Critical role of the major histocompatibility complex and IL-10 in matrilin-1-induced relapsing polychondritis in mice

Relapsing polychondritis (RP) is an autoimmune disease that affects extra-articular cartilage. Matrilin-1-induced relapsing polychondritis (MIRP) is a model for RP and is useful for studies of the pathogenic mechanisms in this disease. There are indications that the major histocompatibility complex (MHC) class II plays a major role in RP, since DR4(+ )patients are more commonly affected than controls. We have now addressed the role of the MHC region, as well as the non-MHC contribution, using congenic mouse strains. Of the MHC congenic strains, B10.Q (H2(q)) was the most susceptible, the B10.P (H2(p)) and B10.R (H2(r)) strains developed mild disease, while B10 strains carrying the v, b, f, or u H2 haplotypes were resistant. A slight variation of susceptibility of H2(q )strains (B10.Q> C3H.Q> DBA/1) was observed and the (B10.Q × DBA/1)F(1 )was the most susceptible of all strains. Furthermore, macrophages and CD4(+ )T cells were the most prominent cell types in inflammatory infiltrates of the tracheal cartilage. Macrophages are the major source of many cytokines, such as interleukin-10 (IL-10), which is currently being tested as a therapeutic agent in several autoimmune diseases. We therefore investigated B10.Q mice devoid of IL-10 through gene deletion and found that they developed a significantly more severe disease, with an earlier onset, than their heterozygous littermates. In conclusion, MHC genes, as well as non-MHC genes, are important for MIRP induction, and IL-10 plays a major suppressive role in cartilage inflammation of the respiratory tract

Förskolegårdens utformning och dess betydelse för barns lek och lärande

Syftet med detta kandidatexamensarbete är att uppmärksamma och skapa en bättre förståelse för hur förskolegårdars utformning påverkar barns möjlighet till lek och lärande. Största delen av uppsatsen utgörs av en litteraturstudie där vi studerat hur en pedagogisk utemiljö kan se ut och vilken betydelse utformningen och vegetationen på förskolegården har för lek och lärande. Vi har även tittat närmare på utformningens olika element för att kunna konstatera vilka delar som är särskilt betydelsefulla i barns utemiljöer. Uppsatsen innehåller även en fallstudie som baseras på observationer och informella intervjuer som genomförts på Uddens förskola i Trelleborg där vi kopplat resultatet från den teoretiska litteraturstudien till praktiken. Genom detta har vi konstaterat vilka värden och brister som finns i förskolans utemiljö samt diskuterat förskolegårdens utvecklingspotential. Genom våra studier har vi konstaterat att leken är viktig för förskolebarns lärande och utveckling. En välutformad lekmiljö lotsar leken och bidrar till barnets lärande och utveckling. Det är viktigt att förskolegården är en plats där barnen känner sig trygga och kan hitta sina egna platser. Därför bör förskolans utemiljö vara tillräckligt rymlig och utformad för att innehålla en variationsrikedom med rumsligheter och zoner för såväl självstyrda, snabba och vilda lekar, pedagogiska moment och stillhet samt lugna och sinnliga upplevelser för återhämtning. Ett särskilt betydelsefullt inslag i utformningen har visat sig vara vegetation och naturinslag av olika karaktär. Andra viktiga element i utformningen som bidrar till en pedagogisk verksamhet och stimulerar barns lek och inlärning är bland annat odling, vatten, djur, topografiska skillnader, en variation i markmaterialet samt olika typer av lekredskap.The purpose of this bachelor thesis is to draw attention to and gain a better understanding of how the design of preschool yards affects children's opportunities to play and learn. The thesis is largely composed of a literature study where we have studied how an educational outdoor environment could look like and what impact design and vegetation in the preschool yard have on play and learning. Furthermore, we have studied different elements in preschool yard design to establish which parts that are particularly important in children's outdoor environment. The thesis also includes a case study based on observations and informal interviews carried out at Uddens preschool in Trelleborg. In the case study we have applied the results of our theoretical studies. As a result we have been able to point out certain flaws and advantages in the outdoor environment and we discuss the potential for development in the preschool yard. Through our studies we have found that play is important for preschool children's learning and development. A well-designed outdoor environment will guide the children’s activities and thus contribute to their learning and development. It is important that the preschool yard is a place where children feel safe and can find their own places. Consequently, the outdoor environment should be spacious and designed to contain a diversity of spatial units and zones for both self-managed, fast and wild games, educational activities and calm, quiet and sensuous experiences for recovery. Vegetation and natural elements of different character have proven to be a particularly important feature of the design. Other key elements in the design that contribute to educational activities and stimulate children's ability to play and learn include garden patches, water, animals, topographical differences, a variation in surface materials as well as various types of play equipment

PLAYSPOTS : a Way to Create More Inviting Public Spaces for Children’s Play through Punctual Installations? An investigation based on a literature review and a case study of playspots in Odense

I denna masterexamensuppsats har vi undersökt möjligheten att skapa mer lekvänliga stadsrum genom punktvisa insatser i form av playspots. En playspot är en mindre lekmiljö, en installation eller ett enskilt element med syfte att uppmuntra eller inspirera till lek i staden. Den största delen av uppsatsen utgörs av en litteraturstudie där vi presenterar och diskuterar ett antal olika aspekter som genom den studerade litteraturen framkommit som särskilt betydelsefulla för att gestalta lekvänliga utemiljöer för barn. Uppsatsen innehåller även en fallstudie som vi utfört i Odense kommun. Här diskuterar vi hur väl vi tycker att kommunen lyckats uppnå en lekvänlig gestaltning av sina 13 playspots och på vilka sätt Odenses playspots kan bidra till att skapa mer lekvänliga stadsrum. I litteraturstudien har vi konstaterat att leken är viktig och betydelsefull för ett barns utveckling, inlärning och välmående. Vi har också dragit slutsatsen att en lekvänlig miljö är en plats där barnet självmant vill leka samt gärna återkommer till. Var barnet väljer att leka, vilken typ av lek som tar form samt hur länge ett barn leker på en plats påverkas av utemiljöns gestaltning. Vi menar således att gestaltningen har en viktig funktion för om en utemiljö kan ses som lekvänlig eller inte. Vi har i litteraturen funnit att det finns 21 aspekter som skulle kunna ses som särskilt betydelsefulla för gestaltningen av en lekvänlig utemiljö. Dessa aspekter har utmynnat i en analysmetod som vi sedan använt oss av då vi i vår fallstudie analyserat Odenses playspots. Vi har funnit att aspekterna kan delas in i två kategorier där båda kategorierna kan ses som lika viktiga för att uppnå en lekvänlig utemiljö. Aspekter som faller under kategori 1 definieras enligt följande: “Aspekter som är önskvärda att uppnå genom gestaltning för att skapa lekvänliga miljöer för barn”. Till kategori 1 hör följande aspekter: Väder- och årstidsanpassning, Tillgänglighet, Rymlighet, Omgivningsanpassning, Rumsindelning, Variation, Multifunktionalitet och Föränderlighet. Aspekter som faller under kategori 2 definieras enligt följande: “Aspekter som är önskvärda att gestalta med för att skapa lekvänliga miljöer för barn”. Dessa skulle kunna användas för att uppnå en eller flera aspekter i kategori 1. Till kategori 2 hör följande aspekter: Ljud, Ljus, Digital teknik och interaktivitet, Färg och mönster, Markmaterial, Vatten, Topografi, Vegetation, Djur, Löst material, Lekredskap, Konstnärliga utsmyckningar och Tillfälliga installationer. Hur lekvänlig en miljö kan sägas vara menar vi beror på hur aspekterna i de båda kategorierna används samt hur de samverkar och kombineras. Aspekterna kan därmed inte ses som enskilda delar då dessa verkar ihop för att skapa intressanta miljöer som lockar till lek. Vilken aspekt som kan ses som viktigast för att gestalta lekvänliga utemiljöer menar vi inte går att säga generellt då detta beror på platsens sammanhang. Genom vår fallstudie har vi kommit fram till att Odenses playspots har en varierande grad av lekvänlighet där vissa upplevs som mer lekvänliga medan andra kunde ha gestaltats på ett betydligt mer lekvänligt vis. Det är dock ett imponerande och inspirerande arbete som staden utfört och fortfarande arbetar med att utveckla. Då Odenses playspots har bidragit till att skapa mer lekvänliga stadsrum genom att synliggöra leken och skapa fler lekvänliga platser i staden skulle Odense också kunna ses som en mer lekvänlig stad jämfört med innan införandet av playspots. Vi menar att Odense kommun på många sätt är en förebild och stad att se upp till när det kommer till att skapa möjlighet för mer lek i stadsrummen. Vi tror att deras strategi och arbetssätt skulle vara inspirerande även för andra kommuner att ta del. Förutom en stark vilja att öka lekmöjligheterna och göra staden mer lekvänlig är Odense kommun inte unik som stad. Vi tror således att det skulle finnas stora möjligheter att på liknande sätt arbeta med punktvisa insatser i form av playspots även i andra städer. I framtiden hoppas vi därför få se fler städer som arbetar på liknande sätt.In this master’s thesis we have investigated the possibility of creating more inviting urban spaces for children through punctual installations, in this case playspots. A playspot is a smaller play space, an installation or an individual element with the purpose of encouraging or inspiring play in the city. The main part of the thesis consists of a literature review in which we present and discuss a number of different aspects identified in the literature as particularly important for the development of play-friendly outdoor environments for children. The thesis also contains a case study conducted in Odense municipality. In this part we discuss how well we think the municipality has managed to achieve a play-friendly design of their 13 playspots and how playspots can be a way to create more inviting urban spaces that encourage play. In the literature review, we have found that play is an important part of a child’s development, learning and well-being. Also, we have come to the conclusion that a play-friendly environment is a place where the child wants to play and to which the child gladly returns. It is a spot where the child chooses to play. What kind of play that takes place and how long the play lasts is dependent on the design of the environment. Therefore, we believe that the design has an important function to determine whether an outdoor environment can be considered play-friendly or not. In the literature, we have found 21 aspects that could be seen as particularly important to incorporate in the design of a play-friendly outdoor environment. These aspects have resulted in an analysis method that has been used in our case study when analyzing the playspots in Odense. We have found that the aspects can be divided into two categories, where both categories can be considered equally important for achieving an inviting environment for play. Aspects in category 1 are defined as follows: "Aspects that are desirable to achieve through design to create play-friendly environments for children". Category 1 includes the following aspects: Weather and seasonal adjustment, Availability, Spaciousness, Surroundings, Spatiality, Variation, Multi-functionality and Changeability. Aspects in category 2 are defined as follows: "Aspects that are desirable to be used to create play-friendly environments for children". These could be applied to achieve one or more aspects of category 1. Category 2 includes the following aspects: Sound, Light, Digital technology and interactivity, Color and patterns, Flooring materials, Water, Topography, Vegetation, Animals, Loose material, Play equipment, Artistic embellishment and Temporary installations. How play-friendly an outdoor environment can be considered to be, depends on how the aspects of both categories are used and how they interact and are combined with each other. Therefore, these aspects should not be seen as individual elements as they work together to create interesting spaces for play. Which aspect that can be regarded as the most important, when it comes to designing inviting outdoor environments, depends on the context of the site. Through our case study, we have reached the conclusion that the playspots in Odense have a varying degree of playability. Some of them are more play-friendly, while others could have been designed in a much more suitable way. Nevertheless, it is an impressive and inspiring work that the municipality has achieved and still is working on developing. The playspots in Odense have created more inviting urban spaces for children by making the play visible and creating more play spaces in the city. In several ways, Odense could be looked upon as a model and a city to be inspired by when it comes to creating opportunities for more play in urban spaces. We believe that their strategy and working methods could be inspirational for other municipalities as well. Odense municipality has a strong willingness to increase children’s opportunities for play and make the city more inviting. However, beyond this Odense is not unique as a city. Therefore, we believe it would be possible to work with punctual installations in other cities as well. In the future, we hope to see more cities working with playspots in a similar way

Six Tissue Transcriptomics Reveals Specific Immune Suppression in Spleen by Dietary Polyunsaturated Fatty Acids

Dietary polyunsaturated fatty acids (PUFA) are suggested to modulate immune function, but the effects of dietary fatty acids composition on gene expression patterns in immune organs have not been fully characterized. In the current study we investigated how dietary fatty acids composition affects the total transcriptome profile, and especially, immune related genes in two immune organs, spleen (SPL) and bone marrow cells (BMC). Four tissues with metabolic function, skeletal muscle (SKM), white adipose tissue (WAT), brown adipose tissue (BAT), and liver (LIV), were investigated as a comparison. Following 8 weeks on low fat diet (LFD), high fat diet (HFD) rich in saturated fatty acids (HFD-S), or HFD rich in PUFA (HFD-P), tissue transcriptomics were analyzed by microarray and metabolic health assessed by fasting blood glucose level, HOMA-IR index, oral glucose tolerance test as well as quantification of crown-like structures in WAT. HFD-P corrected the metabolic phenotype induced by HFD-S. Interestingly, SKM and BMC were relatively inert to the diets, whereas the two adipose tissues (WAT and BAT) were mainly affected by HFD per se (both HFD-S and HFD-P). In particular, WAT gene expression was driven closer to that of the immune organs SPL and BMC by HFDs. The LIV exhibited different responses to both of the HFDs. Surprisingly, the spleen showed a major response to HFD-P (82 genes differed from LFD, mostly immune genes), while it was not affected at all by HFD-S (0 genes differed from LFD). In conclusion, the quantity and composition of dietary fatty acids affected the transcriptome in distinct manners in different organs. Remarkably, dietary PUFA, but not saturated fat, prompted a specific regulation of immune related genes in the spleen, opening the possibility that PUFA can regulate immune function by influencing gene expression in this organ

Prediagnostic plasma concentrations of organochlorines and risk of B-cell non-Hodgkin lymphoma in envirogenomarkers: a nested case-control study

Background: Evidence suggests a largely environmental component to non-Hodgkin’s lymphoma (NHL). Persistent organic pollutants (POPs) including polychlorinated biphenyls (PCBs), DDE and HCB have been repeatedly implicated, but the literature is inconsistent and a causal relationship remains to be determined. Methods: The EnviroGenoMarkers study is nested within two prospective cohorts EPIC-Italy and the Northern Sweden Health and Disease Study. Six PCB congeners, DDE and HCB were measured in blood plasma samples provided at recruitment using gas-chromatography mass spectrometry. During 16 years follow-up 270 incident cases of B-cell NHL (including 76 cases of multiple myeloma) were diagnosed. Cases were matched to 270 healthy controls by centre, age, gender and date of blood collection. Cases were categorised into ordered quartiles of exposure for each POP based on the distribution of exposure in the control population. Logistic regression was applied to assess the association with risk, multivariate and stratified analyses were performed to identify confounders or effect modifiers. Results: The exposures displayed a strong degree of correlation, particularly amongst those PCBs with similar degrees of chlorination. There was no significant difference (p 90th percentile) the association was null for all POPs Conclusion: We report no evidence that a higher body burden of PCBs, DDE or HCB increased the risk of subsequent NHL diagnosis. Significantly inverse associations were noted for males with a number of the investigated POPs. We hypothesize these unexpected relationships may relate to the subtype composition of our population, effect modification by BMI or other unmeasured confounding. This study provides no additional support for the previously observed role of PCBs, DDE and HCB as risk factors for NHL

Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells

Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase-cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a 'folate trap'. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.In this study, Green, Marttila, Kiweler et al. characterize one-carbon metabolism rewiring in response to a dual MTHFD1 and MTHFD2 inhibitor. This work provides insight into one-carbon fluxes, and reveals a previously uncharacterized vulnerability in cancer cells created by folate trapping

A genomic biomarker signature can predict skin sensitizers using a cell-based in vitro alternative to animal tests

<p>Abstract</p> <p>Background</p> <p>Allergic contact dermatitis is an inflammatory skin disease that affects a significant proportion of the population. This disease is caused by an adverse immune response towards chemical haptens, and leads to a substantial economic burden for society. Current test of sensitizing chemicals rely on animal experimentation. New legislations on the registration and use of chemicals within pharmaceutical and cosmetic industries have stimulated significant research efforts to develop alternative, human cell-based assays for the prediction of sensitization. The aim is to replace animal experiments with in vitro tests displaying a higher predictive power.</p> <p>Results</p> <p>We have developed a novel cell-based assay for the prediction of sensitizing chemicals. By analyzing the transcriptome of the human cell line MUTZ-3 after 24 h stimulation, using 20 different sensitizing chemicals, 20 non-sensitizing chemicals and vehicle controls, we have identified a biomarker signature of 200 genes with potent discriminatory ability. Using a Support Vector Machine for supervised classification, the prediction performance of the assay revealed an area under the ROC curve of 0.98. In addition, categorizing the chemicals according to the LLNA assay, this gene signature could also predict sensitizing potency. The identified markers are involved in biological pathways with immunological relevant functions, which can shed light on the process of human sensitization.</p> <p>Conclusions</p> <p>A gene signature predicting sensitization, using a human cell line in vitro, has been identified. This simple and robust cell-based assay has the potential to completely replace or drastically reduce the utilization of test systems based on experimental animals. Being based on human biology, the assay is proposed to be more accurate for predicting sensitization in humans, than the traditional animal-based tests.</p