Targeting age‐specific changes in CD4+ T cell metabolism ameliorates alloimmune responses and prolongs graft survival

Age impacts alloimmunity. Effects of aging on T‐cell metabolism and the potential to interfere with immunosuppressants have not been explored yet. Here, we dissected metabolic pathways of CD4⁺ and CD8⁺ T cells in aging and offer novel immunosuppressive targets. Upon activation, CD4⁺ T cells from old mice failed to exhibit adequate metabolic reprogramming resulting into compromised metabolic pathways, including oxidative phosphorylation (OXPHOS) and glycolysis. Comparable results were also observed in elderly human patients. Although glutaminolysis remained the dominant and age‐independent source of mitochondria for activated CD4⁺ T cells, old but not young CD4⁺ T cells relied heavily on glutaminolysis. Treating young and old murine and human CD4⁺ T cells with 6‐diazo‐5‐oxo‐l‐norleucine (DON), a glutaminolysis inhibitor resulted in significantly reduced IFN‐γ production and compromised proliferative capacities specifically of old CD4⁺ T cells. Of translational relevance, old and young mice that had been transplanted with fully mismatched skin grafts and treated with DON demonstrated dampened Th1‐ and Th17‐driven alloimmune responses. Moreover, DON diminished cytokine production and proliferation of old CD4⁺ T cells in vivo leading to a significantly prolonged allograft survival specifically in old recipients. Graft prolongation in young animals, in contrast, was only achieved when DON was applied in combination with an inhibition of glycolysis (2‐deoxy‐d‐glucose, 2‐DG) and OXPHOS (metformin), two alternative metabolic pathways. Notably, metabolic treatment had not been linked to toxicities. Remarkably, immunosuppressive capacities of DON were specific to CD4⁺ T cells as adoptively transferred young CD4⁺ T cells prevented immunosuppressive capacities of DON on allograft survival in old recipients. Depletion of CD8⁺ T cells did not alter transplant outcomes in either young or old recipients. Taken together, our data introduce an age‐specific metabolic reprogramming of CD4⁺ T cells. Targeting those pathways offers novel and age‐specific approaches for immunosuppression.     

An NK-like CAR T cell transition in CAR T cell dysfunction

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Diversity measures in macroinvertebrate and zooplankton communities related to the trophic status of subtropical reservoirs: Contradictory or complementary responses?

Macroinvertebrate communities have been widely used as a tool for assessing the environmental quality of freshwater ecosystems, whereas zooplankton communities have been to some extent neglected. However, the importance of using different indicators to achieve a more comprehensive framework of assessment regarding water quality has been recognized. This study compared estimates of species richness (number of species) and the Shannon–Wiener index for data on macroinvertebrate and zooplankton communities in tropical reservoirs and related them to their trophic state. The trop+hic classification was obtained by applying the Carlson index (1977) modified by Toledo et al. (1983), and the index of the Brazilian Society of the Environmental Technology Agency. The comparative response of the different indicators was analyzed using a series of bivariate correlations (Draftsman’s plot). The results illustrate that diversity measures, namely species richness, responded differently when related to the trophic classification of reservoirs, depending on the community considered. The species richness of zooplankton was positively related to hypereutrophic conditions, due to the higher number of rotifer species, including tolerant generalist species and at the same time, as a result of the exclusion of species from other groups, whereas for macroinvertebrates, species richness was negatively related to hypereutrophic conditions. Melanoides tuberculatus, which exhibits a high tolerance and competitive ability under such conditions, was the dominant species in macroinvertebrate communities, which excluded endemic species and reduced local richness and diversity. The same indicators applied to the zooplankton and macroinvertebrate communities might therefore provide contradictory responses regarding ecological quality assessment in tropical reservoirs, which suggest that zooplankton should be taken into account among the biological quality elements considered in the ecological quality assessment, management, and restoration of water bodies.     

Testing for Validity and Reliability in Cross-Cultural Research

A set of procedures is offered for assessing interraler reliability and certain aspects of validity of codes in cross-cultural studies. The method assumes that at least two independent raters have coded more than one trait. Each trait coded by one rater is correlated with each trait coded by a second, and all the codings by a single rater are intercorrelated with each other. The results are presented in a multitrait-multi-rater matrix. From this matrix it is possible to determine the interrater reliability and discriminant validity of trails in addition to a higher order concept based on pairs of traits.     

Identification of Tumor Antigens in the HLA Peptidome of Patient-derived Xenograft Tumors in Mouse

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Highlights

• •Sufficient tumor tissues are often unavailable large HLA peptidome discovery.
• •Using patient derived xenograft (PDX) tumors can overcome this limitation.
• •The large PDX HLA peptidomes expand significantly those of the original biopsies.
• •The HLA peptidomes of the PDX tumors included many tumor antigens.

     

The stable evolutionary fixation of a bifunctional tyrosine-pathway protein in enteric bacteria

Abstract The bifunctional T-protein (chorismate mutase-T: cyclohexadienyl dehydrogenase) of l -tyrosine biosynthesis was found to be present in all genera making up the enteric bacteria. The dehydrogenase component of the T-protein was active with both prephenate and l -arogenate, showing it to be a cyclohexadienyl dehydrogenase. The dehydrogenase component, but not the mutase component, of the T-protein was feedback-inhibited by l -tyrosine. Unlike some other bifunctional proteins, the T-protein has evolved recently and is not ubiquitous. However, once the biochemical specialization of bifunctionality becomes established, the results indicate that such character states are strongly conserved through evolutionary time. Thus, bifunctional proteins can provide particularly reliable markers for small (recent origin), intermediate, and large (ancient origin) phylogenetic clusters.     

Virtual water and water footprints do not provide helpful insight regarding international trade or water scarcity

Many authors have estimated the virtual water content of good and services traded internationally, and many have calculated national water footprints that account for the volumes of virtual water imported and exported. Some authors have suggested that international trade of virtual water has been harmful to selected exporting countries with limited water endowments. Some suggest also that current patterns of international trade should be rearranged to make better use of global water resources. Yet, countries do not actually trade in virtual water. They trade in goods and services for which water is one of many inputs. Wise choices regarding water resources and smart strategies regarding international trade cannot be determined by focusing on water alone. The notions of virtual water and water footprints are not helpful indicators of optimal strategies regarding water resources, particularly when considering issues such as water scarcity or international trade. I describe four perspectives regarding virtual water and water footprints, with the goal of demonstrating the inadequacies of these notions in policy discussions and in efforts to determine the optimal allocation and use of water resources. The four perspectives are: (1) international trade should not be modified or regulated to reflect the virtual water content of traded commodities or water footprints in the countries of trading partners, (2) countries do not save water by engaging in virtual water trade, (3) consumers in one country cannot alleviate water scarcity or improve water quality in other countries, and (4) water footprints are not analogous to carbon or ecological footprints.     

A critical rebuttal of the proposed division of the genus Arcobacter into six genera using comparative genomic,phylogenetic, and phenotypic criteria

The proposal to restructure the genus Arcobacter into six distinct genera was critically examined using: comparative analyses of up to 80 Epsilonproteobacterial genome sequences (including 26 arcobacters); phylogenetic analyses of three housekeeping genes and also 342 core genes; and phenotypic criteria. Genome sequences were analysed with tools to calculate Percentage of Conserved Proteins, Average Amino-acid Identity, BLAST-based Average Nucleotide Identity, in silico DNA–DNA hybridisation values, genome-wide Average Nucleotide Identity, Alignment Fractions and G + C percentages. Genome analyses revealed the genus Arcobacter sensu lato to be relatively homogenous, and phylogenetic analyses clearly distinguished the group from other Epsilonproteobacteria. Genomic distinction of the genera proposed by Pérez-Cataluña et al. [2018] was not supported by any of the measures used and a subsequent risk of strain misidentification clearly identified. Similarly, phenotypic analyses supported the delineation of Arcobacter sensu lato but did not justify the position of the proposed novel genera. The present polyphasic taxonomic study strongly supports the continuance of the classification of “aerotolerant campylobacters” as Arcobacter and refutes the proposed genus-level subdivision of Pérez-Cataluña et al. [2018].     

The Alpha and Omega of Galactosylceramides in T Cell Immune Function

Glycosphingolipids are a subgroup of glycolipids that contain an amino alcohol sphingoid base linked to sugars. They are found in the membranes of cells ranging from bacteria to vertebrates. This group of lipids is known to stimulate the immune system through activation of a type of white blood cell known as natural killer T cell (NKT cell). Here we summarize the extensive research that has been done to identify the structures of natural glycolipids that stimulate NKT cells and to determine how these antigens are recognized. We also review studies designed to understand how glycolipid variants, both natural and synthetic, can alter the responses of NKT cells, leading to dramatic changes in the global immune response.     

The physical map ofMus musculus chromosome 11 reveals evolutionary relationship with different syntenic groups of genes inHomo sapiens

Summary The physical localization of sequences homologous to three cloned genes was determined by in situ hybridization to metaphase chromosomes. Previous work had assigned the skeletal myosin heavy chain gene cluster (Myh), the functional locus for the cellular tumor antigen p53 (Trp53-1), and the cellular homologue of the viral erb-B oncogene (Erbb) toMus musculus chromosome 11 (MMU11). Our results provide regional assignments ofMyh andTrp53-1 to chromosome bands B2C, and ofErbb to bands A1A4. Taken together with in situ mapping of three other loci on MMU 11 (Hox-2 homeobox-containing gene cluster, theSparc protein, and theColla-1 collagen gene), which have been reported elsewhere, these data allowed us to construct a physical map of MMU11 and to compare it with the linkage map of this chromosome. The map positions of the homologous genes on human chromosomes suggest evolutionary relationships of distinct regions of MMU11 with six different human chromosome arms: 1p, 5q, 7p, 16p, 17p, and 17q. The delineation of conserved chromosome regions has important implications for the understanding of karyotype evolution in mammalian species and for the development of animal models of human genetic diseases.