Biology subjects

Cortes, D. R. E.

Publications and source records attributed to Cortes, D. R. E..

4 recordsLinked to original sources

bioRxiv2026

In Vivo 4D Oxy-Wavelet MRI as a Non-Invasive Biomarker of Brain Mitochondrial Function across the Lifespan

Mitochondria are essential for cellular energy production and are particularly critical for brain development and function. Neurons rely predominantly on oxidative phosphorylation for energy production, rendering the brain highly vulnerable to mitochondrial dysfunction. Consequently, impaired mitochondrial function contributes to a broad spectrum of neurological and systemic disorders, making mitochondria attractive therapeutic targets. Despite this importance, there is currently no non-invasive, spatially resolved method to assess mitochondrial function in the intact living brain. Here, we establish a non-invasive functional MRI approach--4D Oxy-wavelet MRI--to probe in vivo mitochondrial electron transport chain (ETC) function in a spatially specific manner across the lifespan, from fetal to adult brains. This method employs a low-rank k-t sub-Nyquist acquisition strategy to achieve simultaneous structural and functional imaging with high spatial (78 m) and temporal ([~]14 ms) resolution, enabling motion-robust imaging in multi-fetal mouse pregnancies. Mitochondrial ETC function is interrogated by measuring oxygen homeostasis responses to brief hypoxic challenges, analyzed using computational time-frequency wavelet profiling. We validate this approach in mouse models of mitochondrial respiratory chain disease and late-onset Alzheimers disease, from in utero fetuses to adults, and demonstrate reproducibility and specificity using pharmacological hyperemia and ETC complex I inhibition. We further show parallel wavelet responses in placenta and fetal brain, enabling multi-organ interrogation of the placenta-brain axis. Finally, we present first-in-human feasibility data, supporting translational potential for non-invasive assessment of mitochondrial function in living brains across the lifespan.

bioengineering↗

bioRxiv2025

Non-invasive Free-breathing Gating-free Extracellular Cellular Volume Quantification for Repetitive Myocardial Fibrosis Evaluation in Rodents

BackgroundInterstitial myocardial fibrosis is a crucial pathological feature of many cardiovascular disorders. Myocardial fibrosis resulting in extracellular volume (ECV) expansion can be non-invasively quantified by cardiac MRI (CMR) with T1 mapping before and after gadolinium (Gd) contrast agent administration. However, longitudinal repetitive ECV measurements are challenging in rodents due to the prolonged scan time with cardiac and respiratory gating that is required for conventional T1 mapping and the invasive nature of the rodent intravenous lines. MethodsTo address these challenges, the objective of this study is to establish a fast, free- breathing, and gating-free ECV procedure with a non-invasive subcutaneous catheter for in- scanner Gd administration that can allow longitudinal repetitive ECV evaluations in rodent models. This is achieved by (1) IntraGate sequence for free-breathing gating-free cardiac imaging, (2) non-invasive subcutaneous in-scanner Gd administration, and (3) fast T1 mapping with varied flip angle (VFA) in conjunction with (4) triple jugular vein blood T1 normalization. Additionally, full cine CMR (multi-slice short-axis, long-axis 2-chamber, and long-axis 4- chamber) was acquired during the waiting period for comprehensive systolic cardiac functional and strain analysis. ResultsWe have successfully established a non-invasive fast ECV quantification protocol to enable longitudinal repetitive ECV quantifications in rodents. Non-invasive subcutaneous Gd bolus administration induced reasonable dynamic contrast enhancement (DCE) time course reaching a steady state in [~] 20 min for stable T1 quantification. The free-breathing gating-free VFA T1 quantification scheme allows for rapid cardiac ([~]2.5 min) and jugular vein (49 sec) T1 quantification with no motion artifacts. The triple jugular vein T1 acquisitions (1 pre-contrast and 2 post-contrast) immediately flanking the heart T1 acquisitions enable accurate myocardial ECV quantification. Our data demonstrated that left-ventricular myocardial ECV quantifications were highly reproducible with repeated scans, and the ECV values (0.25) are comparable to reported ranges among humans and rodents. This protocol was successfully applied to ischemic reperfusion injury model to detect myocardial fibrosis that was validated with histopathology. ConclusionWe have established a simple, fast, non-invasive, and robust CMR protocol in rodents that can enable longitudinal repetitive ECV quantifications for cardiovascular disease progression. It can be used to monitor disease regression with interventions. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/664411v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@14b44e5org.highwire.dtl.DTLVardef@985392org.highwire.dtl.DTLVardef@96cef7org.highwire.dtl.DTLVardef@ede47d_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2024

Mitigation of Fetal Irradiation Injury from Mid-Gestation Total Body Radiation with Mitochondrial-Targeted GS-Nitroxide JP4-039

Victims of a radiation terrorist event will include pregnant women and unborn fetuses. Mitochondrial dysfunction and oxidative stress are key pathogenic factors of fetal irradiation injury. The goal of this preclinical study is to investigate the efficacy of mitigating fetal irradiation injury by maternal administration of the mitochondrial-targeted gramicidin S (GS)- nitroxide radiation mitigator, JP4-039. Pregnant female C57BL/6NTac mice received 3 Gy total body ionizing irradiation (TBI) at mid-gestation embryonic day 13.5 (E13.5). Using novel time- and-motion-resolved 4D in utero magnetic resonance imaging (4D-uMRI), we found TBI caused extensive injury to the fetal brain that included cerebral hemorrhage, loss of cerebral tissue, and hydrocephalus with excessive accumulation of cerebrospinal fluid (CSF). Histopathology of the fetal mouse brain showed broken cerebral vessels and elevated apoptosis. Further use of novel 4D Oxy-wavelet MRI capable of probing in vivo mitochondrial function in intact brain revealed significant reduction of mitochondrial function in the fetal brain after 3Gy TBI. This was validated by ex vivo Oroboros mitochondrial respirometry. Maternal administration JP4-039 one day after TBI (E14.5), which can pass through the placental barrier, significantly reduced fetal brain radiation injury and improved fetal brain mitochondrial respiration. This also preserved cerebral brain tissue integrity and reduced cerebral hemorrhage and cell death. As JP4-039 administration did not change litter sizes or fetus viability, together these findings indicate JP4-039 can be deployed as a safe and effective mitigator of fetal radiation injury from mid-gestational in utero ionizing radiation exposure. One Sentence SummaryMitochondrial-targeted gramicidin S (GS)-nitroxide JP4-039 is safe and effective radiation mitigator for mid-gestational fetal irradiation injury.

developmental biology↗

bioRxiv2024

Modeling Normal Mouse Uterine Contraction and Placental Perfusion with Non- invasive Longitudinal Dynamic Contrast Enhancement MRI

The placenta is a transient organ critical for fetal development. Disruptions of normal placental functions can impact health throughout an individuals entire life. Although being recognized by the NIH Human Placenta Project as an important organ, the placenta remains understudied, partly because of a lack of non-invasive tools for longitudinally evaluation for key aspects of placental functionalities. Non-invasive imaging that can longitudinally probe murine placental health in vivo are critical to understanding placental development throughout pregnancy. We developed advanced imaging processing schemes to establish functional biomarkers for non-invasive longitudinal evaluation of placental development. We developed a dynamic contrast enhancement magnetic resonance imaging (DCE-MRI) pipeline combined with advanced image process methods to model uterine contraction and placental perfusion dynamics. Our novel imaging pipeline uses subcutaneous administration of gadolinium for steepest-slope based perfusion evaluation. This enables non-invasive longitudinal monitoring. Additionally, we advance the placental perfusion chamber paradigm with a novel physiologically-based threshold model for chamber localization and demonstrate spatially varying placental chambers using multiple functional metrics that assess mouse placental development and continuing remodeling throughout gestation. Lastly, using optic flow to quantify placental motions arisen from uterine contractions in conjunction with time-frequency analysis, we demonstrated that the placenta exhibited asymmetric contractile motion.

systems biology↗