Outer Membrane Vesicles (OMVs) are bacterial nanoparticles that are spontaneously released during growth both in vitro and in vivo by Gram-negative bacteria. They are spherical, bilayered membrane ...nanostructures that contain many components found within the external surface of the parent bacterium. Naturally, OMVs serve the bacteria as a mechanism to deliver DNA, RNA, proteins, and toxins, as well as to promote biofilm formation and remodel the outer membrane during growth. On the other hand, as OMVs possess the optimal size to be uptaken by immune cells, and present a range of surface-exposed antigens in native conformation and Toll-like receptor (TLR) activating components, they represent an attractive and powerful vaccine platform able to induce both humoral and cell-mediated immune responses. This work reviews the TLR-agonists expressed on OMVs and their capability to trigger individual TLRs expressed on different cell types of the immune system, and then focuses on their impact on the immune responses elicited by OMVs compared to traditional vaccines.
Big data offer a great opportunity for nature-based recreation (NbR) mapping and evaluation. However, it is important to determine when and how it is appropriate to use this resource. We used ...Scotland as a case study to validate the use of data from Flickr as an indicator of NbR on a national scale and at several regional spatial and temporal resolutions. We compared Flickr photographs to visitor statistics in the Cairngorms National Park (CNP) and determined whether temporal variability in photo counts could be explained by known annual estimates of CNP visitor numbers. We then used a unique recent national survey of nature recreation in Scotland to determine whether the spatial distribution of Flickr photos could be explained by known spatial variability in nature use. Following this validation work, we used Flickr data to identify hotspots of wildlife watching in Scotland and investigated how they changed between 2005 and 2015. We found that spatial and temporal patterns in Flickr count are explained by measures of visitation obtained through surveys and that this relationship is reliable down to a 10 Km scale resolution. Our findings have implications for planning and management of NbR as they suggest that photographs uploaded on Flickr reflect patterns of NbR at spatial and temporal scales that are relevant for ecosystem management.
•Evidence of the impact of background exposure to polychlorinated biphenyls (PCBs) on all-cause mortality is limited.•Dietary exposure to PCBs is associated with an increased risk of ...cardiovascular-specific mortality.•Studies assessing PCB exposure in the general population are lacking.
Polychlorinated biphenyls (PCBs) are a large family of man-made organic, ubiquitous, and persistent contaminants with endocrine-disrupting properties. PCBs have been associated with numerous adverse health effects and were classified as carcinogenic to humans, but their long-term impact on mortality risk in the general population is unknown.
To conduct a systematic review and meta-analysis in order to assess whether background exposure levels of PCBs increase all-cause and cancer- and cardiovascular-specific mortality risk in the general population.
We searched the Pubmed, Web of Science, Cochrane Library, and Embase databases for eligible studies up to 1st of January, 2021. We included cohort and nested-case control studies comparing the lowest vs. the highest background exposure level of PCBs in the general population and reporting data for all-cause mortality and/or cancer-/cardiovascular-specific mortality. Studies reporting occupational and accidental exposures were excluded. Random-effects meta-analysis was used to estimate summary relative risks (SRRs) and 95% confidence intervals (CIs). Heterogeneity across studies was assessed by I2 statistics, and publication bias both graphically and using Egger’s and Begg’s tests. Quality of included studies was assessed using the National Toxicology Program/Office of Health Assessment and Translation (NTP/OHAT). Confidence in the body of evidence and related level of evidence were assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) based on the NTP/OHAT framework. The protocol was registered in PROSPERO (CRD42020178079).
The initial search led to 2,132 articles. Eight prospective cohort studies met our inclusion criteria, leading to 72,852 participants including 17,805 deaths. Overall exposure to PCBs was not statistically significantly associated with all-cause mortality (SRR = 1.13, 95% CI = 0.90–1.41, n = 7 studies, low certainty); however, dietary exposure to PCBs was associated with an increased risk of cardiovascular-specific mortality (SRR = 1.38, 95% CI = 1.14–1.66, n = 3 studies, moderate certainty), while no association was found with cancer-specific mortality (SRR = 1.07, 95% CI = 0.72–1.59, n = 5 studies, low certainty).
Our meta-analysis suggests that background exposure to PCBs is associated with an increased risk of cardiovascular-specific mortality in the general population with a “moderate” level of evidence. These findings should be interpreted with caution given the small number of studies on mortality in the general population.
Generalized Modules for Membrane Antigens (GMMA) are outer membrane vesicles derived from Gram-negative bacteria engineered to provide an over-vesiculating phenotype, which represent an attractive ...platform for the design of affordable vaccines. GMMA can be further genetically manipulated to modulate the risk of systemic reactogenicity and to act as delivery system for heterologous polysaccharide or protein antigens. GMMA are able to induce strong immunogenicity and protection in animal challenge models, and to be well-tolerated and immunogenic in clinical studies. The high immunogenicity could be ascribed to their particulate size, to their ability to present to the immune system multiple antigens in a natural conformation which mimics the bacterial environment, as well as to their intrinsic self-adjuvanticity. However, GMMA mechanism of action and the role in adjuvanticity are still unclear and need further investigation. In this review, we discuss progresses in the development of the GMMA vaccine platform, highlighting successful applications and identifying knowledge gaps and potential challenges.
Dietary regimens promoting inflammatory conditions have been implicated in breast cancer development, but studies on the association between pro-inflammatory diet and breast cancer risk have reported ...inconsistent results. We investigated the association between the inflammatory potential of diet and breast cancer risk in a case-control study in France including 872 breast cancer cases and 966 population controls. All women completed a food frequency questionnaire that was used to compute a Dietary Inflammatory Index (DII) based on the inflammatory weight of 33 dietary components. The DII ranged from a median of - 3.22 in the lowest quartile (anti-inflammatory) to + 2.96 in the highest quartile (pro-inflammatory). The odds ratio contrasting quartile 4 to quartile 1 was 1.31 (95% CI 1.00, 1.73; p-trend = 0.02). Slightly higher odds ratios were observed in post-menopausal women, particularly those with body mass index > 25 kg/m
(odds ratio 1.62; 95% CI 0.92, 2.83; p-trend = 0.02), and among ever smokers (odds ratio 1.71; 95% CI 1.11, 2.65; p-trend 0.01). The analyses by breast cancer subtype showed that the DII was associated with breast tumors that expressed either the estrogen (ER) or progesterone (PR) hormone receptors or the Human Epidermal Growth Factor Receptor-2 (HER2), but no association was seen for the triple negative breast tumor subtype. Our results add further evidence that a pro-inflammatory diet is associated with breast cancer risk with possible effect variation according to tumor subtype.
GMMA are exosomes released from engineered Gram-negative bacteria resembling the composition of outer membranes. We applied the GMMA technology for the development of an O-Antigen (OAg) based vaccine ...against Shigella sonnei, the most epidemiologically relevant cause of shigellosis. S. sonnei OAg has been identified as a key antigen for protective immunity, and GMMA are able to induce anti-OAg-specific IgG response in animal models and healthy adults. The contribution of protein-specific antibodies induced upon vaccination with GMMA has never been fully elucidated. Anti-protein antibodies are induced in mice upon immunization with either OAg-negative and OAg-positive GMMA. Here we demonstrated that OAg chains shield the bacteria from anti-protein antibody binding and therefore anti-OAg antibodies were the main drivers of bactericidal activity against OAg-positive bacteria. Interestingly, antibodies that are not targeting the OAg are functional against OAg-negative bacteria. The immunodominant protein antigens were identified by proteomic analysis. Our study confirms a critical role of the OAg on the immune response induced by S. sonnei GMMA. However, little is known about OAg length and density regulation during infection and, therefore, protein exposure. Hence, the presence of protein antigens on S. sonnei GMMA represents an added value for GMMA vaccines compared to other OAg-based formulations.
Outer membrane vesicles (OMV) are exosomes naturally released from the surface of Gram-negative bacteria. Since the '80s, OMVs have been proposed as powerful vaccine platforms due to their intrinsic ...self-adjuvanticity and ability to present multiple antigens in natural conformation. However, the presence of several pathogen-associated molecular patterns (PAMPs), especially lipid A, has raised concerns about potential systemic reactogenicity in humans. Recently, chemical and genetic approaches allowed to efficiently modulate the balance between reactogenicity and immunogenicity for the use of OMV in humans. Several assays (monocyte activation test, rabbit pyrogenicity test, limulus amebocyte lysate, human transfectant cells, and toxicology studies) were developed to test, with highly predictive potential, the risk of reactogenicity in humans before moving to clinical use. In this review, we provide a historical perspective on how different assays were and can be used to successfully evaluate systemic reactogenicity during clinical development and after licensure.
Chronic lymphocytic leukemia (CLL) is an incurable disease accounting for almost one‐third of leukemias in the Western world. Aberrant expression of microRNAs (miRNAs) is a well‐established ...characteristic of CLL, and the robust nature of miRNAs makes them eminently suitable liquid biopsy biomarkers. Using a nested case–control study within the European Prospective Investigation into Cancer and Nutrition (EPIC), the predictive values of five promising human miRNAs (hsa‐miR‐16‐5p, hsa‐miR‐29a‐3p, hsa‐miR‐150‐5p, hsa‐miR‐155‐5p and hsa‐miR‐223‐3p), identified in a pilot study, were examined in serum of 224 CLL cases (diagnosed 3 months to 18 years after enrollment) and 224 matched controls using Taqman based assays. Conditional logistic regressions were applied to adjust for potential confounders. The median time from blood collection to CLL diagnosis was 10 years (p25–p75: 7–13 years). Overall, the upregulation of hsa‐miR‐150‐5p, hsa‐miR‐155‐5p and hsa‐miR‐29a‐3p was associated with subsequent risk of CLL OR1∆Ct‐unit increase (95%CI) = 1.42 (1.18–1.72), 1.64 (1.31–2.04) and 1.75 (1.31–2.34) for hsa‐miR‐150‐5p, hsa‐miR‐155‐5p and hsa‐miR‐29a‐3p, respectively and the strongest associations were observed within 10 years of diagnosis. However, the predictive performance of these miRNAs was modest (area under the curve <0.62). hsa‐miR‐16‐5p and hsa‐miR‐223‐3p levels were unrelated to CLL risk. The findings of this first prospective study suggest that hsa‐miR‐29a, hsa‐miR‐150‐5p and hsa‐miR‐155‐5p were upregulated in early stages of CLL but were modest predictive biomarkers of CLL risk.
What's new?
Aberrant circulating microRNA (miRNA) levels are a well‐established characteristic of chronic lymphocytic leukemia (CLL), but pre‐diagnosis data remain scarce. In this nested case–control study within the European Prospective Investigation into Cancer and Nutrition Study, circulating hsa‐miRNA‐29a‐3p, ‐150‐5p, and ‐155‐5p were upregulated up to 10 years before CLL diagnosis compared to controls, suggesting a role in early disease progression. However, these biomarkers were suboptimal to discriminate CLL from controls. No difference was observed in hsa‐miRNA‐16‐5p and ‐223‐3p expression between pre‐CLL and controls. The ability to detect pre‐clinical biomarkers may help better understand CLL development and open new avenues for personalized treatment.
Molecular interactions between male and female factors during mating profoundly affect the reproductive behavior and physiology of female insects. In natural populations of the malaria mosquito ...Anopheles gambiae, blood-fed females direct nutritional resources towards oogenesis only when inseminated. Here we show that the mating-dependent pathway of egg development in these mosquitoes is regulated by the interaction between the steroid hormone 20-hydroxy-ecdysone (20E) transferred by males during copulation and a female Mating-Induced Stimulator of Oogenesis (MISO) protein. RNAi silencing of MISO abolishes the increase in oogenesis caused by mating in blood-fed females, causes a delay in oocyte development, and impairs the function of male-transferred 20E. Co-immunoprecipitation experiments show that MISO and 20E interact in the female reproductive tract. Moreover MISO expression after mating is induced by 20E via the Ecdysone Receptor, demonstrating a close cooperation between the two factors. Male-transferred 20E therefore acts as a mating signal that females translate into an increased investment in egg development via a MISO-dependent pathway. The identification of this male-female reproductive interaction offers novel opportunities for the control of mosquito populations that transmit malaria.
Studies suggested that exposure to air pollutants, with endocrine disrupting (ED) properties, have a key role in breast cancer (BC) development. Although the population is exposed simultaneously to a ...mixture of multiple pollutants and ED pollutants may act via common biological mechanisms leading to synergic effects, epidemiological studies generally evaluate the effect of each pollutant separately. We aimed to assess the complex effect of exposure to a mixture of four xenoestrogen air pollutants (benzo-a-pyrene (BaP), cadmium, dioxin (2,3,7,8-Tétrachlorodibenzo-p-dioxin TCDD)), and polychlorinated biphenyl 153 (PCB153)) on the risk of BC, using three recent statistical methods, namely weighted quantile sum (WQS), quantile g-computation (QGC) and Bayesian kernel machine regression (BKMR). The study was conducted on 5222 cases and 5222 matched controls nested within the French prospective E3N cohort initiated in 1990. Annual average exposure estimates to the pollutants were assessed using a chemistry transport model, at the participants’ residence address between 1990 and 2011. We found a positive association between the WQS index of the joint effect and the risk of overall BC (adjusted odds ratio (OR) = 1.10, 95% confidence intervals (CI): 1.03–1.19). Similar results were found for QGC (OR = 1.11, 95%CI: 1.03–1.19). Despite the association did not reach statistical significance in the BKMR model, we observed an increasing trend between the joint effect of the four pollutants and the risk of BC, when fixing other chemicals at their median concentrations. BaP, cadmium and PCB153 also showed positive trends in the multi-pollutant mixture, while dioxin showed a modest inverse trend. Despite we found a clear evidence of a positive association between the joint exposure to pollutants and BC risk only from WQS and QGC regression, we observed a similar suggestive trend using BKMR. This study makes a major contribution to the understanding of the joint effects of air pollution.
Display omitted
•We report the joint effect of four xenoestrogens on breast cancer risk.•Weighted quantile sum regression and g-computation show significant mixture effects.•A similar suggestive trend is observed with the Bayesian kernel machine regression.•Benzo apyrene, cadmium and Polychlorinated biphenyl (153) dominate the effect.•Our study greatly improves the understanding of joint effects of air pollutants.
PDF
