Macrophages are strategically located throughout the body tissues, where they ingest and process foreign materials, dead cells and debris and recruit additional macrophages in response to ...inflammatory signals. They are highly heterogeneous cells that can rapidly change their function in response to local microenvironmental signals. In this Review, we discuss the four stages of orderly inflammation mediated by macrophages: recruitment to tissues; differentiation and activation in situ; conversion to suppressive cells; and restoration of tissue homeostasis. We also discuss the protective and pathogenic functions of the various macrophage subsets in antimicrobial defence, antitumour immune responses, metabolism and obesity, allergy and asthma, tumorigenesis, autoimmunity, atherosclerosis, fibrosis and wound healing. Finally, we briefly discuss the characterization of macrophage heterogeneity in humans.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Review on new issues concerning macrophage polarization and the impact of polarization and categorization of macrophage subsets on immunology.
Macrophages are now routinely categorized into ...phenotypic subtypes based on gene expression induced in response to cytokine and pathogen‐derived stimulation. In the broadest division, macrophages are described as being CAMs (M1 macrophages) or AAMs (M2 macrophages) based on their exposure to TLR and IFN signals or Th2 cytokines, respectively. Despite the prolific use of this simple classification scheme, little is known about the precise functions of effector molecules produced by AAMs, especially how representative the CAM and AAM subtypes are of tissue macrophages in homeostasis, infection, or tissue repair and how plasticity in gene expression regulates macrophage function in vivo. Furthermore, correlations between mouse and human tissue macrophages and their representative subtypes are lacking and are a major barrier to understanding human immunity. Here, we briefly summarize current features of macrophage polarization and discuss the roles of various macrophage subpopulations and macrophage‐associated genes in health and disease.
The molecular mechanisms of toxicity of chemically modified phosphorothioate antisense oligonucleotides (PS-ASOs) are not fully understood. Here, we report that toxic gapmer PS-ASOs containing ...modifications such as constrained ethyl (cEt), locked nucleic acid (LNA) and 2'-O-methoxyethyl (2'-MOE) bind many cellular proteins with high avidity, altering their function, localization and stability. We show that RNase H1-dependent delocalization of paraspeckle proteins to nucleoli is an early event in PS-ASO toxicity, followed by nucleolar stress, p53 activation and apoptotic cell death. Introduction of a single 2'-O-methyl (2'-OMe) modification at gap position 2 reduced protein-binding, substantially decreasing hepatotoxicity and improving the therapeutic index with minimal impairment of antisense activity. We validated the ability of this modification to generally mitigate PS-ASO toxicity with more than 300 sequences. Our findings will guide the design of PS-ASOs with optimal therapeutic profiles.
Mangroves are a globally important ecosystem that provides a wide range of ecosystem system services, such as carbon capture and storage, coastal protection and fisheries enhancement. Mangroves have ...significantly reduced in global extent over the last 50 years, primarily as a result of deforestation caused by the expansion of agriculture and aquaculture in coastal environments. However, a limited number of studies have attempted to estimate changes in global mangrove extent, particularly into the 1990s, despite much of the loss in mangrove extent occurring pre-2000. This study has used L-band Synthetic Aperture Radar (SAR) global mosaic datasets from the Japan Aerospace Exploration Agency (JAXA) for 11 epochs from 1996 to 2020 to develop a long-term time-series of global mangrove extent and change. The study used a map-to-image approach to change detection where the baseline map (GMW v2.5) was updated using thresholding and a contextual mangrove change mask. This approach was applied between all image-date pairs producing 10 maps for each epoch, which were summarised to produce the global mangrove time-series. The resulting mangrove extent maps had an estimated accuracy of 87.4% (95th conf. int.: 86.2–88.6%), although the accuracies of the individual gain and loss change classes were lower at 58.1% (52.4–63.9%) and 60.6% (56.1–64.8%), respectively. Sources of error included misregistration in the SAR mosaic datasets, which could only be partially corrected for, but also confusion in fragmented areas of mangroves, such as around aquaculture ponds. Overall, 152,604 km2 (133,996–176,910) of mangroves were identified for 1996, with this decreasing by −5245 km2 (−13,587–1444) resulting in a total extent of 147,359 km2 (127,925–168,895) in 2020, and representing an estimated loss of 3.4% over the 24-year time period. The Global Mangrove Watch Version 3.0 represents the most comprehensive record of global mangrove change achieved to date and is expected to support a wide range of activities, including the ongoing monitoring of the global coastal environment, defining and assessments of progress toward conservation targets, protected area planning and risk assessments of mangrove ecosystems worldwide.
A defining feature of resident gut macrophages is their high replenishment rate from blood monocytes attributed to tonic commensal stimulation of this site. In contrast, almost all other tissues ...contain locally maintained macrophage populations, which coexist with monocyte-replenished cells at homeostasis. In this study, we identified three transcriptionally distinct mouse gut macrophage subsets that segregate based on expression of Tim-4 and CD4. Challenging current understanding, Tim-4
CD4
gut macrophages were found to be locally maintained, while Tim-4
CD4
macrophages had a slow turnover from blood monocytes; indeed, Tim-4
CD4
macrophages were the only subset with the high monocyte-replenishment rate currently attributed to gut macrophages. Moreover, all macrophage subpopulations required live microbiota to sustain their numbers, not only those derived from blood monocytes. These findings oppose the prevailing paradigm that all macrophages in the adult mouse gut rapidly turn over from monocytes in a microbiome-dependent manner; instead, these findings supplant it with a model of ontogenetic diversity where locally maintained subsets coexist with rapidly replaced monocyte-derived populations.
Among patients with out-of-hospital cardiac arrest (OHCA) and ventricular fibrillation, more than half present with refractory ventricular fibrillation unresponsive to initial standard advanced ...cardiac life support (ACLS) treatment. We did the first randomised clinical trial in the USA of extracorporeal membrane oxygenation (ECMO)-facilitated resuscitation versus standard ACLS treatment in patients with OHCA and refractory ventricular fibrillation.
For this phase 2, single centre, open-label, adaptive, safety and efficacy randomised clinical trial, we included adults aged 18–75 years presenting to the University of Minnesota Medical Center (MN, USA) with OHCA and refractory ventricular fibrillation, no return of spontaneous circulation after three shocks, automated cardiopulmonary resuscitation with a Lund University Cardiac Arrest System, and estimated transfer time shorter than 30 min. Patients were randomly assigned to early ECMO-facilitated resuscitation or standard ACLS treatment on hospital arrival by use of a secure schedule generated with permuted blocks of randomly varying block sizes. Allocation concealment was achieved by use of a randomisation schedule that required scratching off an opaque layer to reveal assignment. The primary outcome was survival to hospital discharge. Secondary outcomes were safety, survival, and functional assessment at hospital discharge and at 3 months and 6 months after discharge. All analyses were done on an intention-to-treat basis. The study qualified for exception from informed consent (21 Code of Federal Regulations 50.24). The ARREST trial is registered with ClinicalTrials.gov, NCT03880565.
Between Aug 8, 2019, and June 14, 2020, 36 patients were assessed for inclusion. After exclusion of six patients, 30 were randomly assigned to standard ACLS treatment (n=15) or to early ECMO-facilitated resuscitation (n=15). One patient in the ECMO-facilitated resuscitation group withdrew from the study before discharge. The mean age was 59 years (range 36–73), and 25 (83%) of 30 patients were men. Survival to hospital discharge was observed in one (7%) of 15 patients (95% credible interval 1·6–30·2) in the standard ACLS treatment group versus six (43%) of 14 patients (21·3–67·7) in the early ECMO-facilitated resuscitation group (risk difference 36·2%, 3·7–59·2; posterior probability of ECMO superiority 0·9861). The study was terminated at the first preplanned interim analysis by the National Heart, Lung, and Blood Institute after unanimous recommendation from the Data Safety Monitoring Board after enrolling 30 patients because the posterior probability of ECMO superiority exceeded the prespecified monitoring boundary. Cumulative 6-month survival was significantly better in the early ECMO group than in the standard ACLS group. No unanticipated serious adverse events were observed.
Early ECMO-facilitated resuscitation for patients with OHCA and refractory ventricular fibrillation significantly improved survival to hospital discharge compared with standard ACLS treatment.
National Heart, Lung, and Blood Institute.
When planning a two‐arm group sequential clinical trial with a binary primary outcome that has severe implications for quality of life (e.g., mortality), investigators may strive to find the design ...that maximizes in‐trial patient benefit. In such cases, Bayesian response‐adaptive randomization (BRAR) is often considered because it can alter the allocation ratio throughout the trial in favor of the treatment that is currently performing better. Although previous studies have recommended using fixed randomization over BRAR based on patient benefit metrics calculated from the realized trial sample size, these previous comparisons have been limited by failures to hold type I and II error rates constant across designs or consider the impacts on all individuals directly affected by the design choice. In this paper, we propose a metric for comparing designs with the same type I and II error rates that reflects expected outcomes among individuals who would participate in the trial if enrollment is open when they become eligible. We demonstrate how to use the proposed metric to guide the choice of design in the context of two recent trials in persons suffering out of hospital cardiac arrest. Using computer simulation, we demonstrate that various implementations of group sequential BRAR offer modest improvements with respect to the proposed metric relative to conventional group sequential monitoring alone.
A relationship between non-neurological autoimmune (NNAI) disorders and psychosis has been widely reported but not yet subjected to meta-analysis. We conducted the first meta-analysis examining the ...association between NNAI disorders and psychosis and investigated the effect of 1) temporality (as determined by study design), 2) psychiatric diagnosis, and 3) specific autoimmune disorders.
Major databases were searched for articles published until April 2018; 31 studies, comprising data for >25 million individuals, were eligible. Using random-effects models, we examined the overall association between all NNAI disorders and psychosis; rheumatoid arthritis was examined separately given the well-established negative association with psychosis. Stratified analyses investigated the effect of temporality, psychiatric diagnosis, and specific NNAI disorders.
We observed a positive overall association between NNAI disorders and psychosis (odds ratio OR = 1.26; 95% confidence interval CI, 1.12–1.41) that was consistent across study designs and psychiatric diagnoses; however, considerable heterogeneity was detected (I2 = 88.08). Patterns varied across individual NNAI disorders; associations were positive for pernicious anemia (OR = 1.91; 95% CI, 1.29–2.84), pemphigoid (OR = 1.90; 95% CI, 1.62–2.24), psoriasis (OR = 1.70; 95% CI, 1.51–1.91), celiac disease (OR = 1.53; 95% CI, 1.12–2.10), and Graves’ disease (OR = 1.33; 95% CI, 1.03–1.72) and negative for ankylosing spondylitis (OR = 0.72; 95% CI, 0.54–0.98) and rheumatoid arthritis (OR = 0.65; 95% CI, 0.50–0.84).
While we observed a positive overall association between NNAI disorders and psychosis, this was not consistent across all NNAI disorders. Specific factors, including distinct inflammatory pathways, genetic influences, autoantibodies targeting brain proteins, and exposure to corticosteroid treatment, may therefore underlie this association.
Associations between influenza infection and psychosis have been reported since the eighteenth century, with acute "psychoses of influenza" documented during multiple pandemics. In the late 20
...century, reports of a season-of-birth effect in schizophrenia were supported by large-scale ecological and sero-epidemiological studies suggesting that maternal influenza infection increases the risk of psychosis in offspring. We examine the evidence for the association between influenza infection and schizophrenia risk, before reviewing possible mechanisms
which this risk may be conferred. Maternal immune activation models implicate placental dysfunction, disruption of cytokine networks, and subsequent microglial activation as potentially important pathogenic processes. More recent neuroimmunological advances focusing on neuronal autoimmunity following infection provide the basis for a model of infection-induced psychosis, potentially implicating autoimmunity to schizophrenia-relevant protein targets including the N-methyl-D-aspartate receptor. Finally, we outline areas for future research and relevant experimental approaches and consider whether the current evidence provides a basis for the rational development of strategies to prevent schizophrenia.
Tidal wetlands are expected to respond dynamically to global environmental change, but the extent to which wetland losses have been offset by gains remains poorly understood. We developed a global ...analysis of satellite data to simultaneously monitor change in three highly interconnected intertidal ecosystem types-tidal flats, tidal marshes, and mangroves-from 1999 to 2019. Globally, 13,700 square kilometers of tidal wetlands have been lost, but these have been substantially offset by gains of 9700 km
, leading to a net change of -4000 km
over two decades. We found that 27% of these losses and gains were associated with direct human activities such as conversion to agriculture and restoration of lost wetlands. All other changes were attributed to indirect drivers, including the effects of coastal processes and climate change.
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