Stem-like" TCF1 + CD8 + T cells (T SL ) are necessary for long-term maintenance of T cell responses and the efficacy of immunotherapy but, as tumors contain signals that should drive T-cell terminal-differentiation, how these cells are maintained in tumors remains unclear. In this study, we found that a small number of TCF1 + tumor-specific CD8 + T cells were present in lung tumors throughout their development. Yet, most intratumoral T cells differentiated as tumors progressed, corresponding with an immunologic shift in the tumor microenvironment (TME) from "hot" (T cell-inflamed) to "cold" (non-T cell-inflamed). By contrast, most tumor-specific CD8 + T cells in tumor-draining lymph nodes (dLNs) had functions and gene expression signatures similar to T SL from chronic LCMV infection, and this population was stable over time, despite the changes in the TME. dLN T cells were the developmental precursors of, and were clonally related to, their more differentiated intratumoral counterparts. Our data support the hypothesis that dLN T cells are the developmental precursors of the TCF1 + T cells in tumors which are maintained by continuous migration. Finally, CD8 + T cells similar to T SL were also present in LNs from lung adenocarcinoma patients, suggesting a similar model may be relevant in human disease. Thus, we propose that the dLN T SL reservoir has a critical function in sustaining antitumor T cells during tumor development and protecting them from the terminal differentiation that occurs in the TME.
The positioning of chromosomes in the nucleus of a eukaryotic cell is highly organized and has a complex and dynamic relationship with gene expression. In the human malaria parasite Plasmodium falciparum, the clustering of a family of virulence genes correlates with their coordinated silencing and has a strong influence on the overall organization of the genome. To identify conserved and species-specific principles of genome organization, we performed Hi-C experiments and generated 3D genome models for five Plasmodium species and two related apicomplexan parasites. Plasmodium species mainly showed clustering of centromeres, telomeres, and virulence genes. In P. falciparum, the heterochromatic virulence gene cluster had a strong repressive effect on the surrounding nuclear space, while this was less pronounced in Plasmodium vivax and Plasmodium berghei, and absent in Plasmodium yoelii. In Plasmodium knowlesi, telomeres and virulence genes were more dispersed throughout the nucleus, but its 3D genome showed a strong correlation with gene expression. The Babesia microti genome showed a classical Rabl organization with colocalization of subtelomeric virulence genes, while the Toxoplasma gondii genome was dominated by clustering of the centromeres and lacked virulence gene clustering. Collectively, our results demonstrate that spatial genome organization in most Plasmodium species is constrained by the colocalization of virulence genes. P. falciparum and P. knowlesi, the only two Plasmodium species with gene families involved in antigenic variation, are unique in the effect of these genes on chromosome folding, indicating a potential link between genome organization and gene expression in more virulent pathogens.
in the protist pathogen Toxoplasma gondii and related tissue coccidia A novel fragmented mitochondrial genome Genome Res. May , 2021 31: 823-833 Luisa Berná, Pablo Marquez, Andrés Cabrera, et al. rearrangements reveals misassembly, karyotype differences, and chromosomal Reevaluation of the Toxoplasma gondii and Neospora caninum genomes P
ObjectiveWe sought to understand how U.S. residents responded to COVID-19 as it emerged, and the extent to which spatial-temporal factors impacted response.Materials and MethodsWe mined and reverse-geocoded 269,556 coronavirus-related social media postings on Twitter from January 23rd to March 25th, 2020. We then ranked tweets based on the socioeconomic status of the county they originated from using the Area Deprivation Index (ADI); that we also used to identify areas with high initial disease counts (“hotspots”). We applied topic modeling on the tweets to identify chief concerns and determine their evolution over time. We also investigated how topic proportions varied based on ADI and between hotspots and non-hotspots.ResultsWe identified 45 topics, which shifted from early-outbreak-related content in January, to the presidential election and governmental response in February, to lifestyle changes in March. Highly resourced areas (low ADI) were concerned with stocks, social distancing, and national-level policies, while high ADI areas shared content with negative expression, prayers, and discussion of the CARES Act economic relief package. Within hotspots, these differences stand, with the addition of increased discussion regarding employment in high ADI versus low ADI hotspots.DiscussionTopic modeling captures the major concerns in COVID-19-related discussion on a social media platform in the early months of the pandemic. Our study extends previous studies that utilized topic modeling on COVID-19 related tweets and linked the identified topics to socioeconomic status using ADI. Comparisons between low and high ADI areas indicate differential Twitter discussions, corresponding to greater concern with economic hardship and impacts of the pandemic in less resourced communities, and less focus on general public health messaging.ConclusionThis work demonstrates a novel framework for assessing differential topics of conversation correlating to income, education, and housing disparities. This, with integration of COVID-19 hotspots, offers improved analysis of crisis response on Twitter. Such insight is critical for informed public health messaging campaigns in future waves of the pandemic, which should focus in part specifically on the interests of those who are most vulnerable in the lowest resourced health settings.
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