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BACKGROUNDMeasuring the immune response to SARS-CoV-2 enables assessment of past infection and protective immunity. SARS-CoV-2 infection induces humoral and T cell responses, but these responses vary with disease severity and individual characteristics.METHODSA T cell receptor (TCR) immunosequencing assay was conducted using small-volume blood samples from 302 individuals recovered from COVID-19. Correlations between the magnitude of the T cell response and neutralizing antibody (nAb) titers or indicators of disease severity were evaluated. Sensitivity of T cell testing was assessed and compared with serologic testing.RESULTSSARS-CoV-2-specific T cell responses were significantly correlated with nAb titers and clinical indicators of disease severity, including hospitalization, fever, and difficulty breathing. Despite modest declines in depth and breadth of T cell responses during convalescence, high sensitivity was observed until at least 6 months after infection, with overall sensitivity ~5% greater than serology tests for identifying prior SARS-CoV-2 infection. Improved performance of T cell testing was most apparent in recovered, nonhospitalized individuals sampled > 150 days after initial illness, suggesting greater sensitivity than serology at later time points and in individuals with less severe disease. T cell testing identified SARS-CoV-2 infection in 68% (55 of 81) of samples with undetectable nAb titers (<1:40) and in 37% (13 of 35) of samples classified as negative by 3 antibody assays.CONCLUSIONThese results support TCR-based testing as a scalable, reliable measure of past SARS-CoV-2 infection with clinical value beyond serology.TRIAL REGISTRATIONSpecimens were accrued under trial NCT04338360 accessible at clinicaltrials.gov.FUNDINGThis work was funded by Adaptive Biotechnologies, Frederick National Laboratory for Cancer Research, NIAID, Fred Hutchinson Joel Meyers Endowment, Fast Grants, and American Society for Transplantation and Cell Therapy.

Circulation within a body of water controls not only fluid transport, but just as importantly, chemical, biological, and sedimentological constituents. Transport and dispersal of these constituents is of major concern when it comes to the proper management of rivers, bays, lakes, and nearshore communities, however, most students fail to realize the complexities related to the forcing of this flow field or its variability over time. Through the use of very basic tools, students having access to a small research vessel would be able to map surface and deeper circulation of a small region within a given water body (for ease, “lake” will be used from here on even though it implies any region of interest). Meteorological data will be used to look at the effects of wind forcing while bathymetric information can provide aspects of topographic control. The acquisition of these data during repeated cruises will lead to a better understanding of mean circulation and its variability.

Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas. ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1·8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1·4 mg/m2 and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152. Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48·2 months (95% CI 35·2–not evaluable) in the A+CHP group and 20·8 months (12·7–47·6) in the CHOP group (hazard ratio 0·71 [95% CI 0·54–0·93], p=0·0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group. Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile. Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center.

BackgroundEffective T-cell-mediated anti-tumor activity requires signaling through both the TCR and co-stimulatory receptors. While CD3 bispecific antibodies have shown success in hematologic malignancies, efficacy in solid tumors has been limited, partly due to T-cell exhaustion within the immunosuppressive tumor microenvironment (TME). CD28 co-stimulation is essential for sustained T-cell function and prevention of exhaustion, but non-targeted systemic CD28 activation is toxic in humans. RNDO-564 is a novel, first-in-class CD28 x Nectin-4 bispecific antibody designed to deliver tumor localized co-stimulation within Nectin-4-expressing tumors (figure 1). Nectin-4 is overexpressed in multiple epithelial cancers, including metastatic urothelial carcinoma (mUC). By utilizing tumor-targeted CD28 agonism, RNDO-564 aims to boost anti-tumor T-cell responses while avoiding systemic toxicity.MethodsWe evaluated RNDO-564, an IgG-like bispecific antibody composed of a potency-optimized CD28 binding domain and a high-affinity Nectin-4 binding domain, using in vitro assays with primary human T cells and Nectin-4-positive tumor cells. We conducted mechanistic studies with chronically stimulated T cells to assess the ability of RNDO-564 to restore activity of dysfunctional T cells and with co-culture models to evaluate the potential for bystander killing of Nectin-4-negative tumor cells. We tested in vivo efficacy in a syngeneic mouse model and safety, pharmacokinetics, and immunophenotyping in cynomolgus monkeys.ResultsRNDO-564 induced potent, Nectin-4-dependent co-stimulation, enhancing cytotoxicity and cytokine release in T cells in the presence of TCR stimulation. CD28 agonism rescued dysfunctional T cells, restoring effector function, activation and proliferation. We observed bystander killing of Nectin-4-negative tumor cells, supporting the potential for treating tumors with heterogenous Nectin-4 expression. RNDO-564 induced in vivo dose-dependent tumor growth inhibition as a monotherapy and in combination with PD-1 blockade. Cynomolgus studies confirmed a favorable safety profile with no systemic T-cell activation.ConclusionsRNDO-564 elicits robust Nectin-4-dependent in vitro and in vivo anti-tumor efficacy with a clean safety profile in non-human primates. Mechanistic data highlights its potential to restore T-cell function and overcome tumor antigen heterogeneity. A Phase 1, first-in-human, dose-escalation study in mUC and other Nectin-4-expressing tumors is ongoing.Ethics ApprovalCynomolgus study was approved and designated an IACUC number D16-00594 (A4112-01).Abstract 889 Figure 1Costimulatory bispecific, RNDO-564, for immune primed tumors[Image Omitted. See PDF.]

Ecosystems and societies face increasing pressures from global change, including climate and land use changes. Subsequent impacts to ecosystems are compounded through the interactions, dependencies, and feedbacks with human systems (i.e. social-ecological systems). The interdependence of ecosystems and society is manifested through the invaluable contributions that nature provides to people, commonly referred to as ecosystem services. As climate change alters the structure and functioning of ecosystems, there are corresponding impacts on ecosystem services, consequently impacting human well-being. While climate change impacts on ecosystems are well studied, the subsequent impacts on the services they provide to people are less understood, especially in the case of the non-material benefits people derive from nature (i.e. cultural ecosystem services). Thus, we lack a holistic understanding of the implications of climate change on human well-being. My dissertation draws on a multitude of disciplines to unveil and test innovative methods, tools, and data to overcome historical limitations in studying cultural ecosystem services and assess their vulnerability to climate change. Specifically, I focus on using social sensing data (i.e. sensing/data collected from humans and/or their devices) and machine learning to map, model, and value climate change impacts on cultural ecosystem services in a holistic social-ecological fashion and in understudied data-poor regions of the world. Ultimately, this work develops and tests new approaches to accounting for the non-material benefits of nature to people in order to create a more comprehensive understanding of how climate change will impact human well-being.The first chapter of this dissertation systematically reviews the literature to assess how machine learning and big data are being used in ecosystem service research to overcome major gaps in the field. I find that although cultural ecosystem services are understudied across the general literature, studies that are starting to incorporate these tools are able to address historical limitations to better account for the subjectivity, nonlinearity, and complexity of cultural ecosystem services. The second chapter develops and tests new methods, informed by the insights of chapter one, using machine learning (Random Forest) and social sensing data (Flickr) to map recreational ecosystem services across California, model the social-ecological drivers of recreation, and model the future impacts of climate change on recreation. I find that the social sensing data effectively represents recreational ecosystem service patterns across the landscape. This allowed me to use machine learning (i.e. Random Forest) to connect ecosystem service use to social-ecological drivers, showing access to cultural ecosystem service supply and climate play significant roles in driving flows to people. Further, our machine learning model predicts that climate change will exacerbate peak season recreational patterns, with highly popular regions becoming more suitable for cultural ecosystem service use and vice versa. The third chapter expands on this methodology to test its use at a large scale in a historically understudied and data-poor region. Social sensing data from eBird is used to represent the use of cultural ecosystem services across the continent of Africa, Random Forest is used to explore the social-ecological drivers of cultural ecosystem services, and Maximum Entropy Modeling is used to map cultural ecosystem service suitability and predict future suitability. I find that social sensing data from eBird is a globally available and effective proxy for cultural ecosystem service use. Further, I find that climate change will increasingly constrain the flow of cultural ecosystem services to people across Africa, with biodiversity change also playing a large role, and land use change playing a much more moderate role. Overall, I demonstrate how these tools, data, and methods can be utilized to scale and implement the study of ecosystem service flows and future impacts to them across the world. The fourth chapter expands on chapter three by integrating environmental economics methods to value the non-market utility of cultural ecosystem services and future impacts. I use social sensing data from the eBird citizen science project, machine learning (i.e. Maximum Entropy modeling), and econometric methods (i.e. the travel cost method) to map, model, and value current and future birding cultural ecosystem services across a biodiversity hotspot, South Africa. Leveraging social sensing data, I reveal national patterns of birding-related cultural ecosystem servcies and identify the beneficiaries, enabling the valuation of non-market ecosystem service demand. Additionally, through using both the social sensing data and Maximum Entropy modeling, I discern variations in the value of cultural ecosystem services, the social-ecological drivers, and the differential effects of anticipated climate, biodiversity, and land cover changes on domestic and international beneficiaries. This analysis and valuation showcases the potential of emerging data and tools to enhance and scale more holistic social-ecological analyses that account for non-market non-material ecosystem service value, improving the integration of ecosystem services in management and policy for a future shaped by global change.

Based primarily on reports filed by Paris's 48 'commissaires de police,' Luckett seeks to understand the origins of French revolutionary militancy by examining one of the earliest riots of 1787, which he calls the 'Tonneau riot.' It took place in and around the Rue St-Honore on the evening of Aug 20, 1787. Luckett contends that the riots of 1787-88, of which the Tonneau serves as a typical example, form an integral part of the Revolution since they laid the groundwork for the popular violence that followed.

Cytomegalovirus (CMV) causes serious infection in individuals with deficient T cell immunity. In acquired immunodeficiency syndrome, the retina is a major site of progressive infection, despite the availability of therapy that targets CMV. The administration of highly active antiretroviral therapy to suppress human immunodeficiency virus frequently results in resolution of CMV retinitis, but this may be complicated by ocular inflammation termed “immune recovery uveitis” (IRU). To provide insight into the pathogenesis of IRU, the phenotype and specificity of intraocular T cells in a single patient were analyzed. The T cell infiltrate consisted of a diverse population of CD8+ CMV-specific T cells, but only a minority of these T cells recognized the CMV phosphoprotein 65 and immediate early protein 1, which have been considered major targets of the host response. These results imply that reconstitution of CMV-specific T cells plays a role in IRU and suggest that the specificity of T cells engaged in the control of CMV at local sites of reactivation may be broad

RNA processing mechanisms, such as alternative splicing and RNA editing, have been recognized as critical means to expand the transcriptome. Chimeric RNAs formed by intergenic splicing provide another potential layer of RNA diversification. By analyzing a large set of RNA-Seq data and validating results in over 1,200 blood samples, we identified , a female-specific chimeric transcript. Intriguingly, both parental genes, are expressed in males and females. Mechanistically, is produced by cis-splicing between the two adjacent X-linked genes, originating from the inactive X chromosome. A female-specific chromatin loop, formed between the junction sites, facilitates the alternative splicing of its readthrough precursor. This unique chimeric transcript exhibits evolutionary conservation, evolving to be female-specific from non-human primates to humans. Furthermore, our investigation reveals that is enriched in the myeloid lineage and plays a regulatory role in myeloid differentiation. Notably, female COVID-19 patients who tested negative for this chimeric transcript displayed higher counts of neutrophils, highlighting its potential role in disease pathogenesis. These findings support the notion that chimeric RNAs represent a new repertoire of transcripts that can be regulated independently from the parental genes, and a new class of RNA variance with potential implications in sexual dimorphism and immune responses.