A pentapeptide as minimal antigenic determinant for MHC class I-restricted T lymphocytes

Peptides that are antigenic for T lymphocytes are ligands for two receptors, the class I or II glycoproteins that are encoded by genes in the major histocompatibility complex, and the idiotypic / chain T-cell antigen receptor1–9. That a peptide must bind to an MHC molecule to interact with a T-cell antigen receptor is the molecular basis of the MHC restriction of antigen-recognition by T lymphocytes10,11. In such a trimolecular interaction the amino-acid sequence of the peptide must specify the contact with both receptors: agretope residues bind to the MHC receptor and epitope residues bind to the T-cell antigen receptor12,13. From a compilation of known antigenic peptides, two algorithms have been proposed to predict antigenic sites in proteins. One algorithm uses linear motifs in the sequence14, whereas the other considers peptide conformation and predicts antigenicity for amphipathic -helices15,16. We report here that a systematic delimitation of an antigenic site precisely identifies a predicted pentapeptide motif as the minimal antigenic determinant presented by a class I MHC molecule and recognized by a cytolytic T lymphocyte clone

Nonlinear regional warming with increasing CO₂ concentration

When considering adaptation measures and global climate mitigation goals, stakeholders need regional-scale climate projections, including the range of plausible warming rates. To assist these stakeholders, it is important to understand whether some locations may see disproportionately high or low warming from additional forcing above targets such as 2 K (ref. 1). There is a need to narrow uncertainty2 in this nonlinear warming, which requires understanding how climate changes as forcings increase from medium to high levels. However, quantifying and understanding regional nonlinear processes is challenging. Here we show that regional-scale warming can be strongly superlinear to successive CO2 doublings, using five different climate models. Ensemble-mean warming is superlinear over most land locations. Further, the inter-model spread tends to be amplified at higher forcing levels, as nonlinearities grow—especially when considering changes per kelvin of global warming. Regional nonlinearities in surface warming arise from nonlinearities in global-mean radiative balance, the Atlantic meridional overturning circulation, surface snow/ice cover and evapotranspiration. For robust adaptation and mitigation advice, therefore, potentially avoidable climate change (the difference between business-as-usual and mitigation scenarios) and unavoidable climate change (change under strong mitigation scenarios) may need different analysis methods

T-helper 1 versus T-helper 2 lymphocyte immunodysregulation is the central factor in genesis of Burkitt lymphoma: hypothesis

<p>Abstract</p> <p>Background</p> <p>The HIV epidemic has challenged our previous understanding of endemic Burkitt's lymphoma. Despite the strong association of Burkitt's lymphoma and HIV infection in the Developed world, and against previous postulations that the cancer is due to immunosupression among African children, the HIV epidemic in the Malaria belt has not been associated with a corresponding increase in incidence of childhood Burkitt's lymphoma. Even outside the context of HIV infection, there is substantial evidence for a strong but skewed immune response towards a TH2 response in genesis of Burkitt lymphoma.</p> <p>Presentation of the hypothesis</p> <p>Rather than a global and/or profound immunosupression, the final common pathway in genesis of Burkitt's lymphoma is the dysregulation of the immune response towards a TH2 response dominated by B-lymphocytes, and the concomitant suppression of the TH1 cell-mediated immune surveillance, driven by various viral/parasitic/bacterial infections.</p> <p>Testing the hypothesis</p> <p>Case control studies comparing TH2 and TH1 immune responses in Burkitt lymphoma of different etiological types (sporadic, HIV-related, endemic and post-transplant) to demonstrate significant dominance of TH2 immune response in presence of poor CMI response as a common factor. Immunological profiling to evaluate differences between immune states that are associated (such as recurrent Malaria infection) and those that are not associated (such as severe protein-energy malnutrition) with Burkitt lymphoma. Prospective cohorts profiling chronology of immunological events leading to Burkitt lymphoma in children with EBV infection.</p> <p>Implications of the hypothesis</p> <p>The dysregulation of the immune response may be the missing link in our understanding of Burkitt lymphomagenesis. This will provide possibilities for determination of risk and for control of development of malignancy in individuals/populations exposed to the relevant infections.</p

Application of a Colorimetric Assay to Identify Putative Ribofuranosylaminobenzene 5'-Phosphate Synthase Genes Expressed with Activity in Escherichia coli

Tetrahydromethanopterin (H(4)MPT) is a tetrahydrofolate analog originally discovered in methanogenic archaea, but later found in other archaea and bacteria. The extent to which H(4)MPT occurs among living organisms is unknown. The key enzyme which distinguishes the biosynthetic pathways of H(4)MPT and tetrahydrofolate is ribofuranosylaminobenzene 5'-phosphate synthase (RFAP synthase). Given the importance of RFAP synthase in H(4)MPT biosynthesis, the identification of putative RFAP synthase genes and measurement of RFAP synthase activity would provide an indication of the presence of H(4)MPT in untested microorganisms. Investigation of putative archaeal RFAP synthase genes has been hampered by the tendency of the resulting proteins to form inactive inclusion bodies in Escherichia coli. The current work describes a colorimetric assay for measuring RFAP synthase activity, and two modified procedures for expressing recombinant RFAP synthase genes to produce soluble, active enzyme. By lowering the incubation temperature during expression, RFAP synthase from Archaeoglobus fulgidus was produced in E. coli and purified to homogeneity. The production of active RFAP synthase from Methanothermobacter thermautotrophicus was achieved by coexpression of the gene MTH0830 with a molecular chaperone. This is the first direct biochemical identification of a methanogen gene that codes for an active RFAP synthase

Is looped nasogastric tube feeding more effective than conventional nasogastric tube feeding for dysphagia in acute stroke?

Background: Dysphagia occurs in up to 50% of patients admitted to hospital with acute strokes with up to 27% remaining by seven days. Up to 8% continue to have swallowing problems six months after their stroke with 1.7% still requiring enteral feeding. Nasogastric tubes (NGT) are the most commonly used method for providing enteral nutrition in early stroke, however they are easily and frequently removed leading to inadequate nutrition, early PEG (Percutaneous Endoscopic Gastrostomy) insertion or abandoning of feeding attempts. Looped nasogastric tube feeding may improve the delivery of nutrition to such patients. Methods: Three centre, two arm randomised controlled trial, with 50 participants in each arm comparing loop (the intervention) versus conventional nasogastric tube feeding. The primary outcome measure is proportion of intended feed delivered in the first 2 weeks. The study is designed to show a mean increase of feed delivery of 16% in the intervention group as compared with the control group, with 90% power at a 5% significance level. Secondary outcomes are treatment failures, mean volume of feed received, adverse events, cost-effectiveness, number of chest x-rays, number of nasogastric tubes and tolerability

Of Asian Forests and European Fields: Eastern U.S. Plant Invasions in a Global Floristic Context

Background: Biogeographic patterns of species invasions hold important clues to solving the recalcitrant ‘who’, ‘where’, and ‘why ’ questions of invasion biology, but the few existing studies make no attempt to distinguish alien floras (all non-native occurrences) from invasive floras (rapidly spreading species of significant management concern), nor have invasion biologists asked whether particular habitats are consistently invaded by species from particular regions. Methodology/Principal Findings: Here I describe the native floristic provenances of the 2629 alien plant taxa of the Eastern Deciduous Forest of the Eastern U.S. (EUS), and contrast these to the subset of 449 taxa that EUS management agencies have labeled ‘invasive’. Although EUS alien plants come from all global floristic regions, nearly half (45%) have native ranges that include central and northern Europe or the Mediterranean (39%). In contrast, EUS invasive species are most likely to come from East Asia (29%), a pattern that is magnified when the invasive pool is restricted to species that are native to a single floristic region (25 % from East Asia, compared to only 11 % from northern/central Europe and 2 % from the Mediterranean). Moreover, East Asian invaders are mostly woody (56%, compared to just 23 % of the total alien flora) and are significantly more likely to invade intact forests and riparian areas than European species, which dominate managed or disturbed ecosystems. Conclusions/Significance: These patterns suggest that the often-invoked ‘imperialist dogma ’ view of global invasion

Wet Adhesion and Adhesive Locomotion of Snails on Anti-Adhesive Non-Wetting Surfaces

Creating surfaces capable of resisting liquid-mediated adhesion is extremely difficult due to the strong capillary forces that exist between surfaces. Land snails use this to adhere to and traverse across almost any type of solid surface of any orientation (horizontal, vertical or inverted), texture (smooth, rough or granular) or wetting property (hydrophilic or hydrophobic) via a layer of mucus. However, the wetting properties that enable snails to generate strong temporary attachment and the effectiveness of this adhesive locomotion on modern super-slippy superhydrophobic surfaces are unclear. Here we report that snail adhesion overcomes a wide range of these microscale and nanoscale topographically structured non-stick surfaces. For the one surface which we found to be snail resistant, we show that the effect is correlated with the wetting response of the surface to a weak surfactant. Our results elucidate some critical wetting factors for the design of anti-adhesive and bio-adhesion resistant surfaces

The landscape of Neandertal ancestry in present-day humans

Analyses of Neandertal genomes have revealed that Neandertals have contributed genetic variants to modern humans1–2. The antiquity of Neandertal gene flow into modern humans means that regions that derive from Neandertals in any one human today are usually less than a hundred kilobases in size. However, Neandertal haplotypes are also distinctive enough that several studies have been able to detect Neandertal ancestry at specific loci1,3–8. Here, we have systematically inferred Neandertal haplotypes in the genomes of 1,004 present-day humans12. Regions that harbor a high frequency of Neandertal alleles in modern humans are enriched for genes affecting keratin filaments suggesting that Neandertal alleles may have helped modern humans adapt to non-African environments. Neandertal alleles also continue to shape human biology, as we identify multiple Neandertal-derived alleles that confer risk for disease. We also identify regions of millions of base pairs that are nearly devoid of Neandertal ancestry and enriched in genes, implying selection to remove genetic material derived from Neandertals. Neandertal ancestry is significantly reduced in genes specifically expressed in testis, and there is an approximately 5-fold reduction of Neandertal ancestry on chromosome X, which is known to harbor a disproportionate fraction of male hybrid sterility genes20–22. These results suggest that part of the reduction in Neandertal ancestry near genes is due to Neandertal alleles that reduced fertility in males when moved to a modern human genetic background

Comparative genome and transcriptome analyses of the social amoeba Acytostelium subglobosum that accomplishes multicellular development without germ-soma differentiation

Background Social amoebae are lower eukaryotes that inhabit the soil. They are characterized by the construction of a starvation-induced multicellular fruiting body with a spore ball and supportive stalk. In most species, the stalk is filled with motile stalk cells, as represented by the model organism Dictyostelium discoideum, whose developmental mechanisms have been well characterized. However, in the genus Acytostelium, the stalk is acellular and all aggregated cells become spores. Phylogenetic analyses have shown that it is not an ancestral genus but has lost the ability to undergo cell differentiation. Results We performed genome and transcriptome analyses of Acytostelium subglobosum and compared our findings to other available dictyostelid genome data. Although A. subglobosum adopts a qualitatively different developmental program from other dictyostelids, its gene repertoire was largely conserved. Yet, families of polyketide synthase and extracellular matrix proteins have not expanded and a serine protease and ABC transporter B family gene, tagA, and a few other developmental genes are missing in the A. subglobosum lineage. Temporal gene expression patterns are astonishingly dissimilar from those of D. discoideum, and only a limited fraction of the ortholog pairs shared the same expression patterns, so that some signaling cascades for development seem to be disabled in A. subglobosum. Conclusions The absence of the ability to undergo cell differentiation in Acytostelium is accompanied by a small change in coding potential and extensive alterations in gene expression patterns

Molecular Characterization of a Fus3/Kss1 Type MAPK from Puccinia striiformis f. sp. tritici, PsMAPK1

Puccinia striiformis f. sp. tritici (Pst) is an obligate biotrophic fungus that causes the destructive wheat stripe rust disease worldwide. Due to the lack of reliable transformation and gene disruption method, knowledge about the function of Pst genes involved in pathogenesis is limited. Mitogen-activated protein kinase (MAPK) genes have been shown in a number of plant pathogenic fungi to play critical roles in regulating various infection processes. In the present study, we identified and characterized the first MAPK gene PsMAPK1 in Pst. Phylogenetic analysis indicated that PsMAPK1 is a YERK1 MAP kinase belonging to the Fus3/Kss1 class. Single nucleotide polymerphisms (SNPs) and insertion/deletion were detected in the coding region of PsMAPK1 among six Pst isolates. Real-time RT-PCR analyses revealed that PsMAPK1 expression was induced at early infection stages and peaked during haustorium formation. When expressed in Fusarium graminearum, PsMAPK1 partially rescued the map1 mutant in vegetative growth and pathogenicity. It also partially complemented the defects of the Magnaporthe oryzae pmk1 mutant in appressorium formation and plant infection. These results suggest that F. graminearum and M. oryzae can be used as surrogate systems for functional analysis of well-conserved Pst genes and PsMAPK1 may play a role in the regulation of plant penetration and infectious growth in Pst