Biology subjects

Manfredi, J.

Publications and source records attributed to Manfredi, J..

2 recordsLinked to original sources

bioRxiv2024

Volumetric and Diffusion Tensor Imaging biomarkers indicating long lasting post-concussion abnormalities in a youth pig model of mild Traumatic Brain Injury

Mild Traumatic Brain Injury (mTBI) caused by sports-related incidents in children and youth can lead to prolonged cognitive impairments, underscoring the importance of improved diagnosis and comprehension of its enduring impacts on neuropathology. A pig model was chosen for its similarities to the human brain in terms of gyrencephalic structure, size, and regional proportions, and a closed-head mTBI was induced in adolescent pigs. In this study, 12 (n=4 male and n=8 female) 16-weeks old Yucatan pigs were tested; n=6 received mTBI and n=6 received a Sham procedure. This study utilized T1-weighted imaging to assess volumetric alterations in different regions of the brain and diffusion tensor imaging (DTI) to examine microstructural damage in white matter. The pigs were imaged at one and three months post-injury. Our volumetric analysis of key white and gray matter regions showed significant longitudinal changes in pigs with mTBI compared to sham controls. The observed volume increases may be attributed to swelling, neuroinflammation, or hyperactivity. Fractional anisotropy (FA) values derived from DTI images demonstrated an increase in corpus callosum from 1 month to 3 months only in mTBI pigs. Additionally, comparisons of the left and right internal capsules revealed a decrease in FA in the right internal capsule for mTBI pigs, likely due to the impact being slightly localized to the right side of the brain, which may indicate demyelination. Thus, the injury has disrupted the maturation of white and gray matter of the developing brain. This signifies the need for longitudinal investigations after mTBI to comprehensively assess its long-term effects and contribute to the clinical management of concussion in youth.

bioengineering↗

bioRxiv2024

Basal p53 maintains a distinct transcriptional program from irradiated p53 in tissue, including tumor suppressors

The significance of p53s primary and secondary tumor suppressor programs cannot be overstated. A context- and stress-dependent transcription factor, p53 accumulates to mount its most well-characterized programs in response to a variety of stressors, most notably DNA damage. As cells and tissues never exist in a complete absence of stress, a small amount of p53 exists in cells under physiologic stress, detectable by chromatin immunoprecipitation and sequencing, termed basal p53. Recently, we and others have shown that basal p53 is sufficient to regulate tumor suppressor function. Furthermore, others have suggested the possibility that p53 accumulation in response to experimental stress may be dispensable for its tumor suppression. We previously showed basal p53 occupancy and regulation of known tumor suppressor genes, including PTEN and PHLDA3, in non-transformed breast cells, but this study was limited by experimental stress inherent to cell culture. Given the lack of global characterization of the basal p53 landscape under non-malignant physiologic stress in vivo, we utilized a multi-omics approach to define the murine basal p53 epigenome and its transcriptional program in various normal murine tissues. In this study, we observed basal p53 binding to cis regions of multiple tumor suppressor genes in different tissues, of which some showed p53-dependent regulation of their expression, including Phlda3, Bbc3, Xaf1, and itself. Furthermore, the vast majority of basal p53 target genes were not induced upon irradiation, suggesting basal p53 operates a transcriptional program that is largely distinct from its DNA damage response. Similarly, the basal p53 target gene repertoire is unique to each tissue type.

biochemistry↗