Sea-level rise (SLR) is expected to cause major changes to coastal wetlands, which are among the world's most vulnerable ecosystems and are critical for nonbreeding waterbirds. Because strategies for ...adaptation to SLR, such as nature-based solutions and designation of protected areas, can locally reduce the negative effects of coastal flooding under SLR on coastal wetlands, it is crucial to prioritize adaptation efforts, especially for wetlands of international importance for biodiversity. We assessed the exposure of coastal wetlands important for nonbreeding waterbirds to projected SLR along the Mediterranean coasts of 8 countries by modeling future coastal flooding under 7 scenarios of SLR by 2100 (from 44- to 161-cm rise) with a static inundation approach. Exposure to coastal flooding under future SLR was assessed for 938 Mediterranean coastal sites (≤30 km from the coastline) where 145 species of nonbreeding birds were monitored as part of the International Waterbird Census and for which the monitoring area was delineated by a polygon (64.3% of the coastal sites monitored in the Mediterranean region). Thirty-four percent of sites were threatened by future SLR, even under the most optimistic scenarios. Protected study sites and study sites of international importance for waterbirds were, respectively, 1.5 and 2 times more exposed to SLR than the other sites under the most optimistic scenario. Accordingly, we advocate for the development of a prioritization scheme to be applied to these wetlands for the implementation of strategies for adaptation to SLR to anticipate the effects of coastal flooding. Our study provides major guidance for conservation planning under global change in several countries of the Mediterranean region.
Unusually long major histocompatibility complex (MHC) class I-restricted epitopes are important in immunity, but their 'bulged' conformation represents a potential obstacle to alphabeta T cell ...receptor (TCR)-MHC class I docking. To elucidate how such recognition is achieved while still preserving MHC restriction, we have determined here the structure of a TCR in complex with HLA-B(*)3508 presenting a peptide 13 amino acids in length. This complex was atypical of TCR-peptide-MHC class I interactions, being dominated at the interface by peptide-mediated interactions. The TCR assumed two distinct orientations, swiveling on top of the centrally bulged, rigid peptide such that only limited contacts were made with MHC class I. Although the TCR-peptide recognition resembled an antibody-antigen interaction, the TCR-MHC class I contacts defined a minimal 'generic footprint' of MHC-restriction. Thus our findings simultaneously demonstrate the considerable adaptability of the TCR and the 'shape' of MHC restriction.
Plasticity of the T cell receptor (TCR) is a hallmark of major histocompatibility complex (MHC)-restricted T cell recognition. However, it is unclear whether interactions of TCR and peptide-MHC class ...I (pMHCI) always conform to this paradigm. Here we describe the structure of a TCR, ELS4, in its non-ligand-bound form and in complex with a prominent 'bulged' Epstein-Barr virus peptide bound to HLA-B(*)3501. This complex was atypical of previously characterized TCR-pMHCI interactions in that a rigid face of the TCR crumpled the bulged antigenic determinant. This peptide 'bulldozing' created a more featureless pMHCI determinant, allowing the TCR to maximize MHC class I contacts essential for MHC class I restriction of TCR recognition. Our findings represent a mechanism of antigen recognition whereby the plasticity of the T cell response is dictated mainly by adjustments in the MHC-bound peptide.
MHC class I molecules generally present peptides of 8-10 aa long, forming an extended coil in the HLA cleft. Although longer peptides can also bind to class I molecules, they tend to bulge from the ...cleft and it is not known whether the TCR repertoire has sufficient plasticity to recognize these determinants during the antiviral CTL response. In this study, we show that unrelated individuals infected with EBV generate a significant CTL response directed toward an HLA-B*3501-restricted, 11-mer epitope from the BZLF1 Ag. The 11-mer determinant adopts a highly bulged conformation with seven of the peptide side chains being solvent-exposed and available for TCR interaction. Such a complex potentially creates a structural challenge for TCR corecognition of both HLA-B*3501 and the peptide Ag. Surprisingly, unrelated B*3501 donors recognizing the 11-mer use identical or closely related alphabeta TCR sequences that share particular CDR3 motifs. Within the small number of dominant CTL clonotypes observed, each has discrete fine specificity for the exposed side chain residues of the peptide. The data show that bulged viral peptides are indeed immunogenic but suggest that the highly constrained TCR repertoire reflects a limit to TCR diversity when responding to some unusual MHC peptide ligands.
The aim of this study was to identify pharmaceutical issues encountered during regulatory review in European Procedures. A database of issues from Day 70 assessment reports of 150 EU procedures was ...compiled; most procedures were for generics (108). Frequencies of common deficiencies have been calculated and summarised for use of all stakeholders. Out of the 150 procedures reviewed, covering 309 products, a total of 4796 concerns were identified. Of these concerns, 167 were Potential Serious Risks to Public Health, 67 were raised on drug substance and 100 on the drug product. The distribution of total concerns was as follows: 2168 concerns on drug substance and 2584 on drug product. Most concerns raised were on control of drug substance and drug product (834 & 626 for 3.2.S.4 and 3.2.P.5, respectively), followed by concerns on the manufacturing (482 & 564 for 3.2.S.2 and 3.2.P.3, respectively) and stability 147 & 398 for 3.2.S.7 and 3.2.P.8, respectively). In conclusion, the frequencies and trends of identified deficiencies together with their impact were discussed from a regulatory point of view. The main findings indicate that applicants would benefit from following published guidelines so that delays in the registration of medicines could be avoided.
The Mediterranean Basin is a biodiversity hotspot. Wetlands make a key contribution to this status, but many of them remain outside the Ramsar network fifty years after the establishment of the ...Ramsar Convention. Here we evaluate the extent to which the Mediterranean Ramsar network covers wetlands of international importance for wintering waterbirds using the Ramsar Convention criteria 2 (species of conservation concern), 5 (> 20,000 waterbirds) and 6 (1% of a population). These criteria were applied to 4186 sites in 24 Mediterranean countries using counts of 145 wintering waterbird species from 1991 to 2017. We identified 161 sites of international importance for waterbirds that have not yet been declared as Ramsar sites, which could be added to the 180 current Mediterranean Ramsar sites established based on waterbird criteria (criteria 5 and/or 6). Among these sites, a subset of 32 very important sites reached double the required level for at least one criterion and 95 were not protected by any site conservation status. Coastal wetlands represented half of the Ramsar gap for waterbirds. We identified that an additional 1218 monitored sites could be provisionally considered as internationally important and thus require more survey efforts to assess their status. This study highlights a lack of participation of the Mediterranean countries to build the Ramsar network for wetland protection. Our results should help policymakers and managers to prioritize future Ramsar site designation, notably in the Middle East and Western European region where important gaps were identified.
MLP is a LIM-only protein of terminally differentiated striated muscle cells, where it accumulates at actin-based structures involved in cytoarchitecture organization. To assess its role in muscle ...differentiation, we disrupted the
MLP gene in mice.
MLP (−/−) mice developed dilated cardiomyopathy with hypertrophy and heart failure after birth. Ultrastructural analysis revealed dramatic disruption of cardiomyocyte cytoarchitecture. At birth, these hearts were not hypertrophic, but already abnormally soft, with cell-autonomous and MLP-sensitive alterations in cytoarchitecture. Thus, MLP promotes proper cardiomyocyte cytoarchitecture, whose perturbation can lead to dilated cardiomyopathy. In vivo analysis revealed that MLP-deficient mice reproduce the morphological and clinical picture of dilated cardiomyopathy and heart failure in humans, providing the first model for this condition in a genetically manipulatable organism.
Although HLA class I alleles can bind epitopes up to 14 amino acids in length, little is known about the immunogenicity or the responding T-cell repertoire against such determinants. Here, we ...describe an HLA-B*3508-restricted cytotoxic T lymphocyte response to a 13-mer viral epitope (LPEPLPQGQLTAY). The rigid, centrally bulged epitope generated a biased T-cell response. Only the N-terminal face of the peptide bulge was critical for recognition by the dominant clonotype SB27. The SB27 public T-cell receptor (TcR) associated slowly onto the complex between the bulged peptide and the major histocompatibility complex, suggesting significant remodeling upon engagement. The broad antigen-binding cleft of HLA-B*3508 represents a critical feature for engagement of the public TcR, as the narrower binding cleft of HLA-B*3501(LPEPLPQGQLTAY), which differs from HLA-B*3508 by a single amino acid polymorphism (Arg156 --> Leu), interacted poorly with the dominant TcR. Biased TcR usage in this cytotoxic T lymphocyte response appears to reflect a dominant role of the prominent peptide x major histocompatibility complex class I surface.
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