamphetamine: Implications to HIV infection.

The Human Immunodeficiency Virus (HIV) infects cells in the Central Nervous System (CNS), where the access of antiretrovirals and antibodies that can kill the virus may be challenging. As a result of the early HIV entry in the brain, infected individuals develop inflammation and neurological deficits at various levels, which are aggravated by drugs of abuse. In the non-human primate model of HIV, we have previously shown that drugs of abuse such as Methamphetamine (Meth) increase brain viral load in correlation with a higher number of CCR5-expressing myeloid cells. CCR5 is a chemokine receptor that may be involved in increasing inflammation, but also, it is a co-receptor for viral entry into target cells. CCR5-expressing myeloid cells are the main targets of HIV in the CNS. Thus, the identification of factors and mechanisms that impact the expression of CCR5 in the brain is critical, as changes in CCR5 levels may affect the infection in the brain. Using a well-characterized in vitro system, with the THP1 human macrophage cell line, we have investigated the hypothesis that the expression of CCR5 is acutely affected by Meth, and examined pathways by which this effect could happen. We found that Meth plays a direct role by regulating the abundance and nuclear translocation of transcription factors with binding sites in the CCR5 promoter. However, we found that the main factor that modifies the CCR5 gene promoter at the epigenetic level towards transcription is Dopamine (DA), a neurotransmitter that is produced primarily in brain regions that are rich in dopaminergic neurons. In THP1 cells, the effect of DA on innate immune CCR5 transcription was mediated by DA receptors (DRDs), mainly DRD4. We also identified a role for DRD1 in suppressing CCR5 expression in this myeloid cell system, with potential implications for therapy. The effect of DA on innate immune CCR5 expression was also detectable on the cell surface during acute time-points, using low doses. In addition, HIV Tat acted by enhancing the surface expression of CCR5, in spite of its poor effect on transcription. Overall, our data suggests that the exposure of myeloid cells to Meth in the context of presence of HIV peptides such as Tat, may affect the number of HIV targets by modulating CCR5 expression, through a combination of DA-dependent and-independent mechanisms. Other drugs that increase DA may affect similar mechanisms. The implications of these epigenetic and translational mechanisms in enhancing HIV infection in the brain and elsewhere are demonstrated

Interrater and intrarater reliability of ventilatory thresholds determined in individuals with spinal cord injury

Study design Cross-sectional. Objectives Individualized training regimes are often based on ventilatory thresholds (VTs). The objectives were to study: (1) whether VTs during arm ergometry could be determined in individuals with spinal cord injury (SCI), (2) the intrarater and interrater reliability of VT determination. Setting University research laboratory. Methods Thirty graded arm crank ergometry exercise tests with 1-min increments of recreationally active individuals (tetraplegia (N = 11), paraplegia (N = 19)) were assessed. Two sports physicians assessed all tests blinded, randomly, in two sessions, for VT1 and VT2, resulting in 240 possible VTs. Power output (PO), heart rate (HR), and oxygen uptake (VO2) at each VT were compared between sessions or raters using paired samples t-tests, Wilcoxon signed-rank tests, intraclass correlation coefficients (ICC, relative agreement), and Bland-Altman plots (random error, absolute agreement). Results Of the 240 VTs, 217 (90%) could be determined. Of the 23 undetermined VTs, 2 (9%) were VT1 and 21 (91%) were VT2; 7 (30%) among individuals with paraplegia, and 16 (70%) among individuals with tetraplegia. For the successfully determined VTs, there were no systematic differences between sessions or raters. Intrarater and interrater ICCs for PO, HR, and VO2 at each VT were high to very high (0.82-1.00). Random error was small to large within raters, and large between raters. Conclusions For VTs that could be determined, relative agreement was high to very high, absolute agreement varied. For some individuals, often with tetraplegia, VT determination was not possible, thus other methods should be considered to prescribe exercise intensity