Redox Regulation of Mitochondrial Fission Protein Drp1 by Protein Disulfide Isomerase Limits Endothelial Senescence.

Mitochondrial dynamics are tightly controlled by fusion and fission, and their dysregulation and excess reactive oxygen species (ROS) contribute to endothelial cell (EC) dysfunction. How redox signals regulate coupling between mitochondrial dynamics and endothelial (dys)function remains unknown. Here, we identify protein disulfide isomerase A1 (PDIA1) as a thiol reductase for the mitochondrial fission protein Drp1. A biotin-labeled Cys-OH trapping probe and rescue experiments reveal that PDIA1 depletion in ECs induces sulfenylation of Drp1 at Cys644, promoting mitochondrial fragmentation and ROS elevation without inducing ER stress, which drives EC senescence. Mechanistically, PDIA1 associates with Drp1 to reduce its redox status and activity. Defective wound healing and angiogenesis in diabetic or PDIA1+/- mice are restored by EC-targeted PDIA1 or the Cys oxidation-defective mutant Drp1. Thus, this study uncovers a molecular link between PDIA1 and Drp1 oxidoreduction, which maintains normal mitochondrial dynamics and limits endothelial senescence with potential translational implications for vascular diseases associated with diabetes or aging.This research was supported by NIH R01HL135584 (to M.U.-F.), NIH R21HL112293 (to M.U.-F.), NIH R01HL133613 (to T.F. and M.U.-F.), NIH R01HL116976 (to T.F. and M.U.-F.), NIH R01HL070187 (to T.F.), NIH R01HL112626 (to J.K.), Department of Veterans Affairs Merit Review Grant 2I01BX001232 (to T.F.), AHA 16GRNT31390032 (to M.U.-F.), AHA 15SDG25700406 (to S.V.), AHA 16POST27790038 (to A.D.), and NIH T32HL07829 (to R.C.). We thank Mr. Kyle Taylor at Keyence Corporation for assisting with taking images using the Keyence microscope; Dr. John O’Bryan at UIC for assisting with the BiFC assays; Dr. Leslie Poole at Wake Forest University for providing DCP-Bio1, as well as Dr. Jody Martin and the Center for Cardiovascular Research-supported Vector Core Facility at UIC for amplifying adenoviruses.S

Evaluating Physiological MRI Parameters in Patients with Brain Metastases Undergoing Stereotactic Radiosurgery-A Preliminary Analysis and Case Report

Brain metastases occur in ten to thirty percent of the adult cancer population. Treatment consists of different (palliative) options, including stereotactic radiosurgery (SRS). Sensitive MRI biomarkers are needed to better understand radiotherapy-related effects on cerebral physiology and the subsequent effects on neurocognitive functioning. In the current study, we used physiological imaging techniques to assess cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen (CMRO2) and cerebrovascular reactivity (CVR) before and three months after SRS in nine patients with brain metastases. The results showed improvement in OEF, CBF and CMRO2 within brain tissue that recovered from edema (all p ≤ 0.04), while CVR remained impacted. We observed a global post-radiotherapy increase in CBF in healthy-appearing brain tissue (p = 0.02). A repeated measures correlation analysis showed larger reductions within regions exposed to higher radiotherapy doses in CBF (rrm = −0.286, p < 0.001), CMRO2 (rrm = −0.254, p < 0.001), and CVR (rrm = −0.346, p < 0.001), but not in OEF (rrm = −0.004, p = 0.954). Case analyses illustrated the impact of brain metastases progression on the post-radiotherapy changes in both physiological MRI measures and cognitive performance. Our preliminary findings suggest no radiotherapy effects on physiological parameters occurred in healthy-appearing brain tissue within 3-months post-radiotherapy. Nevertheless, as radiotherapy can have late side effects, larger patient samples allowing meaningful grouping of patients and longer follow-ups are needed

Response of the primary auditory and non-auditory cortices to acoustic stimulation: A manganese-enhanced MRI study

Structural and functional features of various cerebral cortices have been extensively explored in neuroscience research. We used manganese-enhanced MRI, a non-invasive method for examining stimulus-dependent activity in the whole brain, to investigate the activity in the layers of primary cortices and sensory, such as auditory and olfactory, pathways under acoustic stimulation. Male Sprague-Dawley rats, either with or without exposure to auditory stimulation, were scanned before and 24-29 hour after systemic MnCl2 injection. Cortex linearization and layer-dependent signal extraction were subsequently performed for detecting layer-specific cortical activity. We found stimulus-dependent activity in the deep layers of the primary auditory cortex and the auditory pathways. The primary sensory and visual cortices also showed the enhanced activity, whereas the olfactory pathways did not. Further, we performed correlation analysis of the signal intensity ratios among different layers of each cortex, and compared the strength of correlations between with and without the auditory stimulation. In the primary auditory cortex, the correlation strength between left and right hemisphere showed a slight but not significant increase with the acoustic simulation, whereas, in the primary sensory and visual cortex, the correlation coefficients were significantly smaller. These results suggest the possibility that even though the primary auditory, sensory, and visual cortices showed enhanced activity to the auditory stimulation, these cortices had different associations for auditory processing in the brain network.open0

Multiple Advisors with Reputation

This paper examines reputation, the belief of a decision maker about types of advisors, in a two period cheap talk model where the decision maker obtains messages from two advisors. The decision maker believes that an advisor can be one of two types - an advisor who is biased towards suggesting any particular advice (bad advisor) or an advisor who has the same preferences as the decision maker (good advisor). I assume that each advisor perfectly knows the type of the other advisor, but his signal about the state of the world is imperfect. Strong reputational concern makes the good advisor sometimes tell a lie in the first period regardless of the type of the other advisor. It is shown that the presence of the other advisor does affect the message sent by an advisor. The good advisor has a greater incentive to tell a lie when he knows that the other advisor is bad rather than good. If each type of advisor considers his second period sufficiently important, it is better for the decision maker to have a single advisor.Reputation; Cheap talk

BIOPHYSICS MODEL IMPROVEMENT IN MAGNETIC RESONANCE IMAGING: CEREBRAL METABOLIC RATE OF OXYGEN

105 pagesCerebral metabolic rate of oxygen (CMRO2) and oxygen extraction fraction (OEF) are valuable to investigate tissue viability and function. Numerous magnetic resonance imainge (MRI) methods have been proposed to estimate them quantitatively. While those methods are investigated in healthy subjects, a robust framework is elusive from literature for reliable CMRO2 and OEF estimation in pathological scenarios. This thesis developed algorithms that improve the accuracy, robustness and applicability of CMRO2 and OEF for both healthy and pathological subjects. First, quantitative susceptibility mapping (QSM)-based and quantitative blood oxygen-level dependent magnitude (qBOLD)-based CMRO2 method were combined to resolve the issues of the individual methods. Second, the cluster analysis of time evolution (CAT) was proposed to improve robustness of the combined model against noise. With the technical advances in this thesis, CMRO2 and OEF that are robust against noise and sensitive to pathological senarios, e.g. ischemic stroke lesion, can be estimated

Sequential Cheap Talk from Advisors with Reputation

I examine two-period sequential cheap talk in situations where the decision maker seeks advice from two advisors, each of whom knows the type of the other advisor. By considering the current payoff (which is determined by the message of each advisor) and the future payoff (which is connected with the reputation of each advisor), I examine conditions which guarantee the existence of both good and bad reputation effects. Compared to situations of simultaneous cheap talk, the decision maker loses information more easily if he seeks advice sequentially.Cheap talk, reputation.

Cerebral oxygen metabolism from MRI susceptibility

This article provides an overview of MRI methods exploiting magnetic susceptibility properties of blood to assess cerebral oxygen metabolism, including the tissue oxygen extraction fraction (OEF) and the cerebral metabolic rate of oxygen (CMRO2). The first section is devoted to describing blood magnetic susceptibility and its effect on the MRI signal. Blood circulating in the vasculature can have diamagnetic (oxyhemoglobin) or paramagnetic properties (deoxyhemoglobin). The overall balance between oxygenated and deoxygenated hemoglobin determines the induced magnetic field which, in turn, modulates the transverse relaxation decay of the MRI signal via additional phase accumulation. The following sections of this review then illustrate the principles underpinning susceptibility-based techniques for quantifying OEF and CMRO2. Here, it is detailed whether these techniques provide global (OxFlow) or local (Quantitative Susceptibility Mapping - QSM, calibrated BOLD - cBOLD, quantitative BOLD - qBOLD, QSM+qBOLD) measurements of OEF or CMRO2, and what signal components (magnitude or phase) and tissue pools they consider (intravascular or extravascular). Validations studies and potential limitations of each method are also described. The latter include (but are not limited to) challenges in the experimental setup, the accuracy of signal modeling, and assumptions on the measured signal. The last section outlines the clinical uses of these techniques in healthy aging and neurodegenerative diseases and contextualizes these reports relative to results from gold-standard PET