Biology subjects

Panigrahy, A.

Publications and source records attributed to Panigrahy, A..

4 recordsLinked to original sources

bioRxiv2023

Pathogenic mechanisms underlying adverse neurodevelopmental outcome in congenital heart disease

Poor neurodevelopment is often observed with congenital heart disease (CHD), especially with mutations in chromatin modifiers. Here analysis of mice with hypoplastic left heart syndrome (HLHS) arising from mutations in Sin3A associated chromatin modifier Sap130, and adhesion protein Pcdha9, revealed neurodevelopmental and neurobehavioral deficits reminiscent of those in HLHS patients. Microcephaly was associated with impaired cortical neurogenesis, mitotic block, and increased apoptosis. Transcriptional profiling indicated dysregulated neurogenesis by REST, altered CREB signaling regulating memory and synaptic plasticity, and impaired neurovascular coupling modulating cerebral blood flow. Many neurodevelopmental/neurobehavioral disease pathways were recovered, including autism and cognitive impairment. These same pathways emerged from genome-wide DNA methylation and Sap130 chromatin immunoprecipitation sequencing analyses, suggesting epigenetic perturbation. Mice with Pcdha9 mutation or forebrain-specific Sap130 deletion without CHD showed learning/memory deficits and autism-like behavior. These novel findings provide mechanistic insights indicating the adverse neurodevelopment in HLHS may involve cell autonomous/nonautonomous defects and epigenetic dysregulation and suggest new avenues for therapy.

developmental biology↗

bioRxiv2023

Multivariate and Regional Age-Related Change in Basal Ganglia Iron in Neonates

In the perinatal period, reward and cognitive systems begin trajectories, influencing later psychiatric risk. The basal ganglia is important for reward and cognitive processing but early development has not been fully characterized. To assess age-related development, we used a measure of basal ganglia physiology, specifically brain tissue iron, obtained from nT2* signal in rsfMRI, associated with dopaminergic processing. We used data from the Developing Human Connectome Project (N=464) to assess how moving from the prenatal to the postnatal environment affects rsfMRI nT2*, modeling gestational and postnatal age separately for basal ganglia subregions in linear models. We did not find associations with tissue iron and gestational age [Range: 24.29-42.29] but found positive associations with postnatal age [Range:0-17.14] in the pallidum and putamen, but not the caudate. We tested if there was an interaction between preterm birth and postnatal age, finding early preterm infants (GA<35 weeks) had higher iron levels and changed less over time. To assess multivariate change, we used support vector regression to predict age from voxel-wise-nT2* maps. We could predict postnatal but not gestational age when maps were residualized for the other age term. This provides evidence subregions differentially change with postnatal experience and preterm birth may disrupt trajectories.

neuroscience↗

bioRxiv2023

Gestational and postnatal age associations for striatal tissue iron deposition in early infancy

Striatal development is crucial for later motor, cognitive, and reward behavior, but age-related change in striatal physiology during the neonatal period remains understudied. An MRI-based measure of tissue iron deposition, T2*, is a non-invasive way to probe striatal physiology neonatally, linked to dopaminergic processing and cognition in children and adults. Striatal subregions have distinct functions that may come online at different time periods in early life. To identify if there are critical periods before or after birth, we measured if striatal iron accrued with gestational age at birth [range=34.57-41.85 weeks] or postnatal age at scan [range=5-64 days], using MRI to probe the T2* signal in N=83 neonates in three striatal subregions. We found iron increased with postnatal age in the pallidum and putamen but not the caudate. No significant relationship between iron and gestational age was observed. Using a subset of infants scanned at preschool age (N=26), we show distributions of iron shift between timepoints. In infants, the pallidum had the least iron of the three regions but had the most by preschool age. Together, this provides evidence of distinct change for striatal subregions, a possible differentiation between motor and cognitive systems, identifying a mechanism that may impact future trajectories. HighlightsO_LINeonatal striatal tissue iron can be measured using the T2* signal from rsfMRI C_LIO_LInT2* changed with postnatal age in the pallidum and putamen but not in the caudate C_LIO_LInT2* did not change with gestational age in any of the three regions C_LIO_LIPatterns of iron deposition (nT2*) among regions shift from infancy to preschool C_LI

neuroscience↗

bioRxiv2019

Preclinical immunoPET imaging of glioblastoma-infiltrating myeloid cells using Zirconium-89-labeled anti-CD11b antibody

PurposeGlioblastoma is a lethal brain tumor, heavily infiltrated by tumor-associated myeloid cells (TAMCs). TAMCs are emerging as a promising therapeutic target as they suppress antitumor immune responses and promote tumor cell growth. Quantifying TAMCs using non-invasive immunoPET could facilitate patient stratification for TAMC-targeted treatments and monitoring of treatment efficacy. As TAMCs uniformly express the cell surface marker, integrin CD11b, we evaluated a 89Zr-labeled anti-CD11b antibody for non-invasive imaging of TAMCs in a syngeneic orthotopic mouse glioma model.\n\nProceduresA human/mouse cross-reactive anti-CD11b antibody (clone M1/70) was conjugated to a DFO chelator and radiolabeled with Zr-89. PET/CT and biodistribution with or without a blocking dose of anti-CD11b Ab were performed 72 hours post-injection of 89Zr-anti-CD11b Ab in mice bearing established orthotopic syngeneic GL261 gliomas. Flow cytometry and immunohistochemistry of dissected GL261 tumors were conducted to confirm the presence of CD11b+ TAMCs.\n\nResultsSignificant uptake of 89Zr-anti-CD11b Ab was detected at the tumor site (SUVmean = 2.60 {+/-} 0.24) compared with the contralateral hemisphere (SUVmean = 0.6 {+/-} 0.11). Blocking with a 10-fold lower specific activity of 89Zr-anti-CD11b Ab markedly reduced the SUV in the right brain (SUVmean = 0.11 {+/-} 0.06), demonstrating specificity. Spleen and lymph nodes (myeloid cell rich organs) also showed high uptake of the tracer, and biodistribution analysis correlated with the imaging results. CD11b expression within the tumor was validated using flow cytometry and immunohistochemistry, which showed high CD11b expression primarily in the tumoral hemisphere compared to the contralateral hemisphere.\n\nConclusionThese data establish that 89Zr-anti-CD11b Ab immunoPET targets CD11b+ cells (TAMCs) with high specificity in a mouse model of GBM, demonstrating the potential for non-invasive quantification of tumor infiltrating CD11b+ immune cells during disease progression and immunotherapy in patients with GBM.

immunology↗