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Summary: Fungal β-glucans are major drivers of trained immunity which increases long-term protection against secondary infections. Heterogeneity in β-glucan source, structure, and solubility alters interaction with the phagocytic receptor Dectin-1 and could impact strategies to improve trained immunity in humans. Using a panel of diverse β-glucans, we describe the ability of a specific yeast-derived whole-glucan particle (WGP) to reprogram metabolism and thereby drive trained immunity in human monocyte-derived macrophages in vitro and mice bone marrow in vivo. Presentation of pure, non-soluble, non-aggregated WGPs led to the formation of the Dectin-1 phagocytic synapse with subsequent lysosomal mTOR activation, metabolic reprogramming, and epigenetic rewiring. Intraperitoneal or oral administration of WGP drove bone marrow myelopoiesis and improved mature macrophage responses, pointing to therapeutic and food-based strategies to drive trained immunity. Thus, the investment of a cell in a trained response relies on specific recognition of β-glucans presented on intact microbial particles through stimulation of the Dectin-1 phagocytic response.

IntroductionMacrofungi, such as edible mushrooms, have been used as a valuable medical resource for millennia as a result of their antibacterial and immuno-modulatory components. Mushrooms contain dietary fibers known as β-glucans, a class of polysaccharides previously linked to the induction of Trained Immunity. However, little is known about the ability of mushroom-derived β-glucans to induce Trained Immunity.Methods & resultsUsing various powdered forms of the white button mushroom (Agaricus bisporus), we found that mouse macrophages pre-treated with whole mushroom powder (WMP) displayed enhanced responses to restimulation with TLR ligands, being particularly sensitive to Toll-like receptor (TLR)-2 stimulation using synthetic lipopeptides. This trained response was modest compared to training observed with yeast-derived β-glucans and correlated with the amount of available β-glucans in the WMP. Enriching for β-glucans content using either a simulated in-vitro digestion or chemical fractionation retained and boosted the trained response with WMP, respectively. Importantly, both WMP and digested-WMP preparations retained β-glucans as identified by nuclear magnetic resonance analysis and both displayed the capacity to train human monocytes and enhanced responses to restimulation. To determine if dietary incorporation of mushroom products can lead to Trained Immunity in myeloid cells in vivo, mice were given a regimen of WMP by oral gavage prior to sacrifice. Flow cytometric analysis of bone-marrow progenitors indicated alterations in hematopoietic stem and progenitor cells population dynamics, with shift toward myeloid-committed multi-potent progenitor cells. Mature bone marrow-derived macrophages derived from these mice displayed enhanced responses to restimulation, again particularly sensitive to TLR2.DiscussionTaken together, these data demonstrate that β-glucans from common macrofungi can train innate immune cells and could point to novel ways of delivering bio-available β-glucans for education of the innate immune system.

Over the previous three decades, the prevalence and growth of overweight and obese status has risen relentlessly in both the general population and pregnant women. This rise is seen in both higher pre-pregnancy body mass index measurements along with excessive weight gain during pregnancy. Maternal obesity has been shown to exacerbate co-morbidities such as insulin resistance, pregnancy induced hypertension, and infectious states in parturient mothers. These changes have been shown to subsequently increase rates of fetal anomalies and affect fetal growth, as well as various aspects of the delivery such as rates of instrumented vaginal deliveries and an increase in delivery by cesarean section. Maternal obesity increases fetal birth weight, influences the delivery room resuscitation of the neonate by increasing the need for respiratory support, and increases the risk of neonatal hypoxic ischemic encephalopathy. This review also looks at recent studies revealing the strong association between maternal and offspring obesity and other long-term neurodevelopmental outcomes of offspring.

Macrophages are a highly adaptive population of innate immune cells. Polarization with IFNγ and LPS into the ‘classically activated’ M1 macrophage enhances pro-inflammatory and microbicidal responses, important for eradicating bacteria such as Mycobacterium tuberculosis. By contrast, ‘alternatively activated’ M2 macrophages, polarized with IL-4, oppose bactericidal mechanisms and allow mycobacterial growth. These activation states are accompanied by distinct metabolic profiles, where M1 macrophages favor near exclusive use of glycolysis, whereas M2 macrophages up-regulate oxidative phosphorylation (OXPHOS). Here, we demonstrate that activation with IL-4 and IL-13 counterintuitively induces protective innate memory against mycobacterial challenge. In human and murine models, prior activation with IL-4/13 enhances pro-inflammatory cytokine secretion in response to a secondary stimulation with mycobacterial ligands. In our murine model, enhanced killing capacity is also demonstrated. Despite this switch in phenotype, IL-4/13 trained murine macrophages do not demonstrate M1-typical metabolism, instead retaining heightened use of OXPHOS. Moreover, inhibition of OXPHOS with oligomycin, 2-deoxy glucose or BPTES all impeded heightened pro-inflammatory cytokine responses from IL-4/13 trained macrophages. Lastly, this work identifies that IL-10 attenuates protective IL-4/13 training, impeding pro-inflammatory and bactericidal mechanisms. In summary, this work provides new and unexpected insight into alternative macrophage activation states in the context of mycobacterial infection.

Summary: Increased glycolytic metabolism recently emerged as an essential process driving host defense against Mycobacterium tuberculosis (Mtb), but little is known about how this process is regulated during infection. Here, we observe repression of host glycolysis in Mtb-infected macrophages, which is dependent on sustained upregulation of anti-inflammatory microRNA-21 (miR-21) by proliferating mycobacteria. The dampening of glycolysis by miR-21 is mediated through targeting of phosphofructokinase muscle (PFK-M) isoform at the committed step of glycolysis, which facilitates bacterial growth by limiting pro-inflammatory mediators, chiefly interleukin-1β (IL-1β). Unlike other glycolytic genes, PFK-M expression and activity is repressed during Mtb infection through miR-21-mediated regulation, while other less-active isoenzymes dominate. Notably, interferon-γ (IFN-γ), which drives Mtb host defense, inhibits miR-21 expression, forcing an isoenzyme switch in the PFK complex, augmenting PFK-M expression and macrophage glycolysis. These findings place the targeting of PFK-M by miR-21 as a key node controlling macrophage immunometabolic function. : Hackett et al. identify a role for the anti-inflammatory miR-21 in limiting host glycolysis during tuberculosis (TB) infection to favor bacterial replication. This occurs by targeting a pro-glycolytic isoform at the rate-limiting step in glycolysis, PFK-M, a process antagonized by the host Th1-cytokine IFN-γ, to promote full macrophage activation and antimicrobial function. Keywords: macrophage, metabolic reprogramming, tuberculosis, mycobacterium tuberculosis, glycolysis, microRNA, miR-21, interleukin-1b, phosphofructokinase, interferon gamma

Abstract Background Patient and Public Involvement (PPI) in research aims to improve the quality, relevance and appropriateness of research. PPI has an established role in clinical research where there is evidence of benefit, and where policymakers and funders place continued emphasis on its inclusion. However, for preclinical research, PPI has not yet achieved the same level of integration. As more researchers, including our team, aim to include PPI in preclinical research, the development of an evidence‐based approach is important. Therefore, this scoping review aimed to identify and map studies where PPI has been used in preclinical research and develop principles that can be applied in other projects. Methods A scoping review was conducted to search the literature in Medline (PubMed), EMBASE, CINAHL, PsycInfo and Web of Science Core Collection to identify applied examples of preclinical PPI. Two independent reviewers conducted study selection and data extraction separately. Data were extracted relating to PPI in terms of (i) rationale and aims, (ii) approach used, (iii) benefits and challenges, (iv) impact and evaluation and (v) learning opportunities for preclinical PPI. Findings were reviewed collaboratively by PPI contributors and the research team to identify principles that could be applied to other projects. Results Nine studies were included in the final review with the majority of included studies reporting PPI to improve the relevance of their research, using approaches such as PPI advisory panels and workshops. Researchers report several benefits and challenges, although evidence of formal evaluation is limited. Conclusion Although currently there are few examples of preclinical research studies reporting empirical PPI activity, their findings may support those aiming to use PPI in preclinical research. Through collaborative analysis of the scoping review findings, several principles were developed that may be useful for other preclinical researchers. Patient or Public Contribution This study was conducted as part of a broader project aiming to develop an evidence base for preclinical PPI that draws on a 5‐year preclinical research programme focused on the development of advanced biomaterials for spinal cord repair as a case study. A PPI Advisory Panel comprising seriously injured rugby players, clinicians, preclinical researchers and PPI facilitators collaborated as co‐authors on the conceptualization, execution and writing of this review, including refining the findings into the set of principles reported here.

We report the identification of 89 new systems containing ultracool dwarf companions to main-sequence stars and white dwarfs, using the citizen science project Backyard Worlds: Planet 9 and cross-reference between Gaia and CatWISE2020. 32 of these companions and 33 host stars were followed up with spectroscopic observations, with companion spectral types ranging from M7–T9 and host spectral types ranging from G2–M9. These systems exhibit diverse characteristics, from young to old ages, blue to very red spectral morphologies, potential membership to known young moving groups, and evidence of spectral binarity in nine companions. 20 of the host stars in our sample show evidence for higher-order multiplicity, with an additional 11 host stars being resolved binaries themselves. We compare this sample’s characteristics with those of the known stellar binary and exoplanet populations, and find our sample begins to fill in the gap between directly imaged exoplanets and stellar binaries on mass ratio–binding energy plots. With this study, we increase the population of ultracool dwarf companions to FGK stars by ∼42%, and more than triple the known population of ultracool dwarf companions with separations larger than 1000 au, providing excellent targets for future atmospheric retrievals.

We present the discovery of CWISE J050626.96+073842.4 (CWISE J0506+0738), an L/T transition dwarf with extremely red near-infrared colors discovered through the Backyard Worlds: Planet 9 citizen science project. Photometry from UKIRT and CatWISE give a ( J − K ) _MKO color of 2.97 ± 0.03 mag and a J _MKO − W2 color of 4.93 ± 0.02 mag, making CWISE J0506+0738 the reddest known free-floating L/T dwarf in both colors. We confirm the extremely red nature of CWISE J0506+0738 using Keck/NIRES near-infrared spectroscopy and establish that it is a low-gravity, late-type L/T transition dwarf. The spectrum of CWISE J0506+0738 shows possible signatures of CH _4 absorption in its atmosphere, suggesting a colder effective temperature than other known, young, red L dwarfs. We assign a preliminary spectral type for this source of L8 γ –T0 γ . We tentatively find that CWISE J0506+0738 is variable at 3–5 μ m based on multiepoch WISE photometry. Proper motions derived from follow-up UKIRT observations combined with a radial velocity from our Keck/NIRES spectrum and a photometric distance estimate indicate a strong membership probability in the β Pic moving group. A future parallax measurement will help to establish a more definitive moving group membership for this unusual object.

The European Court of Human Rights was created in order to supervise a rather classical legal instrument. But some peculiarities since its origins and several evolutions led to the establishment of a true “European public order” under its influence. This paper questions the possibility to consider the ECtHR as a “constitutional judge” and analyzes some of the most important changes it has produced in the domestic legal systems – above all in the public institutions – of the States parties to the European convention on human rights.

People with aphasia are often unable to access healthcare due to difficulties understanding and using spoken and written language, which impacts every step of their healthcare journey and outcomes. This article argues that it is important to apply the principles of the NHS England Accessible Information Standards (2017) to people with aphasia so they can meet their health information needs and rights. The processes to enable people with aphasia to access and participate in spoken and written communication in healthcare and the methods for training and supporting healthcare staff need to be considered at an individual, service, and organisational level.

Introduction: Patient and public involvement (PPI) aims to improve the quality, relevance, and appropriateness of research and ensure that it meets the needs and expectations of those affected by particular conditions to the greatest possible degree. The evidence base for the positive impact of PPI on clinical research continues to grow, but the role of PPI in preclinical research (an umbrella term encompassing ‘basic’, ‘fundamental’, ‘translational’ or ‘lab-based’ research) remains limited. As funding bodies and policymakers continue to increase emphasis on the relevance of PPI to preclinical research, it is timely to map the PPI literature to support preclinical researchers involving the public, patients, or other service users in their research. Therefore, the aim of this scoping review is to explore the literature on patient and public involvement in preclinical research from any discipline. Methods: This scoping review will search the literature in Medline (PubMed), Embase, CINAHL, PsycINFO, Web of Science Core Collection, Scopus, and OpenGrey.net to explore the application of PPI in preclinical research. This review will follow the Joanna Briggs Institute (JBI) guidelines for scoping reviews. It will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). Two reviewers will independently review articles for inclusion in the final review. Data extraction will be guided by the research questions. The PPI advisory panel will then collaboratively identify themes in the extracted data. Discussion: This scoping review will provide a map of current evidence surrounding preclinical PPI, and identify the body of literature on this topic, which has not been comprehensively reviewed to date. Findings will inform ongoing work of the research team, support the work of other preclinical researchers aiming to include PPI in their own research, and identify knowledge and practice gaps. Areas for future research will be identified.

Abstract Background The ankle brachial index (ABI) is widely used in clinical practice as a non-invasive method to detect the presence and severity of peripheral arterial disease (PAD). Current guidelines suggest that it should be used to monitor potential progression of PAD in affected individuals. As such, it is important that the test is reliable when used for repeated measurements, by the same or different health practitioners. This systematic review aims to examine the literature to evaluate the inter- and intra-rater reliability of the ABI. Methods A systematic search of MEDLINE, EMBASE and CINAHL Complete was conducted to 20 January 2019. Two authors independently reviewed and selected relevant studies and extracted the data. Methodological quality was determined using the Quality Appraisal of Reliability (QAREL) Checklist. Results Fifteen studies of ABI reliability in a range of patient populations were identified as suitable for inclusion in the review: seven considered inter-rater reliability, four intra-rater reliability, and four studies evaluated both inter- and intra-rater reliability. Inter-rater reliability was found to be highly variable, with intraclass correlation coefficients (ICC’s) ranging from poor to excellent (ICC 0.42–1.00), while intra-rater also demonstrated considerable variation, with ICCs from 0.42–0.98. Meta-analysis was not possible due to the lack of statistical information reported. Conclusions Results of included studies suggest the inter- and intra-tester reliability of the ABI is acceptable. However, inconsistencies in obtaining systolic pressure measurements, calculating ABI values, and incomplete reporting of methodologies and statistical analysis make it difficult to determine the validity of the results of included studies. Further research, with more consistent reliability methodology, statistical analysis and reporting conducted in populations at risk of PAD is needed to conclusively determine the ABI reliability.

The “problem of immigrant integration” is a recurrent topic in public discourse in Denmark. One attempt to manage this has been the establishment of mandatory Danish language classes, a sizeable component of a comparably extensive integration program. While language instruction is ostensibly aimed at equipping immigrants with language skills, culture, in an essentialized form, is foregrounded during instruction, where differences between Danes and foreigners are highlighted. With culture mapping neatly onto place, diversity within “a culture” is downplayed, creating homogenizing discourses regarding both Danes and immigrants, with immigrants portrayed as ill-suited for life in Denmark. This focus on culture is a prominent component of state-wide efforts to manage a group of individuals conceptualized as problematic- non-EU immigrants. Interventions aimed at altering the conduct of immigrants serve to alleviate the threat originating in what is imagined to be a risky group of individuals, thereby securing the well-being of the greater population.

Age-related macular degeneration (AMD), a complex disease involving genetic variants and environmental insults, is among the leading causes of blindness in Western populations. Genetic and histologic evidence implicate the complement system in AMD pathogenesis; and smoking is the major environmental risk factor associated with increased disease risk. Although previous studies have demonstrated that cigarette smoke exposure (CE) causes retinal pigment epithelium (RPE) defects in mice, and smoking leads to complement activation in patients, it is unknown whether complement activation is causative in the development of CE pathology; and if so, which complement pathway is required.Mice were exposed to cigarette smoke or clean, filtered air for 6 months. The effects of CE were analyzed in wildtype (WT) mice or mice without a functional complement alternative pathway (AP; CFB(-/-) ) using molecular, histological, electrophysiological, and behavioral outcomes.CE in WT mice exhibited a significant reduction in function of both rods and cones as determined by electroretinography and contrast sensitivity measurements, concomitant with a thinning of the nuclear layers as measured by SD-OCT imaging and histology. Gene expression analyses suggested that alterations in both photoreceptors and RPE/choroid might contribute to the observed loss of function, and visualization of complement C3d deposition implies the RPE/Bruch's membrane (BrM) complex as the target of AP activity. RPE/BrM alterations include an increase in mitochondrial size concomitant with an apical shift in mitochondrial distribution within the RPE and a thickening of BrM. CFB(-/-) mice were protected from developing these CE-mediated alterations.Taken together, these findings provide clear evidence that ocular pathology generated in CE mice is dependent on complement activation and requires the AP. Identifying animal models with RPE/BrM damage and verifying which aspects of pathology are dependent upon complement activation is essential for developing novel complement-based treatment approaches for the treatment of AMD.