Immunochemical characterization of polysaccharide antigens from six clinical strains of Enterococci

BACKGROUND: Enterococci have become major nosocomial pathogens due to their intrinsic and acquired resistance to a broad spectrum of antibiotics. Their increasing drug resistance prompts us to search for prominent antigens to develop vaccines against enterococci. Given the success of polysaccharide-based vaccines against various bacterial pathogens, we isolated and characterized the immunochemical properties of polysaccharide antigens from five strains of Enterococcus faecalis and one strain of vancomycin-resistant E. faecium. RESULTS: We cultured large batches of each strain, isolated sufficient quantities of polysaccharides, analyzed their chemical structures, and compared their antigenic specificity. Three classes of polysaccharides were isolated from each strain, including a polyglucan, a teichoic acid, and a heteroglycan composed of rhamnose, glucose, galactose, mannosamine, and glucosamine. The polyglucans from all six strains are identical and appear to be dextran. Yields of the teichoic acids were generally low. The most abundant polysaccharides are the heteroglycans. The six heteroglycans are structurally different as evidenced by NMR spectroscopy. They also differ in their antigenic specificities as revealed by competitive ELISA. The heteroglycans are not immunogenic by themselves but conjugation to protein carriers significantly enhanced their ability to induce antibodies. CONCLUSION: The six clinical strains of enterococci express abundant, strain-specific cell-surface heteroglycans. These polysaccharides may provide a molecular basis for serological typing of enterococcal strains and antigens for the development of vaccines against multi-drug resistant enterococci

A water cycle for the Anthropocene

International audienceHumor us for a minute and do an online image search of the water cycle. How many diagrams do you have to scroll through before seeing any sign of humans? What about water pollution or climate change—two of the main drivers of the global water crisis? In a recent analysis of more than 450 water cycle diagrams, we found that 85% showed no human interaction with the water cycle and 98% omitted any sign of climate change or waterpollution (Abbott et al., 2019). Additionally, 92% of diagrams depicted verdant, temperate ecosystems with abundant freshwater and 95% showed only a single river basin. It did not matter if the diagrams came from textbooks, scientific articles, or the internet, nor if they were old or new; most showed an undisturbed water cycle, free from human interference. These depictions contrast starkly with the state of the water cycle in the Anthropocene, when land conversion, human water use, and climate change affect nearly every water pool and flux (Wurtsbaugh et al., 2017; Falkenmark et al., 2019; Wine and Davison, 2019). The dimensions and scale of human interference with water are manifest in failing fossil aquifersin the world’s great agricultural regions (Famiglietti, 2014), accelerating ice discharge from the Arctic (Box et al., 2018), and instability in atmospheric rivers that support continental rainfall (Paul et al., 2016).We believe that incorrect water cycle diagrams are a symptom of a much deeper and widespread problem about how humanity relates to water on Earth. Society does not understand how the water cycle works nor how humans fit into it (Attari, 2014; Linton, 2014; Abbott et al., 2019). In response to this crisis of understanding, we call on researchers, educators, journalists, lawyers, and policy makers to change how we conceptualize and present the global water cycle. Specifically, we must teach where water comes from, what determines its availability, and how many individuals and ecosystems are in crisis because of water mismanagement, climate change, and land conversion. Because the drivers of the global water crisis are truly global, ensuring adequate water for humans and ecosystems will require coordinated efforts that extend beyond geopolitical borders and outlast the tenure of individual administrations (Keys et al., 2017; Adler, 2019). This level of coordination and holistic thinking requires widespread understanding of the water cycle and the global water crisis. Making the causes and consequences of the water crisis visible in our diagrams is atractable and important step towards the goal of a sustainable relationship with water that includes ecosystems and society

Human domination of the global water cycle absent from depictions and perceptions

International audienceHuman water use, climate change and land conversion have created a water crisis for billions of individuals and many ecosystems worldwide. Global water stocks and fluxes are estimated empirically and with computer models, but this information is conveyed to policymakers and researchers through water cycle diagrams. Here we compiled a synthesis of the global water cycle, which we compared with 464 water cycle diagrams from around the world. Although human freshwater appropriation now equals half of global river discharge, only 15% of the water cycle diagrams depicted human interaction with water. Only 2% of the diagrams showed climate change or water pollution—two of the central causes of the global water crisis—which effectively conveys a false sense of water security. A single catchment was depicted in 95% of the diagrams, which precludes the representation of teleconnections such as ocean–land interactions and continental moisture recycling. These inaccuracies correspond with specific dimensions of water mismanagement, which suggest that flaws in water diagrams reflect and reinforce the misunderstanding of global hydrology by policymakers, researchers and the public. Correct depictions of the water cycle will not solve the global water crisis, but reconceiving this symbol is an important step towards equitable water governance, sustainable development and planetary thinking in the Anthropocene

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores

Determining crystal structures through crowdsourcing and coursework

We show here that computer game players can build high-quality crystal structures. Introduction of a new feature into the computer game Foldit allows players to build and real-space refine structures into electron density maps. To assess the usefulness of this feature, we held a crystallographic model-building competition between trained crystallographers, undergraduate students, Foldit players and automatic model-building algorithms. After removal of disordered residues, a team of Foldit players achieved the most accurate structure. Analysing the target protein of the competition, YPL067C, uncovered a new family of histidine triad proteins apparently involved in the prevention of amyloid toxicity. From this study, we conclude that crystallographers can utilize crowdsourcing to interpret electron density information and to produce structure solutions of the highest quality

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response

Measuring the Impact of Lead Hazard Control and Healthy Homes Programs: Evaluating Hazard Reduction Using the Healthy Home Rating System

The U.S. Department of Housing and Urban Development’s Office of Lead Hazard Control and Healthy Homes (OLHCHH) use the Healthy Home Rating System (HHRS), a tool developed to quantitatively assess the reduction of health-related housing hazards during the implementation of OLHCHH programs. This study evaluated the reduction of home-based hazards in 62 homes after remediation work was completed. The most common hazards identified in all homes were lead-based paint and domestic hygiene, pests, and refuse. The program was successful in reducing a variety of hazards, resulting in 100% reduction of lead-based paint hazards, 69% of water supply issues, 68% of concerns related to entry by intruders, and 60% reduction in hazards related to flames and hot surfaces. Still, other issues in the home could not be addressed due to cost and limitations in funding. While there is utility in using the HHRS, we need to consider changes to improve upon ways in which data are collected and impact is measured

Emerging diagnostic challenges and characteristics of simian betaretrovirus infections in captive macaque colonies

To better understand Simian betaretrovirus (SRV) seropositivity in virus-negative macaques, we transfused blood from SRV-infected or suspect donors into immunosuppressed naive recipients. Our results do not support typical SRV1-5 infection as the cause, but provide evidence for several possibilities including serological artifact, new/different SRV, or an endogenous virus

A pilot study evaluating the prefeasibility of a behavioral weight loss program in people with multiple sclerosis

Weight loss interventions seldom include individuals with neurologic disease. The aims of the present study were to: 1) develop and assess the prefeasibility of a 6-month telehealth behavioral weight loss program for people with multiple sclerosis (MS) and obesity and 2) examine changes in weight loss (primary outcome), physical activity, and fruit/vegetable consumption at follow-up. Participants with obesity and MS engaged in a 24-week weight loss program. Participants followed established diet, exercise, and self-monitoring guidelines and attended weekly online group meetings. Median percentage weight loss was 10.54 % (SD = 7.19). Participants who adhered more closely to the self-monitoring guidelines (r = 0.81, p =.02), and who averaged higher weekly active minutes (r = 0.91, p =.002) achieved greater percentage weight loss. Six of the eight pilot participants achieved clinically meaningful weight loss (>5%) after 6-months