Chemoenzymatic Probes for Detecting and Imaging Fucose-α(1-2)-galactose Glycan Biomarkers

The disaccharide motif fucose-α(1-2)-galactose (Fucα(1-2)Gal) is involved in many important physiological processes, such as learning and memory, inflammation, asthma, and tumorigenesis. However, the size and structural complexity of Fucα(1-2)Gal-containing glycans have posed a significant challenge to their detection. We report a new chemoenzymatic strategy for the rapid, sensitive detection of Fucα(1-2)Gal glycans. We demonstrate that the approach is highly selective for the Fucα(1-2)Gal motif, detects a variety of complex glycans and glycoproteins, and can be used to profile the relative abundance of the motif on live cells, discriminating malignant from normal cells. This approach represents a new potential strategy for biomarker detection and expands the technologies available for understanding the roles of this important class of carbohydrates in physiology and disease

Interferometric radar observations of filamented structures due to plasma instabilities and their relation to dynamic auroral rays

International audienceSeveral explanations have been proposed for Naturally Enhanced ion-acoustic Echoes observed at mid- and high-latitude Incoherent Scatter observatories. A decisive measure for distinguishing between these explanations is whether or not simultaneously observed up- and down-shifted enhancement occur simultaneously, or if they are the result of temporal and/or spatial averaging. The EISCAT Svalbard Radar has two antennas in the same radar system, which can be used as an interferometer when pointed parallel. In observations from 17 January 2002, between 06:46:10 and 06:46:30 UT, we used this possibility, in combination with direct sampling of the received signals, to yield measurements of "naturally enhanced ion-acoustic echoes" with sufficiently high resolution to resolve such averaging, if any. For the first time, radar interferometry has been employed to estimate the sizes of coherent structures. The observations were coordinated with an image intensified video camera with a narrow field of view. Together, this forms the initial study on the causal relationships between enhanced echoes and fine structure in the auroral activity on sub-kilometer, sub-second scales. The results confirm that the enhanced echoes originate from very localised regions (~300m perpendicular to the magnetic field at 500km altitude) with varying range distribution, and with high time variability (?200ms). The corresponding increase in scattering cross section, up to 50dB above incoherent scattering, eliminates theoretical explanations based on marginal stability. The simultaneously observed up- and down-shifted enhanced shoulders, when caused by sufficiently narrow structures to be detected by the interferometer technique, originate predominantly from the same volume. These results have significant impact on theories attempting to explain the enhancements, in particular it is found that the ion-electron two-stream mechanism favoured by many authors is an unlikely candidate to explain the observations. The video data has helped establish a clear correlation between the enhanced echoes and auroral activity, on sub-second time scales, showing a threshold connection between the auroral intensity and the triggering of the radar enhancements. It appears that the up- and down-shifted enhanced echoes correlate with fine auroral structures in different ways. Key words. Ionosphere (auroral ionosphere; plasma waves and instabilities) ? Radio science (interferometry

Phase calibration of the EISCAT Svalbard Radar interferometer using optical satellite signatures

The link between natural ion-line enhancements in radar spectra and auroral activity has been the subject of recent studies but conclusions have been limited by the spatial and temporal resolution previously available. The next challenge is to use shorter sub-second integration times in combination with interferometric programmes to resolve spatial structure within the main radar beam, and so relate enhanced filaments to individual auroral rays. This paper presents initial studies of a technique, using optical and spectral satellite signatures, to calibrate the received phase of a signal with the position of the scattering source along the interferometric baseline of the EISCAT Svalbard Radar. It is shown that a consistent relationship can be found only if the satellite passage through the phase fringes is adjusted from the passage predicted by optical tracking. This required adjustment is interpreted as being due to the vector between the theoretical focusing points of the two antennae, i.e. the true radar baseline, differing from the baseline obtained by survey between the antenna foot points. A method to obtain a measurement of the true interferometric baseline using multiple satellite passes is outlined

Glycans as receptors for influenza pathogenesis

Influenza A viruses, members of the Orthomyxoviridae family, are responsible for annual seasonal influenza epidemics and occasional global pandemics. The binding of viral coat glycoprotein hemagglutinin (HA) to sialylated glycan receptors on host epithelial cells is the critical initial step in the infection and transmission of these viruses. Scientists believe that a switch in the binding specificity of HA from Neu5Acα2-3Gal linked (α2-3) to Neu5Acα2-6Gal linked (α2-6) glycans is essential for the crossover of the viruses from avian to human hosts. However, studies have shown that the classification of glycan binding preference of HA based on sialic acid linkage alone is insufficient to establish a correlation between receptor specificity of HA and the efficient transmission of influenza A viruses. A recent study reported extensive diversity in the structure and composition of α2-6 glycans (which goes beyond the sialic acid linkage) in human upper respiratory epithelia and identified different glycan structural topologies. Biochemical examination of the multivalent HA binding to these diverse sialylated glycan structures also demonstrated that high affinity binding of HA to α2-6 glycans with a characteristic umbrella-like structural topology is critical for efficient human adaptation and human-human transmission of influenza A viruses. This review summarizes studies which suggest a new paradigm for understanding the role of the structure of sialylated glycan receptors in influenza virus pathogenesis.National Institute of General Medical Sciences (U.S.) (Glue Grant U54 GM62116)National Institutes of Health (U.S.) (Grant GM57073)Singapore-MIT Alliance for Research and Technolog

Immunotherapy: is a minor god yet in the pantheon of treatments for lung cancer?

Immunotherapy has been studied for many years in lung cancer without significant results, making the majority of oncologists quite skeptical about its possible application for non-small cell lung cancer treatment. However, the recent knowledge about immune escape and subsequent 'cancer immunoediting' has yielded the development of new strategies of cancer immunotherapy, heralding a new era of lung cancer treatment. Cancer vaccines, including both whole-cell and peptide vaccines have been tested both in early and advanced stages of non-small cell lung cancer. New immunomodulatory agents, including anti-CTLA4, anti-PD1/PDL1 monoclonal antibodies, have been investigated as monotherapy in metastatic lung cancer. To date, these treatments have shown impressive results of efficacy and tolerability in early clinical trials, leading to testing in several large, randomized Phase III trials. As these results will be confirmed, these drugs will be available in the near future, offering new exciting therapeutic options for lung cancer treatment

Research priorities for managing the impacts and dependencies of business upon food, energy, water and the environment

Delivering access to sufficient food, energy and water resources to ensure human wellbeing is a major concern for governments worldwide. However, it is crucial to account for the ‘nexus’ of interactions between these natural resources and the consequent implications for human wellbeing. The private sector has a critical role in driving positive change towards more sustainable nexus management and could reap considerable benefits from collaboration with researchers to devise solutions to some of the foremost sustainability challenges of today. Yet opportunities are missed because the private sector is rarely involved in the formulation of deliverable research priorities. We convened senior research scientists and influential business leaders to collaboratively identify the top forty questions that, if answered, would best help companies understand and manage their food-energy-water-environment nexus dependencies and impacts. Codification of the top order nexus themes highlighted research priorities around development of pragmatic yet credible tools that allow businesses to incorporate nexus interactions into their decision-making; demonstration of the business case for more sustainable nexus management; identification of the most effective levers for behaviour change; and understanding incentives or circumstances that allow individuals and businesses to take a leadership stance. Greater investment in the complex but productive relations between the private sector and research community will create deeper and more meaningful collaboration and cooperation.This work was supportedby the Economic and Social Research Council [Grant Number ES/L01632X/1] and is part of the Nexus Network Initiative. WJS is funded by Arcadia

A Comparison of Lethal and Non-Lethal Management Approaches to Reduce Damage Associated with Urban Crow Roosts in New York and Virginia

Crow populations have steadily increased in many parts of the country since 1966. Although large winter congregations of crows in urban environments are not a new phenomenon, the number of complaints regarding damage associated with these large (2,000-20,000 individuals) roosts appears to be increasing. In an effort to assist the public in reducing impacts of urban crow roosts, USDA, APHIS, Wildlife Services in Virginia and New York implemented large-scale roost dispersal programs in the winter of 2001-2002. The goal of the programs were to manage local crow populations to minimize associated noise, accumulations of crow fecal droppings on and around residences, strong ammonia odors from fecal droppings, property damage, clean-up costs and threats to human health and safety. Multiple meetings involving the public and key stakeholders were convened where a variety of options and consequences of each option were discussed. Options considered were no action, habitat alteration, cultural methods, roost dispersal, and roost depopulation. Wildlife Services in each state took different approaches to managing crow roosting sites based on state regulations, available tools, scope of the problem, consequences of each management action, effectiveness of methods, and public input. In Virginia, a lethal control program was initiated targeting one roost site (2,000-6 ,000 crows/roost) using the avicide DRC-1339. The goals were to remove a significant percentage of the local crow population and disperse the remaining crows. This project resulted in an estimated 73% reduction in crow numbers at the primary roost site and altered roost dynamics at another roost. The cooperators satisfaction level was an immediate 75% reduction in damage based on a polling of affected property owners. This satisfaction level was based on a reduction in fecal droppings, maintenance costs to clean up fecal droppings, noise, and abundance of crows. In upstate New York, two roost sites (16,000-20,000 crows/roost) were successfully dispersed using a non-lethal hazing program (pyrotechnics, recorded crow distress calls and hand-held lasers). In New York, no avicides were registered at the time of this project and the Cities of Troy and Albany requested that WS try a non-lethal program prior to implementing a lethal control program. The number of crows in the primary roost in the cities of Albany and Troy were reduced by more than 95% over the course of an eight-day program. Significant reduction in crow numbers and damage remained more than eight weeks later. In this paper we will provide a comparison of crow management projects in Virginia and New York and discuss implications of different approaches for managing urban crows

Systematic evaluation of immune regulation and modulation

Cancer immunotherapies are showing promising clinical results in a variety of malignancies. Monitoring the immune as well as the tumor response following these therapies has led to significant advancements in the field. Moreover, the identification and assessment of both predictive and prognostic biomarkers has become a key component to advancing these therapies. Thus, it is critical to develop systematic approaches to monitor the immune response and to interpret the data obtained from these assays. In order to address these issues and make recommendations to the field, the Society for Immunotherapy of Cancer reconvened the Immune Biomarkers Task Force. As a part of this Task Force, Working Group 3 (WG3) consisting of multidisciplinary experts from industry, academia, and government focused on the systematic assessment of immune regulation and modulation. In this review, the tumor microenvironment, microbiome, bone marrow, and adoptively transferred T cells will be used as examples to discuss the type and timing of sample collection. In addition, potential types of measurements, assays, and analyses will be discussed for each sample. Specifically, these recommendations will focus on the unique collection and assay requirements for the analysis of various samples as well as the high-throughput assays to evaluate potential biomarkers

Echocardiography findings in COVID-19 patients admitted to intensive care units: a multi-national observational study (the ECHO-COVID study)

Purpose: Severely ill patients affected by coronavirus disease 2019 (COVID-19) develop circulatory failure. We aimed to report patterns of left and right ventricular dysfunction in the first echocardiography following admission to intensive care unit (ICU). Methods: Retrospective, descriptive study that collected echocardiographic and clinical information from severely ill COVID-19 patients admitted to 14 ICUs in 8 countries. Patients admitted to ICU who received at least one echocardiography between 1st February 2020 and 30th June 2021 were included. Clinical and echocardiographic data were uploaded using a secured web-based electronic database (REDCap). Results: Six hundred and seventy-seven patients were included and the first echo was performed 2 [1, 4] days after ICU admission. The median age was 65 [56, 73] years, and 71% were male. Left ventricle (LV) and/or right ventricle (RV) systolic dysfunction were found in 234 (34.5%) patients. 149 (22%) patients had LV systolic dysfunction (with or without RV dysfunction) without LV dilatation and no elevation in filling pressure. 152 (22.5%) had RV systolic dysfunction. In 517 patients with information on both paradoxical septal motion and quantitative RV size, 90 (17.4%) had acute cor pulmonale (ACP). ACP was associated with mechanical ventilation (OR > 4), pulmonary embolism (OR > 5) and increased PaCO2. Exploratory analyses showed that patients with ACP and older age were more likely to die in hospital (including ICU). Conclusion: Almost one-third of this cohort of critically ill COVID-19 patients exhibited abnormal LV and/or RV systolic function in their first echocardiography assessment. While LV systolic dysfunction appears similar to septic cardiomyopathy, RV systolic dysfunction was related to pressure overload due to positive pressure ventilation, hypercapnia and pulmonary embolism. ACP and age seemed to be associated with mortality in this cohort