A preliminary phylogeographic study of Flavopunctelia and Punctelia inferred from rDNA ITS-sequences

A preliminary phylogeny of the genera Flavopunctelia and Punctelia is presented. Genus and species delimitations have been investigated using ITS rDNA-sequencing of populations from different continents. Current genus delimitations of Flavopunctelia, Punctelia and Parmelia are confirmed and the species status of recently resurrected Punctelia ulophylla is confirmed. The status of three cryptic species, Flavopunctelia soredica, Punctelia perreticulata and P. stictica is discussed. Flavopunctelia borrerioides and Punctelia perreticulata are reported from China for the first time.Esitatakse perekondade Flavopunctelia ja Punctelia esialgne fülogeneesi rekonstruktsioon. Perekondade ja liikide eraldamist on uuritud erinevatelt kontinentidelt pärinevate populatsioonide ITS rDNA sekventside alusel. Senine perekondade Flavopunctelia, Punctelia ja Parmelia piiritlemine on leidnud kinnitust, samuti liigi Punctelia ulophylla staatus. Arutletakse kolme krüptilise liigi, Flavopunctelia soredica, Punctelia perreticulata ja P. stictica staatuse üle. Teatatakse liikide Flavopunctelia borrerioides ja Punctelia perreticulata esmasleidudest HiinasFil: Thell, Arne. Lund University; SueciaFil: Herber, B.. Universitat Hamburg; AlemaniaFil: Aptroot, A.. Centraalbureau voor Schimmelcultures; Países BajosFil: Adler, Monica Teresa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Micología y Botánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Micología y Botánica; ArgentinaFil: Feuerer, T.. Universitat Hamburg; AlemaniaFil: Kärnefelt, Ingvar. Lund University; Sueci

Thymic negative selection is functional in NOD mice

Based on analyses of multiple TCR transgenic (tg) models, the emergence of pathogenic T cells in diabetes-prone NOD mice has been ascribed to a failure to censure autoreactive clones in the thymus. In contrast, using isolated and preselected thymocytes, we show that nonobese diabetic (NOD) genetic variation impairs neither clonal deletion nor downstream transcriptional programs. However, we find that NOD genetic variation influences αβ/γδ-lineage decisions promoted by early expression of tg αβ-TCRs at the double-negative (DN) stage. In B6 and other genetic backgrounds, tg αβ-TCRs behave like γδ-TCRs and commit a large fraction of DNs toward the γδ-lineage, thereby decreasing the size of the double-positive (DP) pool, which is efficiently positively and negatively selected. In NOD DNs, αβ-TCR signalosomes instead behave like pre-TCRs, resulting in high numbers of DPs competing for limited selection niches, and poor positive and negative selection. Once niche effects are neutralized in mixed bone marrow chimeras, positive and negative selection are equally efficient on B6 and NOD backgrounds. Biochemical analysis revealed a selective defect in the activation of Erk1/2 downstream of NOD αβ-TCR signalosomes. Therefore, NOD genetic variation influences αβ/γδ-lineage decisions when the αβ-TCR heterodimer is prematurely expressed, but not the process of negative selection

Synthesis of (E)-4-bromo-3-methoxybut-3-en-2-one, the key fragment in the polyhydroxylated chain common to oscillariolide and phormidolides A-C

The terminal bromomethoxydiene (BMD) moiety of the polyhydroxylated chain present in phormidolides and oscillariolides has been synthesized for first time. Several strategies for the stereoselective synthesis of the 4-bromo-3-methoxybut-3-en-2-ones are described. Furthermore, a preliminary study to successfully introduce this fragment within the polyol chain and introduction of the fatty acid allowed corroborate the end structure of the polyol

Metabolic regulation of regulatory T cell development and function

It is now well established that the effector T cell (Teff) response is regulated by a series of metabolic switches. Quiescent T cells predominantly require ATP-generating processes, whereas proliferating Teff require high metabolic flux through growth-promoting pathways, such as glycolysis. Pathways that control metabolism and immune cell function are intimately linked, and changes in cell metabolism at both the cell and system levels have been shown to enhance or suppress specific T cell effector functions. Furthermore, functionally distinct T cell subsets have been shown to require distinct energetic and biosynthetic pathways to support their specific functional needs. In particular, naturally occurring regulatory T cells (Treg) are characterized by a unique metabolic signature distinct to that of conventional Teff cells. We here briefly review the signaling pathways that control Treg metabolism and how this metabolic phenotype integrates their differentiation and function. Ultimately, these metabolic features may provide new opportunities for the therapeutic modulation of unwanted immune responses

PPARγ is a Major Driver of the Accumulation and Phenotype of Adipose-Tissue TregT_{reg} Cells

Obesity and type-2 diabetes have increased markedly over the past few decades, in parallel. One of the major links between these two disorders is chronic, low-grade inflammation. Prolonged nutrient excess promotes the accumulation and activation of leukocytes in visceral adipose tissue (VAT) and ultimately other tissues, leading to metabolic abnormalities such as insulin resistance, type-2 diabetes and fatty-liver disease. Although invasion of VAT by pro-inflammatory macrophages is considered to be a key event driving adipose-tissue inflammation and insulin resistance, little is known about the roles of other immune system cell types in these processes. A unique population of VAT-resident regulatory T $(T_{reg})$ cells was recently implicated in control of the inflammatory state of adipose tissue and, thereby, insulin sensitivity. Here we identify peroxisome proliferator-activated receptor (PPAR)-γ, the ‘master regulator’ of adipocyte differentiation, as a crucial molecular orchestrator of VAT $T_{reg}$ cell accumulation, phenotype and function. Unexpectedly, PPAR-γ expression by VAT $T_{reg}$ cells was necessary for complete restoration of insulin sensitivity in obese mice by the thiazolidinedione drug pioglitazone. These findings suggest a previously unknown cellular mechanism for this important class of thiazolidinedione drugs, and provide proof-of-principle that discrete populations of $T_{reg}$ cells with unique functions can be precisely targeted to therapeutic ends

Genetic determinants of co-accessible chromatin regions in activated T cells across humans.

Over 90% of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, we analyzed ATAC-seq and RNA-seq profiles from stimulated primary CD4+ T cells in up to 105 healthy donors. We found that regions of accessible chromatin (ATAC-peaks) are co-accessible at kilobase and megabase resolution, consistent with the three-dimensional chromatin organization measured by in situ Hi-C in T cells. Fifteen percent of genetic variants located within ATAC-peaks affected the accessibility of the corresponding peak (local-ATAC-QTLs). Local-ATAC-QTLs have the largest effects on co-accessible peaks, are associated with gene expression and are enriched for autoimmune disease variants. Our results provide insights into how natural genetic variants modulate cis-regulatory elements, in isolation or in concert, to influence gene expression

Der Jurastadel in Pittmannsdorf

Der um 1792 errichtete Pittmannsdorfer Stadel ist nicht nur einer der ältesten erhaltenen Jurastadel mit verbretterter Holzständerkonstruktion in der Region, er ist auch einer der letzten seiner Art. Mit seinen zum Teil kunstvoll verzierten Balken kräftigen Durchschnitts ist er zudem ein handwerklich bemerkenswert hochwertig ausgeführtes Zeugnis des regionaltypischen Stadelbaus und damit der ländlichen Baukultur der Zeit um 1800. Das Heft informiert über die Bedeutung, die Erbauung, die Nutzung und die Instandsetzung dieses wichtigen Baudenkmals

Marker-Independent Assessment of Molecular Activation Patterns in Macrophages

Tissue repair, regeneration, and fibrosis are processes regulated by inflammatory monocytes and monocyte-derived macrophages (MDMs) that circulate in peripheral blood or reside in tissue. After a traumatic injury, monocytes and macrophages undergo significant phenotypic and functional changes that allow them to play essential roles in the initiation, maintenance, and resolution stages of tissue repair. Macrophages are also highly sensitive to physical stimuli in their environment and sense, for example, the degree of stiffness of the surrounding extracellular matrix. This makes them promising targets in biomaterial research, as the macrophage response is a crucial factor for long-term implant survival and performance. In addition, designing implant materials in a way that reduces inflammation and facilitates tissue integration has the potential to significantly reduce surgical costs and increase the quality of life for many patients. The research on how the physical properties of implant materials influence macrophage biology is still in its infancy. This work investigates how alternative analysis methods to classical immunological techniques can help overcome the current challenges in macrophage biomaterial research. It was therefore investigated how standard methods like flow cytometry perform in identifying macrophage phenotype after detachment from extracellular matrix-mimicking biomaterials. Our findings show that the detachment of adherent macrophages from a substrate induces significant bias depending on the analyzed surface antigens. Raman microspectroscopy (RM) is a non-invasive spectroscopic method that does not require fixation or antibody staining of biological samples. RM was therefore implemented as an alternative for single cell analysis of adherent macrophages. It was shown that macrophage activation can be robustly identified based on distinct Raman fingerprint spectra and that this method can be employed on macrophages adherent to biomaterial substrates to identify activation and phenotype in a marker-independent manner. Lipid Raman spectra were found to be significantly altered between macrophage phenotypes, making lipids an ideal target for the identification of macrophage polarization using RM. Lastly, it was investigated, if the myeloid leukemia-derived monocytic cell line THP-1 shows similar molecular activation when compared to primary MDMs as identified by RM. THP-1 protein and phospholipid levels were significantly altered by proinflammatory activation in THP-1 macrophages while MDMs also showed altered nucleic acid and non-membrane intracellular lipid composition. Altogether the findings of this thesis will contribute to a faster and more efficient development of regenerative biomaterials

Dual role of B7 costimulation in obesity-related nonalcoholic steatohepatitis and metabolic dysregulation

The low-grade inflammatory state present in obesity contributes to obesity-related metabolic dysregulation, including nonalcoholic steatohepatitis (NASH) and insulin resistance. Intercellular interactions between immune cells or between immune cells and hepatic parenchymal cells contribute to the exacerbation of liver inflammation and steatosis in obesity. The costimulatory molecules, B7.1 and B7.2, are important regulators of cell-cell interactions in several immune processes; however, the role of B7 costimulation in obesity-related liver inflammation is unknown. Here, diet-induced obesity (DIO) studies in mice with genetic inactivation of both B7.1 and B7.2 (double knockout; DKO) revealed aggravated obesity-related metabolic dysregulation, reduced insulin signalling in the liver and adipose tissue (AT), glucose intolerance, and enhanced progression to steatohepatitis resulting from B7.1/B7.2 double deficiency. The metabolic phenotype of B7.1/B7.2 double deficiency upon DIO was accompanied by increased hepatic and AT inflammation, associated with largely reduced numbers of regulatory T cells (Tregs) in these organs. In order to assess the role of B7 costimulation in DIO in a non-Treg-lacking environment, we performed antibody (Ab)-mediated inhibition of B7 molecules in wild-type mice in DIO. Antibody-blockade of both B7.1 and B7.2 improved the metabolic phenotype of DIO mice, which was linked to amelioration of hepatic steatosis and reduced inflammation in liver and AT. Conclusion: Our study demonstrates a dual role of B7 costimulation in the course of obesity-related sequelae, particularly NASH. The genetic inactivation of B7.1/B7.2 deteriorates obesity-related liver steatosis and metabolic dysregulation, likely a result of the intrinsic absence of Tregs in these mice, rendering DKO mice a novel murine model of NASH. In contrast, inhibition of B7 costimulation under conditions where Tregs are present may provide a novel therapeutic approach for obesity-related metabolic dysregulation and, especially, NAS