Capital markets, CDFIs, and organizational credit risk

Tansey, C. W.; Swack, Michael E.; Tansey, Michael M.; Stein, Vicky

doi:10.34051/p/2020.123

Cited by 1 publication

(2 citation statements)

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“…Additionally, more microglia were also observed especially in α-Syn rich regions in mice lacking NRF2. In this context, it has long been recognized that activated microglia surround Lewy bodies in postmortem PD brains [47][48][49][50]. α-Syn, which is a major constituent of Lewy bodies, has been shown to bind to and activate microglia through toll-like receptors (TLRs) that mediate innate immunity [30,51,52].…”

Section: Discussionmentioning

confidence: 99%

“…Briefly, mice are transferred to individual testing cages approximately 1 hr before the dark phase and weighed nestlets are placed in the feeder bin of the cage (5 nestlets, ~12g/cage). The amount of nestlets that were retrieved (nestlet pulldown) and broken down (nestlet usage) for nest building was measured every 12 hours over a 72 hour period (12,24,36,48,60 and 72 hours) by weighing the unused material in the feeder and inside the cage [31]. Data were presented as percent of nestlet pulldown and percent used as normalized to control (hα-Syn -/Nrf2 +/+ ).…”

Section: Behavioral Analysesmentioning

confidence: 99%

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NRF2 Loss Accentuates Parkinsonian Pathology and Behavioral Dysfunction in Human α-Synuclein Overexpressing Mice

Anandhan¹,

Nguyen²,

Syal³

et al. 2021

Aging and disease

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Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a central regulator of cellular stress responses and its transcriptional activation promotes multiple cellular defense and survival mechanisms. The loss of NRF2 has been shown to increase oxidative and proteotoxic stress, two key pathological features of neurodegenerative disorders such as Parkinson's disease (PD). Moreover, compromised redox homeostasis and protein quality control can cause the accumulation of pathogenic proteins, including alpha-synuclein (α-Syn) which plays a key role in PD. However, despite this link, the precise mechanisms by which NRF2 may regulate PD pathology is not clear. In this study, we generated a humanized mouse model to study the importance of NRF2 in the context of α-Syn-driven neuropathology in PD. Specifically, we developed NRF2 knockout and wild-type mice that overexpress human α-Syn (hα-Syn + /Nrf2 -/and hα-Syn + /Nrf2 +/+ respectively) and tested changes in their behavior through nest building, challenging beam, and open field tests at three months of age. Cellular and molecular alterations in α-Syn, including phosphorylation and subsequent oligomerization, as well as changes in oxidative stress, inflammation, and autophagy were also assessed across multiple brain regions. It was observed that although monomeric α-Syn levels did not change, compared to their wild-type counterparts, hα-Syn + /Nrf2 -/mice exhibited increased phosphorylation and oligomerization of α-Syn. This was associated with a loss of tyrosine hydroxylase expressing dopaminergic neurons in the substantia nigra, and more pronounced behavioral deficits reminiscent of early-stage PD, in the hα-Syn + /Nrf2 -/mice. Furthermore, hα-Syn + /Nrf2 -/mice showed significantly amplified oxidative stress, greater expression of inflammatory markers, and signs of increased autophagic burden, especially in the midbrain, striatum and cortical brain regions. These results support an important role for NRF2, early in PD progression. More broadly, it indicates NRF2 biology as fundamental to PD pathogenesis and suggests that targeting NRF2 activation may delay the onset and progression of PD.

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