77 research outputs found

    Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

    Get PDF
    Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies

    Finishing the euchromatic sequence of the human genome

    Get PDF
    The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

    Organic matter dynamics in the Florida coastal Everglades: A molecular marker and isotopic approach

    No full text
    Everglades National Park (ENP) is about to undergo the world\u27s largest wetland restoration with the aim of improving the quality, timing and distribution of water flow. The changes in water flow are hypothesized to alter the nutrient fluxes and organic matter (OM) dynamics within ENP, especially in the estuarine areas. This study used a multi-proxy approach of molecular markers and stable δ 13C isotope measurements, to determine the present day OM dynamics in ENP. OM dynamics in wetland soils/sediments have proved to be difficult to understand using traditional geochemical approaches. These are often inadequate to describe the multitude of OM sources (e.g. higher land plant, emergent vegetation, submerged vegetation) to the soils/sediments and the complex diagenetic processes that can alter the OM characteristics. A multi-proxy approach, however, that incorporates both molecular level and bulk parameter information is ideal to comprehend complex OM dynamics in aquatic environments. Therefore, biomass-specific molecular markers or proxies can be useful in tracing the sources and processing of OM. This approach was used to examine the OM dynamics in the two major drainage basins, Shark River Slough and Taylor River Slough, of ENP. Freshwater to marine transects were sampled in both systems for soils/sediments and suspended particulate organic matter (SPOM) to be characterized through bulk OM analyses, lipid biomarker determinations (e.g. sterols, fatty acids, hydrocarbons and triterpenoids) and compound-specific stable carbon isotope (δ 13C) determinations. One key accomplishment of the research was the assessment of a molecular marker proxy (Paq) to distinguish between emergent/higher plant vegetation from submerged vegetation within ENP. This proxy proved to be quite useful at tracing OM inputs to the soils/sediments of ENP. A second key accomplishment was the development of a 3-way model using vegetation specific molecular markers. This novel, descriptive model was successfully applied to the estuarine areas of Taylor and Shark River sloughs, providing clear evidence of mixing of freshwater, estuarine and marine derived OM in these areas. In addition, diagenetic transformations of OM in these estuaries were found to be quite different between Taylor and Shark Rivers, and are likely a result of OM quality and hydrological differences

    Assessing Source Contributions to Particulate Organic Matter in a Subtropical Estuary: A biomarker approach

    No full text
    Assessing the sources and quantifying the contributions of particulate organic matter (POM) in estuaries is a challenge. Here we apply source-specific biomarkers to assess POM sources in an estuary receiving suspended material from freshwater wetlands, fringe mangroves and coastal environments. A three end-member mixing model, including terrestrial, estuarine and marine end-member contributions was developed and successfully validated to assess general OM dynamics and hydrologic processes that control POM distributions within the Shark River estuary in South Florida. Low tide and wet season conditions coincided with an enhanced signal of the freshwater end-member biomarker abundance, while high tide and dry season conditions resulted in enhanced POM input of marine origin. Incoming tide was observed to be an important factor in the re-suspension and tidal pumping of mangrove-derived POM, which seems to be the dominant source of particulate organic carbon (POC) in the estuary. The three end-member conceptual model was tested to obtain a rough estimate of POC source strength, with the ultimate goal of constraining carbon budgets in this sub-tropical estuary. Mangrove-derived POC flux of ca. 5.3 × 105 to 1.0 × 106 kg/yr POC from the Shark River to the Gulf of Mexico were estimated, but end-member values used in the assessment need to be better constrained to reduce the degree of variability

    Affects and Cognition in a Social Theory of Unconscious Processes

    Get PDF
    The final, definitive version of this article has been published in the Journal, Group Analysis, Vol 38 / Issue 1, 2005, Copyright The Group-Analytic Society , by SAGE Publications Ltd at : http://gaq.sagepub.com/This paper argues that affects and cognition cannot be separated in human consciousness and that human consciousness is fundamentally a social phenomenon. This contention is based on a number of arguments. First, research into brain functioning indicates that those centres of the brain that deal with emotion also deal with the capacity to select rational and moral actions. Second, is the argument that attachment and separation behaviours, that is, social acts, are essential for the human body’s capacity to regulate itself. Next, the paper reviews G. H. Mead’s theory of symbolic interactionism, according to which human consciousness and self consciousness arise in social acts so that the individual is social through and through. The notion of “the” unconscious is then explored. It is argued that this is a fundamentally individualistic notion of what is unconscious in human action and as such is incompatible with the contention that human consciousness is a social process. Suggestions are made for thinking of what is unconscious in terms of social processes. The paper concludes with a section on how one might think abut disturbance and pathology from the perspective of complex responsive processes.Peer reviewe

    Organic Biogeochemistry of Detrital Flocculent Material (Floc) in a Subtropical, Coastal Wetland

    No full text
    Flocculent materials (floc), in aquatic systems usually consist of a non-consolidated layer of biogenic, detrital material relatively rich in organic matter which represents an important food-web component for invertebrates and fish. Thus, variations in its composition could impact food webs and change faunal structure. Transport, remineralization rates and deposition of floc may also be important factors in soil/sediment formation. In spite of its relevance and sensitivity to external factors, few chemical studies have been carried out on the biogeochemistry of floc material. In this study, we focused on the molecular characterization of the flocculent organic matter (OM), the assessment of its origin and its environmental fate at five stations along a freshwater to marine ecotone, namely the Taylor Slough, Everglades National Park (ENP), Florida. To tackle this issue, suspended, unconsolidated, detrital floc samples, soils/sediments and plants were analyzed for bulk properties, biomarkers and pigments. Both geochemical proxies and biomass-specific biomarkers were used to assess OM sources and transformations. Our results show that the detrital organic matter of the flocculent material is largely regulated by local vegetation inputs, ranging from periphyton, emergent and submerged plants and terrestrial plants such as mangroves, with molecular evidence of different degrees of diagenetic reworking, including fungal activity. Evidence is presented for both hydrodynamic transport of floc materials, and incorporation of floc OM into soils/sediments. However, some molecular parameters showed a decoupling between floc and underlying soil/sediment OM, suggesting that physical transport, incorporation and degradation/remineralization of OM in floc may be controlled by a combination of a variety of complex biogeochemical variables including hydrodynamic transport, hydroperiod characteristics, primary productivity, nutrient availability, and OM quality among others. Further investigations are needed to better understand the ecological role of floc in freshwater and coastal wetlands

    Determination of brevetoxin in recent marine sediments

    No full text
    Harmful algal blooms (HAB) of Karenia brevis ( K. brevis) produce a suite of lipid soluble polyether brevetoxins, known to cause environmental, health and economic ill effects. There is evidence that K. brevis has increased in abundance over the past 50 years, but the dataset is incomplete. The objective of this paper was to analyze sediment from an area where K. brevis blooms have occurred and investigate if these compounds are incorporated into the underlying sediment, thus potentially allowing the use of brevetoxins as an indicator of past K. Brevis blooms. The results from LC-ESI-MS-MS analyses of brevetoxin analogs detected in surficial sediments from three sites (Fort Meyers Beach [FMB], Big Hickory Pass [BHP] and Big Carlos Pass [BCP]) along the Southwest Florida coastline with prior HAB history are promising. The analogs detected from BHP sediments were PbTx-2 and PbTx-3 with values of 0.81 and 3.1 ng g −1 dry sediment, respectively. The detected PbTx-2 from BCP was 3.6 ng g −1 dry sediment, while the detected PbTx-3 from BCP was 9.7 ng g −1 dry sediment. PbTx-3 was only detected at the FMB site (2.7 ng g −1 dry sediment). The detection of brevetoxins in recent sediments where K. brevis have occurred indicates brevetoxin incorporation into marine sediments

    Brevetoxin persistence in sediments and seagrass epiphytes of east Florida coastal waters

    No full text
    ► A Karenia brevis bloom developed in the Intracoastal Waterway along the east Florida coast in summer 2007. ► In summer 2008 brevetoxins were found in sediments of the northern Intracoastal Waterway. ► Brevetoxins were also found in summer 2008 within seagrass epiphytes in the southern Intracoastal Waterway. ► Generally, brevetoxins were present in either sediments or seagrass epiphytes at any station. A bloom of Karenia brevis Davis developed in September 2007 near Jacksonville, Florida and subsequently progressed south through east Florida coastal waters and the Atlantic Intracoastal Waterway (ICW). Maximum cell abundances exceeded 10 6 cells L −1 through October in the northern ICW between Jacksonville and the Indian River Lagoon. The bloom progressed further south during November, and terminated in December 2007 at densities of 10 4 cells L −1 in the ICW south of Jupiter Inlet, Florida. Brevetoxins were subsequently sampled in sediments and seagrass epiphytes in July and August 2008 in the ICW. Sediment brevetoxins occurred at concentrations of 11–15 ng PbTx-3 equivalents (g dry wt sediment) −1 in three of five basins in the northern ICW during summer 2008. Seagrass beds occur south of the Mosquito Lagoon in the ICW. Brevetoxins were detected in six of the nine seagrass beds sampled between the Mosquito Lagoon and Jupiter Inlet at concentrations of 6–18 ng (g dry wt epiphytes) −1. The highest brevetoxins concentrations were found in sediments near Patrick Air Force Base at 89 ng (g dry wt sediment) −1. In general, brevetoxins occurred in either seagrass epiphytes or sediments. Blades of the resident seagrass species have a maximum life span of less than six months, so it is postulated that brevetoxins could be transferred between epibenthic communities of individual blades in seagrass beds. The occurrence of brevetoxins in east Florida coast sediments and seagrass epiphytes up to eight months after bloom termination supports observations from the Florida west coast that brevetoxins can persist in marine ecosystems in the absence of sustained blooms. Furthermore, our observations show that brevetoxins can persist in sediments where seagrass communities are absent

    Rapidly increasing ethanol concentrations in rainwater and air

    No full text
    Atmospheric science: ethanol increases Concentrations of ethanol have increased in both rain water and the atmosphere due to the use of ethanol biofuels. Biofuel use has doubled in the past decade as a means to reduce transport-related greenhouse gas emissions. However, the corresponding impact on ethanol sources and sinks remains largely unquantified. Joan Willey from the University of North Carolina Wilmington, and colleagues, investigate these changes using a unique record of rainwater and atmospheric ethanol concentrations from Wilmington, NC. From 2010 to 2017, atmospheric and rainwater ethanol concentrations have increased fourfold, suggesting current sinks are insufficient in removing ethanol at the rate at which it is being added, impacting air quality and other atmospheric processes. As ethanol concentrations are projected to increase further through the continued expansion of biofuels, more work is needed to fully examine their environmental impacts
    corecore