Biology subjects

Warner, A.

Publications and source records attributed to Warner, A..

6 recordsLinked to original sources

bioRxiv2026

The Regional Vulnerability Index (RVI) as a Neuroimaging-Based Biomarker for Autism: Associations with Likelihood, Cognition, and Longitudinal Social Outcomes

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with symptoms spanning cognitive, social and behavioral domains and leading to lifelong challenges. Autism is heritable but specific genetic and environmental factors that shape its early neurodevelopmental trajectory remain unknown. Despite the clinical variability, neuroimaging findings from Enhancing Neuro Imaging Genetics through Meta Analysis (ENIGMA)-ASD consortium identified stable and replicable patterns of cortical and subcortical differences that were consistent with those reported by an independent consortium, the Cognitive Genetics Collaborative Research Organization (COCORO) in Japan. Here we developed and evaluated a regional vulnerability index (RVI), a similarity metric that quantifies how closely a persons brain resembles the specific pattern of an individual with autism. RVI-ASD is based on combining the regional effect sizes for regional brain measurements published by the ENIGMA-ASD group with microstructural white matter integrity differences reported by COCORO. RVI-ASD showed significantly higher effect size for case-control differences relative to any individual brain measure (d=0.30 vs. d=0.01-0.21) in individuals with autism, particularly in the adolescent-to-adult sample (N=2,577; Mean age = 16.1; SD=5.0). We next calculated RVI-ASD in the baseline and follow-up (ages 10 and 12) data from normally developing participants of the ABCD study (N=4,201). We tested the longitudinal stability, heritability, genotype-by-age interaction and sensitivity of RVI-ASD to known factors and cognitive measurements. RVI-ASD were stable on the 2-year follow up (ICC=0.76-0.92); showed significant heritability (h{superscript 2}=0.55-0.83, p<10-16) but was not affected by gene-by-age interaction. RVI-ASD showed significant positive correlation with paternal age, while correlation with maternal age was non-significant. Baseline and follow-up RVI-ASD were negatively correlated with cognitive measures including total, fluid and crystallized intelligence (r=-0.09 to -0.11, p<10-6). RVI-ASD scores tracked with core autism phenotypes including poor eye contact and rigid routines (p < .01). In a sub-sample of children with symptoms of autism (N=20), we found that earlier age of symptom onset was strongly correlated with higher White Matter RVI (r = -0.61), linking early behavioral emergence to the neuroanatomical signature. Longitudinal changes in subcortical RVI-ASD are significantly correlated with change in social functioning. The RVI-ASD is a neuroimaging-based biomarker linked to stable and reproducible brain patterns in autism. RVI-ASD allows researchers to study associations with factors associated with the likelihood for autism and cognition across large and inclusive non-clinical samples, thus moving beyond simple case-control models to understand the biological pathways of autism.

neuroscience↗

bioRxiv2024

The Elevated Expression of ORF75, a Lytic KSHV Gene, in Kaposi Sarcoma Lesions is Driven by a GC-rich DNA cis Element in its Promoter Region

The spindle cells of Kaposi sarcoma (KS) lesions primarily express Kaposi sarcoma herpesvirus (KSHV) latent genes with minimal expression of lytic genes. However, recent transcriptome analyses of KS lesions have shown high expression of KSHV open reading frame (ORF) 75, which is considered a late lytic gene based on analyses in primary effusion lymphoma (PEL) lines. ORF75 encodes a pseudo-amidotransferase that is part of the viral tegument, acts as a suppressor of innate immunity, and is essential for viral lytic replication. We assessed a representative KS lesion by RNAscope and found that ORF75 RNA was expressed in the majority of latency-associated nuclear antigen (LANA)-expressing cells. Luciferase fusion reporter constructs of the ORF75 promoter were analyzed for factors potentially driving its expression in KS. The ORF75 promoter construct showed high basal transcriptional activity in vitro in endothelial cells, mediated by a proximal consensus specificity protein 1 (Sp1) (GGGGCGGGGC) element along with two distal CCAAT boxes. Sp proteins formed complexes with the proximal consensus Sp1 element to activate ORF75 promoter transcription. We also found evidence that a repressive factor or factors in B cells, but not endothelial or epithelial cells, interacted with more distal elements in the ORF75 promoter region to repress constitutive ORF75 expression in B cells. Alternate forms of Sp1 were found to accumulate during latency and showed substantial enrichment during viral lytic replication in PEL cells and infected endothelial cells, but their functional significance is unclear. We also found that ORF75 can in turn upregulate its own expression and that of other KSHV genes. Thus, while ORF75 acts primarily as a lytic gene in PEL cell lines, Sp proteins induce substantial constitutive ORF75 transcription in infected endothelial cells and this can account for its high expression in KS lesions. Author SummaryIn our study, we explored KSHV ORF75, a tegument protein that is increasingly being appreciated as playing a vital role in KSHV replication and inactivating the innate immune response. ORF75 is characterized as a late lytic protein but has been recently found to be consistently expressed in Kaposis sarcoma (KS) lesions, which generally express only latent KSHV genes. Our findings reveal that ORF75 is constitutively expressed in endothelial and epithelial cells, and to a lesser extent B-cells. We found that constitutive expression of ORF75 is largely mediated by specificity (Sp) proteins binding to a proximal Sp1 site in the ORF75 promoter region. Moreover, we found that the lower expression of ORF75 in KSHV-infected B cells is due to suppressive factors acting at a more distal region of the ORF75 promoter. We further found that ORF75 can enhance expression of its own RNA as well as that of several other KSHV proteins, including replication and transcription activator (RTA) and latency associated nuclear antigen (LANA). This constitutive expression of ORF75, a late lytic gene, can explain how it can play such an important role in the earlier steps in KSHV lytic activation and underscores the importance of this gene.

microbiology↗

bioRxiv2022

NOS2 and COX2 Blockade Limits TNBC Disease Progression and Alters CD8+ T Cell Spatial Orientation and Density

Anti-tumor immune polarization is a key predictor of clinical outcomes to cancer therapy. An emerging concept influencing clinical outcome involves the spatial location of CD8+ T cells, within the tumor. Our earlier work demonstrated immunosuppressive effects of NOS2/ COX2 tumor expression. Here, we show that NOS2/COX2 levels influence the polarization and spatial location of lymphoid cells including CD8+ T cells. Importantly, elevated tumor NOS2/COX2 correlated with exclusion of CD8+ T cells from the tumor epithelium. In contrast, tumors expressing low NOS2/COX2 had increased CD8+ T cell penetration into the tumor epithelium. Consistent with a causative relationship between these observations, pharmacological inhibition of COX2 with indomethacin dramatically reduced tumor growth of the 4T1 model of TNBC in both WT and Nos2-/- mice. This regimen led to complete tumor regression in [~]20% of tumor-bearing Nos2-/- mice, and these animals were resistant to tumor rechallenge. Th1 cytokines were elevated in the blood of treated mice and intratumoral CD4+ and CD8+ T cells were higher in mice that received indomethacin when compared to control untreated mice. Multiplex immunofluorescence imaging confirmed our phenotyping results and demonstrated that targeted Nos2/Cox2 blockade improved CD8+ T cell penetration into the 4T1 tumor core. These findings are consistent with our observations in low NOS2/COX2 expressing breast tumors` proving that COX2 activity is responsible for limiting the spatial distribution of effector T cells in TNBC. Together these results suggest that clinically available NSAIDs may provide a cost-effective, novel immunotherapeutic approach for treatment of aggressive tumors including triple negative breast cancer.

cancer biology↗

bioRxiv2022

Transcriptional analysis identifies overlapping and tissue-distinct profiles between Kaposi sarcoma tumors of the skin and gastrointestinal tract

Kaposi sarcoma (KS), caused by Kaposi sarcoma herpesvirus (KSHV), is a multicentric tumor characterized by abnormal vasculature and proliferation of KSHV-infected spindle cells. KS commonly involves the skin but in severe cases KS can also involve the gastrointestinal tract (GI). Here, we sought to compare the cellular and KSHV gene expression signatures of skin and GI KS lesions. Skin and GI KS were compared to normal matched samples using bulk RNA sequencing.Twenty-two paired samples of KS and normal tissue were obtained (skin (10 pairs) and GI (12 pairs)) from 19 patients with KS of whom 17 had concurrent HIV infection. Seven paired samples were from patients who had received prior KS therapy. Three patients provided both skin and GI samples at the same timepoint. These analyses identified 370 differentially expressed genes unique to cutaneous KS and 58 DEGs unique to GI KS compared to normal skin or GI tissues. Twenty-six differentially expressed genes overlapped between skin and GI KS, which included FLT4, which encodes for a VEGF-C and VEGF-D receptor, and STC1. KSHV infection of primary lymphatic endothelial cells (LECs) resulted in increased angiogenesis, and repression of STC1 or FLT4 inhibited angiogenesis. The analyses of KSHV expression from KS lesions identified certain lytic genes, specifically ORF75, that were consistently expressed, and these expression patterns differed from laboratory infection of LECs with KSHV and KSHV gene expression in PEL cell lines. This study demonstrates that complex patterns of gene expression are found in KS tissue that differ from the canonical latent/lytic programs seen in KSHV cell lines and also demonstrates differences in viral gene and clinically relevant host gene expression in skin and GI KS that may offer insights into the pathogenesis of these forms of KS. One sentence summaryKaposi sarcoma that manifests in the skin and gastrointestinal tracts differ by human and viral gene expression.

microbiology↗

bioRxiv2019

Cdc48/VCP and endocytosis regulate TDP-43 and FUS toxicity and turnover

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease. TDP-43 (TAR DNA-binding protein 43) and FUS (fused in sarcoma) are aggregation-prone RNA-binding proteins that in ALS can mis-localize to the cytoplasm of affected motor neuron cells, often forming cytoplasmic aggregates in the process. Such mis-localization and aggregation are implicated in ALS pathology, though the mechanisms of TDP-43 and FUS cytoplasmic toxicity remains unclear. Recently, we determined that the endocytic function aids turnover of TDP-43 and reduces TDP-43 toxicity. Here, we identified that Cdc48 and Ubx3, a Cdc48 co-factor implicated in endocytic function, regulates the turnover and toxicity of TDP-43 and FUS expressed in S. cerevisiae. Cdc48 physically interacts and co-localizes with TDP-43, as does VCP in ALS patient tissue. In yeast, FUS toxicity also depends strongly on endocytic function, but not autophagy under normal conditions. FUS expression also impairs endocytic function, as previously observed with TDP-43. Taken together, our data identifies a role for Cdc48/VCP and endocytosis function in regulating TDP-43 and FUS toxicity and turnover. Furthermore, endocytic dysfunction may be a common defect affecting cytoplasmic clearance of ALS aggregation-prone proteins and may represent a novel therapeutic target of promise.

molecular biology↗

bioRxiv2019

A High-Resolution Head and Brain Computer Model for Forward and Inverse EEG Simulation

To conduct computational forward and inverse EEG studies of brain electrical activity, researchers must construct realistic head and brain computer models, which is both challenging and time consuming. The availability of realistic head models and corresponding imaging data is limited in terms of imaging modalities and patient diversity. In this paper, we describe a detailed head modeling pipeline and provide a high-resolution, multimodal, open-source, female head and brain model. The modeling pipeline specifically outlines image acquisition, preprocessing, registration, and segmentation; three-dimensional tetrahedral mesh generation; finite element EEG simulations; and visualization of the model and simulation results. The dataset includes both functional and structural images and EEG recordings from two high-resolution electrode configurations. The intermediate results and software components are also included in the dataset to facilitate modifications to the pipeline. This project will contribute to neuroscience research by providing a high-quality dataset that can be used for a variety of applications and a computational pipeline that may help researchers construct new head models more efficiently.

bioengineering↗