MEMRI detects neuronal activity and connectivity in hypothalamic neural circuit responding to leptin.

Hypothalamus plays the central role in regulating energy homeostasis. To understand the hypothalamic neurocircuit in responding to leptin, Manganese-Enhanced MRI (MEMRI) was applied. Highly elevated signal could be mapped in major nuclei of the leptin signaling pathway, including the arcuate nucleus (ARC), paraventricular nucleus (PVN), ventromedial hypothalamus (VMH) and dorsomedial hypothalamus (DMH) in fasted mice and the enhancement was reduced by leptin administration. However, whether changes in MEMRI signal reflect Ca2+ channel activity, neuronal activation or connectivity in the leptin signaling pathway are not clear. By blocking L-type Ca2+ channels, the signal enhancement in the ARC, PVN and DMH, but not VMH, was reduced. By disrupting microtubule with colchicine, signal enhancement of the secondary neural areas like DMH and PVN was delayed which is consistent with the known projection density from ARC into these regions. Finally, strong correlation between c-fos expression and MEMRI signal increase rate was observed in the ARC, VMH and DMH. Together, we provide experimental evidence that MEMRI signal could represent activity and connectivity in certain hypothalamic nuclei and hence may be used for mapping activated neuronal pathway in vivo. This understanding would facilitate the application of MEMRI for evaluation of hypothalamic dysfunction in metabolic diseases.

Specific inhibition of p25/Cdk5 activity by the Cdk5 inhibitory peptide reduces neurodegeneration in vivo.

The aberrant hyperactivation of Cyclin-dependent kinase 5 (Cdk5), by the production of its truncated activator p25, results in the formation of hyperphosphorylated tau, neuroinflammation, amyloid deposition, and neuronal death in vitro and in vivo. Mechanistically, this occurs as a result of a neurotoxic insult that invokes the intracellular elevation of calcium to activate calpain, which cleaves the Cdk5 activator p35 into p25. It has been shown previously that the p25 transgenic mouse as a model to investigate the mechanistic implications of p25 production in the brain, which recapitulates deregulated Cdk5-mediated neuropathological changes, such as hyperphosphorylated tau and neuronal death. To date, strategies to inhibit Cdk5 activity have not been successful in targeting selectively aberrant activity without affecting normal Cdk5 activity. Here we show that the selective inhibition of p25/Cdk5 hyperactivation in vivo, through overexpression of the Cdk5 inhibitory peptide (CIP), rescues against the neurodegenerative pathologies caused by p25/Cdk5 hyperactivation without affecting normal neurodevelopment afforded by normal p35/Cdk5 activity. Tau and amyloid pathologies as well as neuroinflammation are significantly reduced in the CIP-p25 tetra transgenic mice, whereas brain atrophy and subsequent cognitive decline are reversed in these mice. The findings reported here represent an important breakthrough in elucidating approaches to selectively inhibit the p25/Cdk5 hyperactivation as a potential therapeutic target to reduce neurodegeneration.

Manufacturing of Al Alloy Microrods by Micro Cutting in a Micromachining Center.

This paper presents the micromanufacturing of aluminum (Al) alloy microrods using micro turning as a competing process to other nontraditional micromachining methods. In that regard, the challenges in such manufacturing have been identified and overcome. The strategies of step-by-step cutting have also been delineated. In addition, the influence of step size and step length on the cutting and thrust forces were investigated. The chip morphology for micromachining was examined using scanning electron microscopic imagery. The safe dimension of the microrod was calculated and, subsequently, used to fabricate microrod, conical tip rod, and grooved rod from 3 mm long and 1.5 mm diameter rod using an appropriately coded computer numerical control (CNC) micromachining center. Our results showed that the thrust force was responsible for part deflection, emphasizing the necessity for computing safe dimensions. At shallow step sizes, the thrust force was more dominant, causing plastic deformation associated with rubbing and burnishing. The chips produced were irregular and sliced in nature. Conversely, at high step sizes, the cutting force superseded the thrust force, resulting in chips that were spread more along the width as opposed to the depth. The chips also had a smoother interacting surface. Finally, micro turning was successfully implemented to manufacture milli-scale structures (i.e., 3 mm long) with micro features (150 to 230 µm diameter) on aluminum alloy materials.