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The response of macrophage aggregates in fish to a variety of environmental stressors has been useful as a biomarker of exposure to habitat degradation. Total volume of macrophage aggregates (MAV) was estimated in the liver and spleen of white perch Morone americana from Chesapeake Bay using stereological approaches. Hepatic and splenic MAV were compared between fish populations from the rural Choptank River (n = 122) and the highly urbanized Severn River (n = 131). Hepatic and splenic MAV increased with fish age, were greater in females from the Severn River only, and were significantly greater in fish from the more polluted Severn River (higher concentrations of polycyclic aromatic hydrocarbons, organochlorine pesticides, and brominated diphenyl ethers). Water temperature and dissolved oxygen had a significant effect on organ volumes, but not on MAV. Age and river were most influential on hepatic and splenic MAV, suggesting that increased MAV in Severn River fish resulted from chronic exposures to higher concentrations of environmental contaminants and other stressors. Hemosiderin was abundant in 97% of spleens and was inversely related to fish condition and positively related to fish age and trematode infections. Minor amounts of hemosiderin were detected in 30% of livers and positively related to concentrations of benzo[a]pyrene metabolite equivalents in the bile. This study demonstrated that hepatic and splenic MAV were useful indicators in fish from the 2 tributaries with different land use characteristics and concentrations of environmental contaminants. More data are needed from additional tributaries with a wider gradient of environmental impacts to validate our results in this species.

There have been recent extensive studies and rapid advancement on the pathogenesis underlying idiopathic pulmonary fibrosis (IPF), and intricate pathogenesis of IPF has been suggested. The purpose of this study was to clarify the logical relationship between these mechanisms. An extensive search was undertaken of the PubMed using the following keywords: “etiology,” “pathogenesis,” “alveolar epithelial cell (AEC),” “fibroblast,” “lymphocyte,” “macrophage,” “epigenomics,” “histone,” acetylation,” “methylation,” “endoplasmic reticulum stress,” “mitochondrial dysfunction,” “telomerase,” “proteases,” “plasminogen,” “epithelial-mesenchymal transition,” “oxidative stress,” “inflammation,” “apoptosis,” and “idiopathic pulmonary fibrosis.” This search covered relevant research articles published up to April 30, 2020. Original articles, reviews, and other articles were searched and reviewed for content; 240 highly relevant studies were obtained after screening. IPF is likely the result of complex interactions between environmental, genetic, and epigenetic factors: environmental exposures affect epigenetic marks; epigenetic processes translate environmental exposures into the regulation of chromatin; epigenetic processes shape gene expression profiles; in turn, an individual's genetic background determines epigenetic marks; finally, these genetic and epigenetic factors act in concert to dysregulate gene expression in IPF lung tissue. The pathogenesis of IPF involves various imbalances including endoplasmic reticulum, telomere length homeostasis, mitochondrial dysfunction, oxidant/antioxidant imbalance, Th1/Th2 imbalance, M1–M2 polarization of macrophages, protease/antiprotease imbalance, and plasminogen activation/inhibition imbalance. These affect each other, promote each other, and ultimately promote AEC/fibroblast apoptosis imbalance directly or indirectly. Excessive AEC apoptosis and impaired apoptosis of fibroblasts contribute to fibrosis. IPF is likely the result of complex interactions between environmental, genetic, and epigenetic factors. The pathogenesis of IPF involves various imbalances centered on AEC/fibroblast apoptosis imbalance.

Tumor associated macrophages (TAMs) play a critical role in biology of various cancers, including breast cancer. In the current study, we defined “M1” macrophage and “M1”/“M2” ratio by transcriptomic signatures using xCell. We investigated the association between high level of “M1” macrophage or “M1”/“M2” ratio and the tumor immune microenvironment by analyzing the transcriptome of publicly available cohorts, TCGA and METABRIC. We found that “M1” high tumors were not associated with prolonged survival compared with “M1” low tumors, or with the response to neoadjuvant chemotherapy. “M1” high tumors were associated with clinically aggressive features and “M1” high tumors enriched the cell proliferation and cell cycle related gene sets in GSEA. At the same time, “M1” high tumors were associated with high immune activity and favorable tumor immune microenvironment, as well as high expression of immune check point molecules. Strikingly, all these results were mirrored in “M1”/“M2” ratio high tumors. In conclusion, transcriptomically defined “M1” or “M1”/“M2” high tumors were associated with aggressive cancer biology and favorable tumor immune microenvironment but not with survival benefit, which resembled only part of their conventional clinical characteristics.

A 70-days feeding trial was performed to determine the effect of diets with whole plant-origin proteins added with different ratios of taurine:methionine on the growth, macrophage burst activity and antioxidant capacity of rainbow trout (Oncorhynchus mykiss) fingerlings. Triplicated groups of 70 fingerlings of an initial weight of 0.54±0.1 g (mean±±SD) were fed diets with soy protein isolate and Spirulina powder as protein sources (46% crude protein) and added (10 g/kg diet) with different taurine and methionine ratios: 0.0 and 10.0 (diet T0/M100), 2.5 and 7.5 (diet T25/M75), 5.0 and 5.0 (diet T50/M50), 7.5 and 2.5 (diet T75/M25) and 10.0 and 0.0 (diet T100/M0), respectively. At the end of the trial, growth performance, lipid and protein contents in liver and muscle, macrophage burst activity and liver antioxidant activity, were determined. The growth performance, macrophage burst activity and antioxidant activity were improved as the taurine increased in the diets. The ratio of 7.5 and 2.5 g/kg of taurine:methionine in diets with SPI and Spirulina powder as protein sources (diet T75/M25), seems to be the best inclusion for rainbow trout fingerlings., Highlights • Several ratios of taurine:methionine for rainbow trour fed while plant-protein diets. • Taurine improved antioxidant capacity of heptocites and burst activity of macropahges. • 10 g/kg of taurine:methionine inclusion is optimal for rainbow trout fed whole plant protein diets.

With the reduced availability of antibiotics, poultry producers are looking for feed additives to stimulate the immune system of their birds. Some beta-glucans have been shown to improve gut health in poultry subjected to a bacterial challenge, to increase the flow of new immunocytes into the various lymphoid organs, to increase macrophage function, to increase antibody titers after a vaccination and to function as an anti-inflammatory immunomodulator. As a result, beta-glucans may provide a tool for producers trying to reduce or eliminate the use of antibiotics in poultry diets.

This article contains errors in Figs. 5 and 6, for which we apologize. In Fig. 5f, the image ‘E12.5 tail’ was inadvertently replaced with a duplicate of the image ‘E12.5 trunk’ from the same panel. In Figure 6d, the image ‘E9.5/OH-TAM E8.5, embryo’ was inadvertently replaced with a duplicate of the image ‘E10.5/ OH-TAM E8.5, embryo’ from Fig. 6b. The corrected versions of these figures appear in the Author Correction associated with this Article.

The article "Reducing macrophage numbers alleviates temporomandibular joint ankylosis", written by Lu Zhao, E Xiao, Linhai He, Denghui Duan, Yang He, Shuo Chen, Yi Zhang and Yehua Gan, was originally published electronically on the publisher's internet portal.

Evidence supports the theory that bacterial communities colonizing Echinacea purpurea contribute to the innate immune enhancing activity of this botanical. Previously, we reported that only about half of the variation in in vitro monocyte stimulating activity exhibited by E. purpurea extracts could be accounted for by total bacterial load within the plant material. In the current study, we test the hypothesis that the type of bacteria, in addition to bacterial load, is necessary to fully account for extract activity. Bacterial community composition within commercial and freshly harvested (wild and cultivated) E. purpurea aerial samples was determined using high-throughput 16S rRNA gene pyrosequencing. Bacterial isolates representing 38 different taxa identified to be present within E. purpurea were acquired, and the activity exhibited by the extracts of these isolates varied by over 8000-fold. Members of the Proteobacteria exhibited the highest potency for in vitro macrophage activation and were the most predominant taxa. Furthermore, the mean activity exhibited by the Echinacea extracts could be solely accounted for by the activities and prevalence of Proteobacteria members comprising the plant-associated bacterial community. The efficacy of E. purpurea material for use against respiratory infections may be determined by the Proteobacterial community composition of this plant, since ingestion of bacteria (probiotics) is reported to have a protective effect against this health condition.

BACKGROUND. In inflammatory blood vessel diseases, macrophages represent a key component of the vascular infiltrates and are responsible for tissue injury and wall remodeling. METHODS. To examine whether inflammatory macrophages in the vessel wall display a single distinctive effector program, we compared functional profiles in patients with either coronary artery disease (CAD) or giant cell arteritis (GCA). RESULTS. Unexpectedly, monocyte-derived macrophages from the 2 patient cohorts displayed disease-specific signatures and differed fundamentally in metabolic fitness. Macrophages from CAD patients were high producers for T cell chemoattractants (CXCL9, CXCL10), the cytokines IL-1β and IL-6, and the immunoinhibitory ligand PD-L1. In contrast, macrophages from GCA patients upregulated production of T cell chemoattractants (CXCL9, CXCL10) but not IL-1β and IL-6, and were distinctly low for PD-L1 expression. Notably, disease-specific effector profiles were already identifiable in circulating monocytes. The chemokinehicytokinehiPD-L1hi signature in CAD macrophages was sustained by excess uptake and breakdown of glucose, placing metabolic control upstream of inflammatory function. CONCLUSIONS. We conclude that monocytes and macrophages contribute to vascular inflammation in a disease-specific and discernible pattern, have choices to commit to different functional trajectories, are dependent on glucose availability in their immediate microenvironment, and possess memory in their lineage commitment. FUNDING. Supported by the NIH (R01 AR042527, R01 HL117913, R01 AI108906, P01 HL129941, R01 AI108891, R01 AG045779 U19 {"type":"entrez-nucleotide","attrs":{"text":"AI057266","term_id":"3331132","term_text":"AI057266"}}AI057266, R01 AI129191), I01 {"type":"entrez-nucleotide","attrs":{"text":"BX001669","term_id":"26186629","term_text":"BX001669"}}BX001669, and the Cahill Discovery Fund.

The main intent of this work (after the by chance finding, in archived histological slides) is to characterize one previously non-described liver lesion of the Iberian barbel from the Vizela River (Portugal). This ran through a textile and dyeing industrial region. The lesion type was made of groups of foamy cells (presumptive macrophages), which appear either as a "smaller non-nodular form," without a connective tissue capsule and displaying an irregular profile, or as a "bigger nodular form," presenting a thin capsule and a circular profile. The nodular forms could appear multi-layered, resembling "cross-sectioned onions". The lesions number, dimension, and structural complexity were greater in bigger fish, appearing only after a history of poor water quality. In extreme cases, the lesions slightly protruded the liver surface. Special histological staining proved the connective tissue nature of the capsule (and its eventual septa), the presence of proteins, glycoproteins, lipofuscin, melanin, iron (putative hemosiderin), and copper, in a variable number of foamy cells within the lesions. At times, degenerating hepatocytes appeared at the border of the lesions. It is proposed that this lesion type incorporates both macrophages and degenerating hepatocytes, looking as one (unpublished) form of a macrophage aggregate. The term "foamy-cell nodules" was advanced for this abnormality. The lesion could have been induced by pollution, because: no parasites were ever associated with the lesion; there was co-existence of the lesion with a water quality status scored as "bad"; such lesion neither existed in fish sampled after mitigation and remediation measures nor in reference fish.

Overcrowding conditions and temperatures shifts regularly manifest in large-scale infections of farmed fish, resulting in economic losses for the global aquaculture industries. Increased understanding of the functional mechanisms of fish antimicrobial host defenses is an important step forward in prevention of pathogen-induced morbidity and mortality in aquaculture setting. Like other vertebrates, macrophage-lineage cells are integral to fish immune responses and for this reason, much of the recent fish immunology research has focused on fish macrophage biology. These studies have revealed notable similarities as well as striking differences in the molecular strategies by which fish and higher vertebrates control their respective macrophage polarization and functionality. In this review, we address the current understanding of the biological mechanisms of teleost macrophage functional heterogeneity and immunity, focusing on the key cytokine regulators that control fish macrophage development and their antimicrobial armamentarium.

Macrophage behavior is of great interest in response to tissue injury and promotion of regeneration. With increasing numbers of zebrafish reporter-based assays, new capabilities now exist to characterize macrophage migration, and their responses to biochemical cues, such as reactive oxygen species. Real time detection of macrophage behavior in response to oxidative stress using quantitative measures is currently beyond the scope of commercially available software solutions, presenting a gap in understanding macrophage behavior. To address this gap, we developed an image analysis pipeline solution to provide real time quantitative measures of cellular kinetics and reactive oxygen species content in vivo after tissue injury. This approach, termed Zirmi, differs from current software solutions that may only provide qualitative, single image analysis, or cell tracking solutions. Zirmi is equipped with user-defined algorithm parameters to customize quantitative data measures with visualization checks for an analysis pipeline of time-based changes. Moreover, this pipeline leverages open-source PhagoSight, as an automated keyhole cell tracking solution, to avoid parallel developments and build upon readily available tools. This approach demonstrated standardized space- and time-based quantitative measures of (1) fluorescent probe based oxidative stress and (2) macrophage recruitment kinetic based changes after tissue injury. Zirmi image analysis pipeline performed at execution speeds up to 10-times faster than manual image-based approaches. Automated segmentation methods were comparable to manual methods with a DICE Similarity coefficient > 0.70. Zirmi provides an open-source, quantitative, and non-generic image analysis pipeline. This strategy complements current wide-spread zebrafish strategies, for automated standardizations of analysis and data measures.

Reticulo-endothelial macrophages are central for the regulation of iron homeostasis, thanks to their ability to recycle red blood cell-derived iron. Macrophages are also key innate immune cells which exhibit remarkable functional plasticity. These two roles are tightly interconnected: on the one hand, macrophage polarisation dictates the expression of iron-regulated genes and determines cell iron handling; on the other, iron availability affects immune effector functions. Recent observations support a role for free haem and iron in shaping macrophage plasticity towards an M1-like pro-inflammatory phenotype. These findings have implications for the pathophysiology of sickle cell disease, hallmarked by haemolysis and elevated circulating haem and iron, as well as for the tumour microenvironment, characterised by haemolytic red blood cell extravasation and iron-loaded macrophages. Consistently, haem scavenging suppresses the pro-inflammatory profile of macrophages, reducing chronic inflammation in sickle cell disease, whereas nanoparticle-mediated iron delivery to the tumour microenvironment elicits pro-inflammatory macrophages with tumour killing properties, thus delaying tumour growth. This line of research paved the way for the therapeutic modulation of macrophage plasticity achievable through the application of different iron sources or scavengers/chelators according to the desired beneficial effect.

We investigated the influence of nutritional conditions on histological changes in melano-macrophage (MM) accumulation in the kidney caused by long-term starvation. These data were used to determine nutritional indices for olive flounder, Paralichthys olivaceus (Temminck and Schlegel). Experimental groups were established: control, fed and starved. All fish were fed daily with commercial feed at 1–3% of their total body weight for 2 weeks before the start of the experiment (initial control). The control group received feed at 1–3% of their total body weight and the fed group received feed ad libitum, while the starved group fasted throughout the experiment. Ten fish were removed from the initial control at the start of the experiment and each of the three groups every 4 weeks during the 12 weeks of the experiment to examine to investigate kidney MM accumulation. Kidney MMs with dark brown pigment were randomly distributed in the kidneys of starved fish, increasing rapidly after week 4, while deposition levels remained low throughout the experiment in the control and fed groups. These results suggest that catabolic tissue breakdown is a major factor contributing to the formation of pigments within MMs. These results suggest that the degree of MMs deposition in the kidney can be used as alternative indicators to identify starvation in wild and cultured olive flounder.

Two experiments were conducted to study the interaction between dietary lutein and fat levels in broiler chicks hatched from lutein depleted (Experiment I) and repleted (Experiment II) eggs. In both experiments, a 2 x 3 factorial arrangement of treatments resulted in six dietary treatments (fat at 3% and 6% and lutein at 0, 25 and 50 mg/kg feed) that were fed for 23 days to 18 birds per treatment (in three replications). In Experiment I, the anti-dinitrophenyl-keyhole-lympet-hemocyanin (anti-DNP-KLM) serum antibody response at day 22 and macrophage phagocytotic index at day 17 did not differ among treatment groups (p > 0.05). The concavalin A and phytohaemagglutinin-P lymphocyte proliferation index at day 19 was greater in birds fed 50 mg of lutein and 3% fat than in birds fed all other diets (p < 0.05). Independent of the level of dietary fat, dietary lutein increased macrophage (day 23) nitrite production measured 46 h after in vitro stimulation with LPS (p < 0.05). Among the birds fed lutein at 25 or 50 mg/kg feed, birds fed 3% fat had higher LPS-induced nitrite production compared to the birds fed 6% fat after 46 (p = 0.014) or 70 h (p < 0.001). In Experiment II, macrophage nitrite production was measured at 54 h after LPS stimulation on days 11, 15, 19 and 23. An interaction between dietary lutein and fat levels on nitrite production was observed on day 19 (p = 0.012), where macrophages from birds fed 0 mg lutein and 3% fat had the highest nitrite production (p = 0.012). Macrophages from birds fed lutein at 25 and 50 mg/kg diet and 3% fat had higher (p = 0.012) nitrite production than birds fed 6% fat. Thus, in birds hatched from lutein deplete and replete eggs, modulation of macrophage nitrite production by lutein is dependent on the level of dietary fat.

Aims To develop a rapid detection procedure for Listeria monocytogenes in infant formula and lettuce using a macrophage-based enrichment protocol and real-time PCR. Methods and Results A macrophage cell culture system was employed for the isolation and enrichment of L. monocytogenes from infant formula and lettuce for subsequent identification using real-time PCR. Macrophage monolayers were exposed to infant formula and lettuce contaminated with a serial dilution series of L. monocytogenes. As few as approx. 10 CFU ml−1 or g−1 of L. monocytogenes were detected in infant formula and lettuce after 16 h postinfection by real-time PCR. Internal positive PCR controls were utilized to eliminate the possibility of false-negative results. Co-inoculation with Listeria innocua did not reduce the L. monocytogenes detection sensitivity. Intracellular L. monocytogenes could also be isolated on Listeria selective media from infected macrophage lysates for subsequent confirmation. Conclusions The detection method is highly sensitive and specific for L. monocytogenes in infant formula and lettuce and establishes a rapid identification time of 20 and 48 h for presumptive and confirmatory identification, respectively. Significance and Impact of the Study The method is a promising alternative to many currently used q-PCR detection methods which employ traditional selective media for enrichment of contaminated food samples. Macrophage enrichment of L. monocytogenes eliminates PCR inhibitory food elements and contaminating food microflora which produce cleaner samples that increase the rapidity and sensitivity of detection.

Summary: The Macrophage Pathway Knowledgebase (MACPAK) is a computational system that allows biomedical researchers to query and study the dynamic behaviors of macrophage molecular pathways. It integrates the knowledge of 230 reviews that were carefully checked by specialists for their accuracy and then converted to 230 dynamic mathematical pathway models. MACPAK comprises a total of 24 009 entities and 12 774 processes and is described in the Cell System Markup Language (CSML), an XML format that runs on the Cell Illustrator platform and can be visualized with a customized Cytoscape for further analysis. Availability: MACPAK can be accessed via an interactive web site at http://macpak.csml.org. The CSML pathway models are available under the Creative Commons license. Contact: masao@hgc.jp

Water extracts from meats and offals were incubated with a macrophage cell line (RAW 264.7), and nitrite in the medium was measured as an index of the macrophage stimulating activity. Ten of 38 water extracts had macrophage stimulants and chicken meat, chicken gizzard, cattle reticulorumen, swine stomach, and swine cerebrum had high activities.

Toxicologists and pathologists are often faced with the dilemma of categorizing changes observed in the respiratory tract of laboratory animals as either "adaptive" or "toxic." However, it is often difficult to interpret the nature of a given change as either "adaptive" or "toxic." Certain lesions or changes in the respiratory tract are to be expected from the concentration of materials given or the experimental design of a study. Careful analysis suggests that some of these changes may be more properly described as adaptive rather than toxic within the context of a given study or situation. Tissue changes discussed in this paper include squamous metaplasia of laryngeal epithelium, goblet cell change in respiratory epithelium, macrophage accumulation within alveoli, and bronchiolization of alveolar epithelium. Examples provided show that some of these changes observed in inhalation studies are similar in severity but slightly increased in frequency over sham control animals. The introduction of exogenous material into the respiratory tract of laboratory animals in an experimental setting should be expected to result in certain changes. The challenge scientists must accept is to interpret these changes so that toxic events may be separated from adaptive changes. In order to meet this challenge, studies incorporating several species and novel technologies may have to be utilized.

Mononuclear phagocytes, including circulating monocytes and tissue macrophages, play a central role in resistance to viruses. This resitance can be expressed both non-specifically, and specifically in indiction, regulation and amplification of humoral and cell mediated immune responses to viruses. These lead to the extrinsic effect of macrophages on other virus-infected cells or free virus, and the intrinsic effect on viruses within macrophages. While these interactions usually appear to be protective, immunopathologic consequences as well as macrophage dysfunctions have also been noted. The outcome of any given interaction (viral elimination, peristance, latency or transformation) varies markedly with the type of macrophage. The molecular mechanisms involved in these very diverse macrophage-virus interactions are currently under study.

Discrete, round to ovoid macrophage aggregations (MA) containing pigment are commonly found widely distr ibuted in the spleen, l i ve r , and kidney of the higher te leos t i i (Agius 1980). These cel lu lar aggregations have been variously named (Grove 1968), most recently melano-macrophage centers (MMC) by Roberts (1975). The la t ter author, El l ls (1974), and Ferguson (1976) have suggested that MA have analogies to the germinal centers of homeotherms.

Air pollution is associated with a high burden or morbidity and mortality, but exposure cannot be quantified rapidly or cheaply. The particulate burden of macrophages from induced sputum may provide a biomarker. We compare the feasibility of two methods for digital quantification of airway macrophage particulate load. Induced sputum samples were processed and analysed using ImageJ and Image SXM software packages. We compare each package by resources and time required. 13 adequate samples were obtained from 21 patients. Median particulate load was 0.38 μm2 (ImageJ) and 4.0 % of the total cellular area of macrophages (Image SXM), with no correlation between results obtained using the two methods (correlation coefficient = −0.42, p = 0.256). Image SXM took longer than ImageJ (median 26 vs 54 mins per participant, p = 0.008) and was less accurate based on visual assessment of the output images. ImageJ’s method is subjective and requires well-trained staff. Induced sputum has limited application as a screening tool due to the resources required. Limitations of both methods compared here were found: the heterogeneity of induced sputum appearances makes automated image analysis challenging. Further work should refine methodologies and assess inter- and intra-observer reliability, if these methods are to be developed for investigating the relationship of particulate and inflammatory response in the macrophage.

When the human genome was sequenced, it came as a surprise that it contains "only" 21,306 protein-coding genes. However, complexity and diversity are multiplied by alternative splicing, non-protein-coding transcripts, or post-translational modifications (PTMs) on proteome level. Here, we discuss how the multi-tasking potential of proteins can substantially enhance the complexity of the proteome further, while at the same time offering mechanisms for the fine-regulation of cell responses. Discoveries over the past two decades have led to the identification of "surprising" and previously unrecognized functionalities of long known cytokines, inflammatory mediators, and intracellular proteins that have established novel molecular networks in physiology, inflammation, and cardiovascular disease. In this mini-review, we focus on alarmins and atypical chemokines such as high-mobility group box protein-1 (HMGB-1) and macrophage migration-inhibitory factor (MIF)-type proteins that are prototypical examples of these classes, featuring a remarkable multitasking potential that allows for an elaborate fine-tuning of molecular networks in the extra- and intracellular space that may eventually give rise to novel "task"-based precision medicine intervention strategies.

FOLLOWING recent reports on the effect of ‘smog’1, and of the increasing incidence of air pollution in industrial and urban areas2, we have been prompted to investigate the activity of the macrophage system following inhalation of an atmosphere contaminated with sulphur dioxide. The choice of this gas was made due to its predominance in air-pollution, and to its ability to cause immediate and obvious reactions on the respiratory tract3.

This book suffers from the defects of many publications of symposia or special meetings. It details some papers presented at a meeting held in May 1970 on various aspects of cell mediated immunity. This is an extremely fast moving field and although the basic information in the text is correct, much of it, particularly interpretations and understanding of mechanisms, have been altered considerably by information available since May 1970. The review of Valentine on "The Transformation and Proliferation of Lymphocytes 'in Vitro' " does not give sufficient chemical or biochemical background on the various nonspecific stimulants. There is a good review on "Inhibition of Macrophage Migration" by Lamelin. The review by Wolstencroft, particularly in relation to the "Lymphokines," does not provide the reader with the most up-to-date information. The section by Revillard on the "Clinical Applications of 'in Vitro' Tests" is a useful compilation of data that have been very