Browsing by Subject "Morphology"
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Item A Cataclysmorphic Prophecy(2021-05) Moore, Alex; Potter, William; Riede, Danielle; Winship, AndrewOur bodies and minds are incessantly morphing, driven by environmental stimuli. You could reduce the entire experience of being alive to simply being fluid and responsive. In considering the significance of this morphability, we should also consider the significance of “place”. This relationship with place is rooted in ecology, the branch of biology which deals with living things and their relationships with their physical surroundings. In my body of work I examine my own relationship with place, its effects on my identity, and my ability to morph.Item Correlation Analysis of Histopathology and Proteogenomics Data for Breast Cancer(American Society for Biochemistry and Molecular Biology, 2019-08-09) Zhan, Xiaohui; Cheng, Jun; Huang, Zhi; Han, Zhi; Helm, Bryan; Liu, Xiaowen; Zhang, Jie; Wang, Tian-Fu; Ni, Dong; Huang, Kun; Medicine, School of MedicineTumors are heterogeneous tissues with different types of cells such as cancer cells, fibroblasts, and lymphocytes. Although the morphological features of tumors are critical for cancer diagnosis and prognosis, the underlying molecular events and genes for tumor morphology are far from being clear. With the advancement in computational pathology and accumulation of large amount of cancer samples with matched molecular and histopathology data, researchers can carry out integrative analysis to investigate this issue. In this study, we systematically examine the relationships between morphological features and various molecular data in breast cancers. Specifically, we identified 73 breast cancer patients from the TCGA and CPTAC projects matched whole slide images, RNA-seq, and proteomic data. By calculating 100 different morphological features and correlating them with the transcriptomic and proteomic data, we inferred four major biological processes associated with various interpretable morphological features. These processes include metabolism, cell cycle, immune response, and extracellular matrix development, which are all hallmarks of cancers and the associated morphological features are related to area, density, and shapes of epithelial cells, fibroblasts, and lymphocytes. In addition, protein specific biological processes were inferred solely from proteomic data, suggesting the importance of proteomic data in obtaining a holistic understanding of the molecular basis for tumor tissue morphology. Furthermore, survival analysis yielded specific morphological features related to patient prognosis, which have a strong association with important molecular events based on our analysis. Overall, our study demonstrated the power for integrating multiple types of biological data for cancer samples in generating new hypothesis as well as identifying potential biomarkers predicting patient outcome. Future work includes causal analysis to identify key regulators for cancer tissue development and validating the findings using more independent data sets.Item CRMP2 Is Involved in Regulation of Mitochondrial Morphology and Motility in Neurons(MDPI, 2021-10-17) Brustovetsky, Tatiana; Khanna, Rajesh; Brustovetsky, Nickolay; Pharmacology and Toxicology, School of MedicineRegulation of mitochondrial morphology and motility is critical for neurons, but the exact mechanisms are unclear. Here, we demonstrate that these mechanisms may involve collapsin response mediator protein 2 (CRMP2). CRMP2 is attached to neuronal mitochondria and binds to dynamin-related protein 1 (Drp1), Miro 2, and Kinesin 1 light chain (KLC1). Treating neurons with okadaic acid (OA), an inhibitor of phosphatases PP1 and PP2A, resulted in increased CRMP2 phosphorylation at Thr509/514, Ser522, and Thr555, and augmented Drp1 phosphorylation at Ser616. The CRMP2-binding small molecule (S)-lacosamide ((S)-LCM) prevented an OA-induced increase in CRMP2 phosphorylation at Thr509/514 and Ser522 but not at Thr555, and also failed to alleviate Drp1 phosphorylation. The increased CRMP2 phosphorylation correlated with decreased CRMP2 binding to Drp1, Miro 2, and KLC1. (S)-LCM rescued CRMP2 binding to Drp1 and Miro 2 but not to KLC1. In parallel with CRMP2 hyperphosphorylation, OA increased mitochondrial fission and suppressed mitochondrial traffic. (S)-LCM prevented OA-induced alterations in mitochondrial morphology and motility. Deletion of CRMP2 with a small interfering RNA (siRNA) resulted in increased mitochondrial fission and diminished mitochondrial traffic. Overall, our data suggest that the CRMP2 expression level and phosphorylation state are involved in regulating mitochondrial morphology and motility in neurons.Item Identifying Factors Controlling Cell Shape and Virulence Gene Expression in Borrelia Burgdorferi(2019-08) Grothe, Amberly Nicole; Yang, X. Frank; Gilk, Stacey; Nelson, DavidLyme disease is a multi-system inflammatory disorder that is currently the fastest growing arthropod-borne disease in the United States. The Lyme disease pathogen, Borrelia burgdorferi, exists within an enzootic cycle consisting of Ixodes tick vectors and a variety of vertebrate hosts. Borrelia lies within a distinct clade of microorganisms known as spirochetes which exhibit a unique spiral morphology. The underlying genetic mechanisms controlling for borrelial morphologies are still being discovered. One flagellar protein, FlaB, has been indicated to affect both spiral shape and motility of the organisms and significantly impacts the organism’s ability to establish infection. Due to the potential connection between morphological characteristics and pathogenesis, we sought to screen and identify morphological mutants in an attempt to identify genes associated with morphological phenotypes of Borrelia burgdorferi. Among Borrelia’s unique features is the presence of abundant lipoproteins making up its cellular membrane as opposed to the typical lipopolysaccharides. These proteins confer a wide variety of functions to the microorganism, among which include the abilities to circulate between widely differing hosts and to establish infection. Two important outer surface proteins, OspC and OspA, are found to be inversely expressed throughout the borrelial life cycle. OspC, in particular, becomes highly expressed during tick-feeding and transmission to the mammalian host. It has been found to be essential for establishment of infection. A global regulatory pathway has been shown to control for OspC, however there are missing links in this pathway between the external stimuli (such as temperature, pH, and cell density) and the regulatory pathway. We have performed a screening process to identify OspC expression mutants in order to identify novel genes associated with this pathway.Item Involvement of CRMP2 in Regulation of Mitochondrial Morphology and Motility in Huntington’s Disease(MDPI, 2021-11-15) Brustovetsky, Tatiana; Khanna, Rajesh; Brustovetsky, Nickolay; Pharmacology and Toxicology, School of MedicineMitochondrial morphology and motility (mitochondrial dynamics) play a major role in the proper functioning of distant synapses. In Huntington's disease (HD), mitochondria become fragmented and less motile, but the mechanisms leading to these changes are not clear. Here, we found that collapsin response mediator protein 2 (CRMP2) interacted with Drp1 and Miro 2, proteins involved in regulating mitochondrial dynamics. CRMP2 interaction with these proteins inversely correlated with CRMP2 phosphorylation. CRMP2 was hyperphosphorylated in postmortem brain tissues of HD patients, in human neurons derived from induced pluripotent stem cells from HD patients, and in cultured striatal neurons from HD mouse model YAC128. At the same time, CRMP2 interaction with Drp1 and Miro 2 was diminished in HD neurons. The CRMP2 hyperphosphorylation and dissociation from Drp1 and Miro 2 correlated with increased fission and suppressed motility. (S)-lacosamide ((S)-LCM), a small molecule that binds to CRMP2, decreased its phosphorylation at Thr 509/514 and Ser 522 and rescued CRMP2's interaction with Drp1 and Miro 2. This was accompanied by reduced mitochondrial fission and enhanced mitochondrial motility. Additionally, (S)-LCM exerted a neuroprotective effect in YAC128 cultured neurons. Thus, our data suggest that CRMP2 may regulate mitochondrial dynamics in a phosphorylation-dependent manner and modulate neuronal survival in HD.Item Neurocognitive markers of childhood abuse in individuals with PTSD: Findings from the INTRuST Clinical Consortium(Elsevier, 2020-02-01) Bomyea, Jessica; Simmons, Alan N.; Shenton, Martha E.; Coleman, Michael J.; Bouix, Sylvain; Rathi, Yogesh; Pasternak, Ofer; Coimbra, Raul; Shutter, Lori; George, Mark S.; Grant, Gerald; Zafonte, Ross D.; McAllister, Thomas W.; Stein, Murray B.; Psychiatry, School of MedicineTo date, few studies have evaluated the contribution of early life experiences to neurocognitive abnormalities observed in posttraumatic stress disorder (PTSD). Childhood maltreatment is common among individuals with PTSD and is thought to catalyze stress-related biobehavioral changes that might impact both brain structure and function in adulthood. The current study examined differences in brain morphology (brain volume, cortical thickness) and neuropsychological performance in individuals with PTSD characterized by low or high self-reported childhood maltreatment, compared with healthy comparison participants. Data were drawn from the INjury and TRaUmatic STress (INTRuST) Clinical Consortium imaging repository, which contains MRI and self-report data for individuals classified as PTSD positive (with and without a history of mild traumatic brain injury [mTBI]), individuals with mTBI only, and healthy comparison participants. The final sample included 36 individuals with PTSD without childhood maltreatment exposure (PTSD, n = 30 with mTBI), 31 individuals with PTSD and childhood maltreatment exposure (PTSD + M, n = 26 with mTBI), and 114 healthy comparison participants without history of childhood maltreatment exposure (HC). The PTSD + M and PTSD groups demonstrated cortical thinning in prefrontal and occipital regions, and poorer verbal memory and processing speed compared to the HC group. PTSD + M participants demonstrated cortical thinning in frontal and cingulate regions, and poorer executive functioning relative to the PTSD and HC groups. Thus, neurocognitive features varied between individuals with PTSD who did versus did not have exposure to childhood maltreatment, highlighting the need to assess developmental history of maltreatment when examining biomarkers in PTSD.Item Prognostic stratification of glioblastoma patients by unsupervised clustering of morphology patterns on whole slide images furthering our disease understanding(Frontiers Media, 2024-05-20) Baheti, Bhakti; Innani, Shubham; Nasrallah, MacLean; Bakas, Spyridon; Pathology and Laboratory Medicine, School of MedicineIntroduction: Glioblastoma (GBM) is a highly aggressive malignant tumor of the central nervous system that displays varying molecular and morphological profiles, leading to challenging prognostic assessments. Stratifying GBM patients according to overall survival (OS) from H&E-stained whole slide images (WSI) using advanced computational methods is challenging, but with direct clinical implications. Methods: This work is focusing on GBM (IDH-wildtype, CNS WHO Gr.4) cases, identified from the TCGA-GBM and TCGA-LGG collections after considering the 2021 WHO classification criteria. The proposed approach starts with patch extraction in each WSI, followed by comprehensive patch-level curation to discard artifactual content, i.e., glass reflections, pen markings, dust on the slide, and tissue tearing. Each patch is then computationally described as a feature vector defined by a pre-trained VGG16 convolutional neural network. Principal component analysis provides a feature representation of reduced dimensionality, further facilitating identification of distinct groups of morphology patterns, via unsupervised k-means clustering. Results: The optimal number of clusters, according to cluster reproducibility and separability, is automatically determined based on the rand index and silhouette coefficient, respectively. Our proposed approach achieved prognostic stratification accuracy of 83.33% on a multi-institutional independent unseen hold-out test set with sensitivity and specificity of 83.33%. Discussion: We hypothesize that the quantification of these clusters of morphology patterns, reflect the tumor's spatial heterogeneity and yield prognostic relevant information to distinguish between short and long survivors using a decision tree classifier. The interpretability analysis of the obtained results can contribute to furthering and quantifying our understanding of GBM and potentially improving our diagnostic and prognostic predictions.Item Protective Effects of Estradiol and Dihydrotestosterone following Spinal Cord Injury(Mary Ann Liebert, 2018-03-15) Sengelaub, Dale R.; Han, Qi; Liu, Nai-Kui; Maczuga, Melissa A.; Szalavari, Violetta; Valencia, Stephanie A.; Xu, Xiao-Ming; Neurological Surgery, School of MedicineSpinal cord injury (SCI) results in lesions that destroy tissue and disrupt spinal tracts, producing deficits in locomotor and autonomic function. We previously demonstrated that motoneurons and the muscles they innervate show pronounced atrophy after SCI, and these changes are prevented by treatment with testosterone. Here, we assessed whether the testosterone active metabolites estradiol and dihydrotestosterone have similar protective effects after SCI. Young adult female rats received either sham or T9 spinal cord contusion injuries and were treated with estradiol, dihydrotestosterone, both, or nothing via Silastic capsules. Basso-Beattie-Bresnahan locomotor testing was performed weekly and voiding behavior was assessed at 3 weeks post-injury. Four weeks after SCI, lesion volume and tissue sparing, quadriceps muscle fiber cross-sectional area, and motoneuron dendritic morphology were assessed. Spontaneous locomotor behavior improved after SCI, but hormone treatments had no effect. Voiding behavior was disrupted after SCI, but was significantly improved by treatment with either estradiol or dihydrotestosterone; combined treatment was maximally effective. Treatment with estradiol reduced lesion volume, but dihydrotestosterone alone and estradiol combined with dihydrotestosterone were ineffective. SCI-induced decreases in motoneuron dendritic length were attenuated by all hormone treatments. SCI-induced reductions in muscle fiber cross-sectional areas were prevented by treatment with either dihydrotestosterone or estradiol combined with dihydrotestosterone, but estradiol treatment was ineffective. These findings suggest that deficits in micturition and regressive changes in motoneuron and muscle morphology seen after SCI are ameliorated by treatment with estradiol or dihydrotestosterone, further supporting a role for steroid hormones as neurotherapeutic agents in the injured nervous system.Item Protective effects of gonadal hormones on spinal motoneurons following spinal cord injury(Medknow Publications, 2018-06) Sengelaub, Dale R.; Xu, Xiao-Ming; Neurological Surgery, School of MedicineSpinal cord injury (SCI) results in lesions that destroy tissue and disrupt spinal tracts, producing deficits in locomotor and autonomic function. The majority of treatment strategies after SCI have concentrated on the damaged spinal cord, for example working to reduce lesion size or spread, or encouraging regrowth of severed descending axonal projections through the lesion, hoping to re-establish synaptic connectivity with caudal targets. In our work, we have focused on a novel target for treatment after SCI, surviving spinal motoneurons and their target musculature, with the hope of developing effective treatments to preserve or restore lost function following SCI. We previously demonstrated that motoneurons, and the muscles they innervate, show pronounced atrophy after SCI. Importantly, SCI-induced atrophy of motoneuron dendrites can be attenuated by treatment with gonadal hormones, testosterone and its active metabolites, estradiol and dihydrotestosterone. Similarly, SCI-induced reductions in muscle fiber cross-sectional areas can be prevented by treatment with androgens. Together, these findings suggest that regressive changes in motoneuron and muscle morphology seen after SCI can be ameliorated by treatment with gonadal hormones, further supporting a role for steroid hormones as neurotherapeutic agents in the injured nervous system.Item Topographic organization underlies intrinsic andmorphological heterogeneity of central amygdala neurons expressing corticotropin-releasing hormone(Wiley, 2022) Li, Jun-Nan; Chen, Kevin; Sheets, Patrick L.; Pharmacology and Toxicology, School of MedicineThe central nucleus of the amygdala (CeA) network consists of a heterogeneous population of inhibitory GABAergic neurons distributed across distinct subregions. While the specific roles for molecularly defined CeA neurons have been extensively studied, our understanding of functional heterogeneity within classes of molecularly distinct CeA neurons remains incomplete. In addition, manipulation of genetically defined CeA neurons has produced inconsistent behavioral results potentially due to broad targeting across CeA subregions. Therefore, elucidating heterogeneity within molecularly defined neurons in subdivisions of the CeA is pivotal for gaining a complete understanding of how CeA circuits function. Here, we used a multifaceted approach involving transgenic reporter mice, brain slice electrophysiology, and neuronal morphology to dissect the heterogeneity of corticotropin‐releasing hormone (CRH) neurons in topographically distinct subregions of the CeA. Our results revealed that intrinsic and morphological properties of CRH‐expressing (CRH+) neurons in the lateral (CeL) and medial (CeM) subdivisions of the CeA were significantly different. We found that CeL‐CRH+ neurons are relatively homogeneous in morphology and firing profile. Conversely, CeM‐CRH+ neurons displayed heterogeneous electrophysiological and morphological phenotypes. Overall, these results show phenotypic differences between CRH+ neurons in CeL and CeM.