The energetic bases of T cell recognition are unclear. Here, we studied the 'energetic landscape' of peptide-major histocompatibility complex (pMHC) recognition by an immunodominant alphabeta T cell ...receptor (TCR). We quantified and evaluated the effect of natural and systematic substitutions in the complementarity-determining region (CDR) loops on ligand binding in the context of the structural detail of each component of the immunodominant TCR-pMHC complex. The CDR1 and CDR2 loops contributed minimal energy through direct recognition of the antigen and instead had a chief function in stabilizing the ligated CDR3 loops. The underlying energetic basis for recognition lay in the CDR3 loops. Therefore the energetic burden of the CDR loops in the TCR-pMHC interaction is variable among TCRs, reflecting the inherent adaptability of the TCR in ligating different ligands.
The authors summarize the results obtained over a period of about 150 years by various authors on the taxonomic position of Sparrows present in southern Italy, Sicily and Malta, identified on several ...occasions as Passer italiae, P. hispaniolensis or as hybrids of the two species. Based on the latest research and the analysis of the genome of the sparrows of Corsica, Crete, southern Italy, Sicily and Malta, it appears that it has finally been possible to establish that these populations possess a different degree of hybridization between P. italiae and P. hispaniolensis, with less genes of P. hispaniolensis in northern regions and more in southern ones. Therefore, the authors propose to name these populations Passer italiae x hispaniolensis.
Thousands of potentially antigenic peptides are encoded by an infecting pathogen; however, only a small proportion induce measurable CD8(+) T cell responses. To investigate the factors that control ...peptide immunogenicity, we have examined the cytotoxic T lymphocyte (CTL) response to a previously undefined epitope ((77)APQPAPENAY(86)) from the BZLF1 protein of Epstein-Barr virus (EBV). This peptide binds well to two human histocompatibility leukocyte antigen (HLA) allotypes, HLA-B*3501 and HLA-B*3508, which differ by a single amino acid at position 156 ((156)Leucine vs. (156)Arginine, respectively). Surprisingly, only individuals expressing HLA-B*3508 show evidence of a CTL response to the (77)APQPAPENAY(86) epitope even though EBV-infected cells expressing HLA-B*3501 process and present similar amounts of peptide for CTL recognition, suggesting that factors other than peptide presentation levels are influencing immunogenicity. Functional and structural analysis revealed marked conformational differences in the peptide, when bound to each HLA-B35 allotype, that are dictated by the polymorphic HLA residue 156 and that directly affected T cell receptor recognition. These data indicate that the immunogenicity of an antigenic peptide is influenced not only by how well the peptide binds to major histocompatibility complex (MHC) molecules but also by its bound conformation. It also illustrates a novel mechanism through which MHC polymorphism can further diversify the immune response to infecting pathogens.
Multimodal management has been proposed as key to any effective drug intervention in cachexia. This article attempts to reflect on clinical and regulatory considerations of multimodal management ...treatment as a regulatory requirement in anticachexia drug therapy. To date, no European Union (EU) regulatory guidelines have been published and therefore this review could attempt to present and discuss some central issues to consider when developing an anticachexia drug.
The following themes are considered: EU regulatory pathways for drug approval (conditional and exceptional circumstances as well as adaptive licensing); selection criteria for randomized clinical trials allowing the identification and characterization of the population of interest that is an at-risk population with undisputable clinical need; issues related to primary and secondary outcome measures that are adequate to determine the efficacy of the intervention and the approach for the development of clinical biomarkers for cachexia.
Conversely, the incorporation of multimodal treatment in anticachexia drug therapy is expected to increase the effectiveness of intervention. This aspect is the aspect that appeals to pharmaceutical companies; however, at the same time, this raises regulatory and clinical issues that need to be kept in mind when designing randomised clinical trials.
► We estimate adult survival probabilities at colonies in Malta and France. ► Survival probabilities of breeding adults are too low to sustain stable populations. ► Conservation measures on land had ...positive effect on survival probabilities. ► In Malta, current mortality occurs mainly outside the breeding season. ► Mortality outside breeding season must be reduced to save the Yelkouan shearwater.
Many seabird species are experiencing population declines, with key factors being high adult mortality caused by fishery by-catch and predation by introduced predators on nesting islands. In the Mediterranean, both of these pressures are intensive and widespread. We studied the adult survival of an endemic Mediterranean seabird, the Yelkouan shearwater (
Puffinus yelkouan), between 1969–1994 and 2007–2010 in Malta and between 2004–2010 in France using mark–recapture methods. Mean annual survival probabilities for breeding adults were below 0.9 for all colonies and periods. Between 1969–1994, annual survival for adults of unknown breeding status was on average 0.74 (95% confidence interval: 0.69–0.80) in Malta, possibly as a result of various human disturbances (including illegal shooting), light pollution and fisheries by-catch. Over the period 2004–2010, we found strong support for variation in adult survival probabilities between breeders and non-breeders, and islands with and without introduced predators in France. Survival probabilities for non-breeders (0.95, 0.81–1.0) appeared to be higher than for breeders (0.82, 0.70–0.94), but were imprecise partly due to low recapture probabilities. In Malta, we found evidence for heterogeneity in survival probabilities between two unknown groups (probably breeders and non-breeders), and seasonal variation in survival probability. Birds were more likely to survive the period including the peak breeding season than an equally long period during which they roam widely at sea. Although annual adult survival probability was still low (0.85, 0.58–1.0), colony protection measures appear to have reduced mortality at nesting cliffs. A population model indicated that colonies in France and Malta would currently require continuous immigration of 5–12 pairs per year to maintain stable populations. Our estimates of adult survival probabilities over the past four decades are consistent with overall population declines. Threats to Yelkouan shearwaters require immediate management actions to avoid ongoing population declines in the western Mediterranean.
To predict the impact of climate change over the whole species distribution range, comparison of adult survival variations over large spatial scale is of primary concern for long‐lived species ...populations that are particularly susceptible to decline if adult survival is reduced. In this study, we estimated and compared adult survival rates between 1989 and 1997 of six populations of Cory's shearwater (Calonectris diomedea) spread across 4600 km using capture–recapture models. We showed that mean annual adult survival rates are different among populations along a longitudinal gradient and between sexes. Variation in adult survival is synchronized among populations, with three distinct groups: (1) both females and males of Corsica, Tremiti, and Selvagem (annual survival range 0.88–0.96); (2) both females and males of Frioul and females from Crete (0.82–0.92); and (3) both females and males of Malta and males from Crete (0.74–0.88). The total variation accounted for by the common pattern of variation is on average 71%, suggesting strong environmental forcing. At least 61% of the variation in survival is explained by the Southern Oscillation Index fluctuations. We suggested that Atlantic hurricanes and storms during La Niña years may increase adult mortality for Cory's shearwater during winter months. For long‐lived seabird species, variation in adult survival is buffered against environmental variability, although extreme climate conditions such as storms significantly affect adult survival. The effect of climate at large spatial scales on adult survival during the nonbreeding period may lead to synchronization of variation in adult survival over the species' range and has large effects on the meta‐population trends. One can thus worry about the future of such long‐lived seabirds species under the predictions of higher frequency of extreme large‐scale climatic events.
Thermal adjustment of waterbird communities to climate warming is crucial but hampered by natural habitat conversion, increasing their climatic debt. As it is, in contrast, facilitated in protected ...areas, assessing the adequacy of the current protected areas network with respect to future climate and land-use changes and identifying priority sites to protect is of major importance. In this study, we assess the thermal adjustment limitations that non-breeding waterbird communities might experience by the end of the 21st century in the Mediterranean region to highlight priorities for wetland protection. Priorities were set by combining the exposure of waterbird communities to natural habitat conversion and climate warming with their thermal specialization. The latter was calculated using winter abundance data of 151 species from 2932 sites of the International Waterbird Census in 21 Mediterranean countries. Exposure was assessed using future projections of temperature and land-use under four CMIP6 scenarios (SSP1–2.6, SSP2–4.5, SSP3–7.0, and SSP5–8.5). We found that strictly protected areas are located in wetlands whose waterbird communities, without protection, would likely experience high limitations in thermal adjustment in the coming decades. This highlights that the location of existing protected areas may effectively support the thermal adjustment of waterbird communities to future climate warming. However, 490 sites considered at risk lack protection, including 32 sites of international importance for waterbirds, stressing the need to strengthen the protected areas network in these sites in priority. Our study provides important guidance for conservation planning in the Mediterranean region to support waterbird responses to climate change.
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The underlying generic properties of alphabeta TCRs that control MHC restriction remain largely unresolved. To investigate MHC restriction, we have examined the CTL response to a viral epitope that ...binds promiscuously to two human leukocyte Ags (HLAs) that differ by a single amino acid at position 156. Individuals expressing either HLA-B*3501 (156Leucine) or HLA-B*3508 (156Arginine) showed a potent CTL response to the 407HPVGEADYFEY417 epitope from EBV. Interestingly, the response was characterized by highly restricted TCR beta-chain usage in both HLA-B*3501+ and HLA-B*3508+ individuals; however, this conserved TRBV9+ beta-chain was associated with distinct TCR alpha-chains depending upon the HLA-B*35 allele expressed by the virus-exposed host. Functional assays confirmed that TCR alpha-chain usage determined the HLA restriction of the CTLs. Structural studies revealed significant differences in the mobility of the peptide when bound to HLA-B*3501 or HLA-B*3508. In HLA-B*3501, the bulged section of the peptide was disordered, whereas in HLA-B*3508 the bulged epitope adopted an ordered conformation. Collectively, these data demonstrate not only that mobile MHC-bound peptides can be highly immunogenic but can also stimulate an extremely biased TCR repertoire. In addition, TCR alpha-chain usage is shown to play a critical role in controlling MHC restriction between closely related allomorphs.
Three juvenile Cory's Shearwaters Calonectris diomedea diomedea were fitted with back-mounted satellite tags and tracked during post-fledging migration. The birds spent several weeks in the central ...Mediterranean before migrating westwards. Two tags stopped transmitting after 21 and 35 days; the third bird passed through the Strait of Gibraltar and along the West African coast until transmitting ceased after day 43, by which time it was 114.6 km off the coast and 4,390 km from Malta. Cory's Shearwaters from other Mediterranean islands winter further south in equatorial waters, in the eastern South Atlantic or in the northeast tropical Atlantic associated with the Canary current, and further research is needed to define the wintering areas of Maltese Cory's Shearwaters.
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