Biology subjects

Goodarzi, N.

Publications and source records attributed to Goodarzi, N..

4 recordsLinked to original sources

bioRxiv2026

Tau-induced elevation in promoter-proximal RNA polymerase II pausing is linked to decreased expression of long neuronal genes in a Drosophila tauopathy model.

Tauopathies, including Alzheimers disease, are age-related neurodegenerative disorders characterized by abnormal phosphorylation and buildup of microtubule-associated protein tau. Gene expression dysregulation is a key molecular feature of tauopathies, but how aging and disease interact to disrupt crucial transcriptional regulators and pathways remains largely unknown. Here, we examined how pathological tau affects gene expression programs in age-related neurodegenerative disease using a well-established Drosophila melanogaster tauopathy model with neuronal expression of the toxic human tauR406W. Transcriptomic analysis of tau-expressing fly heads showed a preferential downregulation of long neuronal genes with long introns. Notably, we found that these downregulated genes in the tauopathy model are marked by increased accumulation of initiating RNA polymerase II (RNAP II) near the transcription start site and reduced elongating RNAP II within gene bodies, indicating a problem with the transition from initiation to elongation. By calculating an RNAP II Pause Index (PI) for each gene, we identified a strong link between promoter-proximal RNAP II stalling, gene expression deficits, and gene length in the tauopathy model. Overall, we have uncovered the genomic and transcriptomic features of tau-dependent downregulated genes and identified increased RNAP II promoter-proximal stalling as a significant mechanism of transcription stress in tauopathy.

molecular biology↗

bioRxiv2024

Human-immune-system humanized-DRAGA mice are a valuable model to study novel immunotherapies for HIV-1

Humanized (h)DRAGA mice are a promising in vivo model for investigating immunotherapies for treating HIV infections. These mice are not only susceptible to HIV infection, but they also develop functional human immune cells, including T cells and B cells as well as follicular-like structures that mimic lymphoid B cell follicles, where HIV-producing cells concentrate during infection in a manner similar to that found in humans. This study evaluated the safety, tissue targeting, and efficacy of follicular-targeting HIV-specific chimeric antigen receptor (CAR)-T cells (CAR/CXCR5-T cells) in HIV-infected hDRAGA mice. Intravenously-infused CAR/CXCR5-T cells persisted in hDRAGA mice for the duration of the study, peaking six days post-infusion. This study indicated that CAR/CXCR5-T cell treatment is safe, with 100% survival rate of treated mice and no noticeable changes in pathology. Six days after infusion, CAR/CXCR5-T cells had accumulated in the follicle-like structures, with many appearing in direct contact with HIV-producing cells. However, CAR/CXCR5-T cell treatment did not appear to reduce viral loads compared to controls, perhaps because many of the engineered CAR/CXCR5-T cells were themselves infected with HIV, with some CAR/CXCR5-T cells showing evidence of HIV virion release. Future studies will investigate whether CAR/CXCR5-T cells engineered for resistance against HIV infection are effective in reducing viral loads. This study supports the approach of using the HIV-infected hDRAGA mouse model to test cellular immunotherapies for HIV, as the model recapitulates many aspects of HIV infection in human lymphoid follicles.

immunology↗

bioRxiv2023

Immune Evasion, Infectivity, and Fusogenicity of SARS-CoV-2 Omicron BA.2.86 and FLip Variants

Evolution of SARS-CoV-2 requires the reassessment of current vaccine measures. Here, we characterized BA.2.86 and the XBB-lineage variant FLip by investigating their neutralization alongside D614G, BA.1, BA.2, BA.4/5, XBB.1.5, and EG.5.1 by sera from 3-dose vaccinated and bivalent vaccinated healthcare workers, XBB.1.5-wave infected first responders, and monoclonal antibody (mAb) S309. We assessed the biology of the variant Spikes by measuring viral infectivity and membrane fusogenicity. BA.2.86 is less immune evasive compared to FLip and other XBB variants, consistent with antigenic distances. Importantly, distinct from XBB variants, mAb S309 was unable to neutralize BA.2.86, likely due to a D339H mutation based on modeling. BA.2.86 had relatively high fusogenicity and infectivity in CaLu-3 cells but low fusion and infectivity in 293T-ACE2 cells compared to some XBB variants, suggesting a potentially differences conformational stability of BA.2.86 Spike. Overall, our study underscores the importance of SARS-CoV-2 variant surveillance and the need for updated COVID-19 vaccines.

microbiology↗

bioRxiv2023

Immune Evasion and Membrane Fusion of SARS-CoV-2 XBB Subvariants EG.5.1 and XBB.2.3

Immune evasion by SARS-CoV-2 paired with immune imprinting from monovalent mRNA vaccines has resulted in attenuated neutralizing antibody responses against Omicron subvariants. In this study, we characterized two new XBB variants rising in circulation -- EG.5.1 and XBB.2.3, for their ability of neutralization and syncytia formation. We determined the neutralizing antibody in sera of individuals that received a bivalent mRNA vaccine booster, BA.4/5-wave infection, or XBB.1.5-wave infection. Bivalent vaccination-induced antibodies neutralized efficiently ancestral D614G, but to a much less extent, two new EG.5.1 and XBB.2.3 variants. In fact, the enhanced neutralization escape of EG.5.1 appeared to be driven by its key defining mutation XBB.1.5-F456L. Notably, infection by BA.4/5 or XBB.1.5 afforded little, if any, neutralization against EG.5.1, XBB.2.3 and previous XBB variants -- especially in unvaccinated individuals, with average neutralizing antibody titers near the limit of detection. Additionally, we investigated the infectivity, fusion activity, and processing of variant spikes for EG.5.1 and XBB.2.3 in HEK293T-ACE2 and CaLu-3 cells but found no significant differences compared to earlier XBB variants. Overall, our findings highlight the continued immune evasion of new Omicron subvariants and, more importantly, the need to reformulate mRNA vaccines to include XBB spikes for better protection.

immunology↗