Immune phenotypes and target antigens of clonally expanded bone marrow T cells in treatment-naïve multiple myeloma

Multiple myeloma is a hematologic malignancy of monoclonal plasma cells that accumulate in the bone marrow. Despite their clinical and pathophysiological relevance, the roles of bone marrow infiltrating T cells in treatment-naïve patients are incompletely understood. We investigated whether clonally expanded T cells i) were detectable in multiple myeloma bone marrow, ii) showed characteristic immune phenotypes, and iii) whether dominant clones recognized antigens selectively presented on multiple myeloma cells. Single-cell index sorting and T-cell receptor (TCR)αβ sequencing of bone marrow T cells from 13 treatment-naïve patients showed dominant clonal expansion within CD8+ cytolytic effector compartments, and only a minority of expanded T-cell clones expressed the classical immune checkpoint molecules PD 1, CTLA 4, or TIM 3. To identify their molecular targets, TCRs of 68 dominant bone marrow clones from five selected patients were re-expressed and incubated with multiple myeloma and non multiple myeloma cells from corresponding patients. Only one out of 68 TCRs recognized antigen presented on multiple myeloma cells. This TCR was HLA-C-restricted, self-peptide-specific, and could be activated by multiple myeloma cells of multiple patients. The remaining dominant T-cell clones did not recognize multiple myeloma cells and were, in part, specific for antigens associated with chronic viral infections. In conclusion, we showed that dominant bone marrow T-cell clones in treatment naïve patients rarely recognize antigens presented on multiple myeloma cells and exhibit low expression of classical immune checkpoint molecules. Our data provide experimental context for experiences from clinical immune checkpoint inhibition trials and will inform future T cell-dependent therapeutic strategies

Transcriptomic profiling of SARS-CoV-2 infected human cell lines identifies HSP90 as target for COVID-19 therapy

Detailed knowledge of the molecular biology of SARS-CoV-2 infection is crucial for understanding of viral replication, host responses and disease progression. Here, we report gene expression profiles of three SARS-CoV and SARS-CoV-2 infected human cell lines. SARS-CoV-2 elicited an approximately two-fold higher stimulation of the innate immune response compared to SARS-CoV in the human epithelial cell line Calu-3, including induction of miRNA-155. Single-cell RNA sequencing of infected cells showed that genes induced by virus infections were broadly upregulated, whereas interferon beta/lambda genes an pro-inflammatory cytokines such as IL-6 were expressed only in small subsets of infected cells. Temporal analysis suggested that transcriptional activities of interferon regulatory factors precede those of nuclear factor κB. Lastly, we identified heat shock protein 90 (HSP90) as a protein relevant for the infection. Inhibition of the HSP90 activity resulted in a reduction of viral replication and pro-inflammatory cytokine expression in primary human airway epithelial cells

Stress modulation as a means to improve yeasts for lignocellulose bioconversion

The second-generation (2G) fermentation environment for lignocellulose conversion presents unique challenges to the fermentative organism that do not necessarily exist in other industrial fermentations. While extreme osmotic, heat, and nutrient starvation stresses are observed in sugar- and starch-based fermentation environments, additional pre-treatment-derived inhibitor stress, potentially exacerbated by stresses such as pH and product tolerance, exist in the 2G environment. Furthermore, in a consolidated bioprocessing (CBP) context, the organism is also challenged to secrete enzymes that may themselves lead to unfolded protein response and other stresses. This review will discuss responses of the yeast Saccharomyces cerevisiae to 2G-specific stresses and stress modulation strategies that can be followed to improve yeasts for this application. We also explore published –omics data and discuss relevant rational engineering, reverse engineering, and adaptation strategies, with the view of identifying genes or alleles that will make positive contributions to the overall robustness of 2G industrial strains

Remembering our town: social memory, folklore, and (trans) locality in three ethnic neighborhoods in Boston

Thesis (Ph.D.)--Boston UniversityPLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at [email protected]. Thank you.Through case studies of three Boston-area neighborhoods, East Boston, South Boston, and North Quincy, this dissertation examines the vernacular memory practices of the residents of historically ethnic neighborhoods to show the ways in which everyday representations of the past allow individuals to strategically negotiate a meaningful sense of shared identity. Using field interviews, vernacular digital sources, previously recorded oral histories, amateure historical texts, memoirs, and other expressive memory works, this study examines locally produced representations of historical identity that range from the social imagining of translocal past to personal memories of neighborhood life that are deeply rooted in an understanding of local space as ethnic place. Chapters One through Three trace the scholarly literature on space and place, social memory, and folklore studies in order to demonstrate the way in which, through a process of selection and emphasis, local folk histories have often been used to strategically reaffirm the connection between contested spaces and a certain ethnic identity. They further show how individuals use their own personal narrative repertoire to situate themselves within these traditionalized or naturalized understandings of neighborhood space. Chapters Four and Five explore a variety of contests and conflicts over the traditionalized sense of space and place examined in the initial chapters. Developing the notion that cultural symbols, such as the shamrock or the flag of the People's Republic of China, and practices, such as the celebrations surrounding Columbus Day or the Autumn Moon Festival, can bring together or "index" a variety of identity constructs, these chapters demonstrate the ways that these symbols can be strategically deployed in order to build or disrupt traditionalized understandings of the connections between neighborhoods and ethnic identity. Finally, Chapter Six suggests that, as a result of the emerging vernacular use of geospatial media technologies, the cultural symbols, narratives, and practices that are integral to the construction of local conceptual maps can now be accessed virtually. This makes available the possibility that meaningful local identities can be formed by actors who are interacting with these traditional understandings of local place virtually but who are not physically present in local spaces.2031-01-0

mRNAs, proteins and the emerging principles of gene expression control

Gene expression involves transcription, translation and the turnover of mRNAs and proteins. The degree to which protein abundances scale with mRNA levels and the implications in cases where this dependency breaks down remain an intensely debated topic. Here we review recent mRNA-protein correlation studies in the light of the quantitative parameters of the gene expression pathway, contextual confounders and buffering mechanisms. Although protein and mRNA levels typically show reasonable correlation, we describe how transcriptomics and proteomics provide useful non-redundant readouts. Integrating both types of data can reveal exciting biology and is an essential step in refining our understanding of the principles of gene expression control

Navigating Crisis and Chronicity in the Everyday: Former Child Soldiers in Urban Sierra Leone

The aftermath of war is typically referred to as ‘post-conflict’, often insinuating a stage of relative calm following a period of armed violence, upheaval and strife. However, the assumption that the post-war context brings forth peace, prosperity and stability negates the reality that conflict, violence and poverty may become embedded in the post-war social fabric. Following its decade long civil war, Sierra Leone continues to contend with a political, social and economic reality marked by widespread poverty, violence, and devastated health and social service systems, highlighting that for many, ‘crisis’ has in fact become chronic and endemic in the post-war period. Drawing on interviews with 11 former child soldiers living in an urban settlement, this article underscores the blurred distinction between periods of war and peace. Moreover, using the concept of social navigation, the paper explores the strategies the youth deliberately and tactfully employed in negotiating a volatile post-conflict terrain. Their narratives reveal their active, rather than passive, efforts in fostering their own social, economic and physical wellbeing in light of ever-changing, and unstable circumstances

Addressing Marginality and Exclusion: The Resettlement Experiences of War-Affected Young People in Quebec, Canada

Accessing meaningful forms of support can be an onerous experience for young people resettling from war-affected contexts. In addition to facing linguistic and financial barriers in this process, these young people negotiate care systems that are often structurally and culturally insensitive to their unique needs, values, beliefs, and intersectional experiences of oppression. Drawing on interviews with 22 young people from war-affected areas living in Quebec, Canada, this paper critically examines how dominant cultural norms and social relations in Quebec’s health, social and educational services network shape their experiences in seeking care, healing and belonging. Alternative care systems and approaches, as proposed by the participants, are then explored. The findings emphasize the need for spaces and care services where war-affected young people’s identities and lived realities are validated and represented