Self-reactive T cells must escape thymic negative selection to mediate pathogenic autoimmunity. In the NOD mouse model of autoimmune diabetes, several β cell-cytotoxic CD8 T cell populations are known, with the most aggressive of these represented by AI4, a T cell clone with promiscuous Ag-recognition characteristics. We identified a long-elusive β cell-specific ligand for AI4 as an unusually short H-2D(b)-binding 7-mer peptide lacking a C-terminal anchor residue and derived from the insulin A chain (InsA14-20). Crystallography reveals that compensatory mechanisms permit peptides lacking a C-terminal anchor to bind sufficiently to the MHC to enable destructive T cell responses, yet allow cognate T cells to avoid negative selection. InsA14-20 shares two solvent-exposed residues with previously identified AI4 ligands, providing a structural explanation for AI4's promiscuity. Detection of AI4-like T cells, using mimotopes of InsA14-20 with improved H-2D(b)-binding characteristics, establishes the AI4-like T cell population as a consistent feature of the islet infiltrates of NOD mice. Our work establishes undersized peptides as previously unrecognized targets of autoreactive CD8 T cells and presents a strategy for their further exploration as Ags in autoimmune disease.
Although we have evidence that many organisms are exhibiting declines in body size in response to climate warming, we have little knowledge of underlying mechanisms or how associated phenotypic suites may coevolve. The better we understand coadaptations among physiology, morphology, and life history, the more accurate our predictions will be of organismal response to changing thermal environments. This is especially salient for ectotherms because they comprise 99% of species worldwide and are key to functioning ecosystems.
Background: Temporal lobe mass lesions are the most common intracranial space-occupying lesions in children, among various brain lobes. The temporal lobe is critically involved in higher cognitive functions, and surgical interventions often risk causing damage to these functions. If necessary interventions and prehabilitation can be conducted preoperatively, it might be possible to achieve a larger extent of lesion resection with minimal cognitive impairment.
Aberration of mitochondrial function is a shared feature of many human pathologies, characterised by changes in metabolic flux, cellular energetics, morphology, composition, and dynamics of the mitochondrial network. While some of these changes serve as compensatory mechanisms to maintain cellular homeostasis, their chronic activation can permanently affect cellular metabolism and signalling, ultimately impairing cell function. Here, we use a Drosophila melanogaster model expressing a proofreading-deficient mtDNA polymerase (POLγ) in a genetic screen to find genes that mitigate the harmful accumulation of mtDNA mutations.
Accurate identification of decreasing trends is a prerequisite for successful conservation, but can be challenging when immigration compensates local declines in abundance. Here, we show that a potential declining trend driven by low vital rates was overridden and converted into a spectacular increase by massive immigration into the population of a semi-social raptor, the black kite Milvus migrans, breeding in a highly contaminated area near a major landfill. Immigration was promoted by a growing food-base of live prey, coupled with the attraction exerted by the progressive gathering of a large flock of non-breeders at the area, resulting in an "attraction spiral" that lured large numbers of breeders to settle into a contaminated population incapable of self-sustenance.
Department of Physical Therapy, School of Health and Social Services, Saitama Prefectural University, 820 San-Nomiya, Koshigaya-Shi, Saitama, 343-8540, Japan.
Accumulation of senescent neurons in the dorsal root ganglion (DRG) is an important tissue phenotype that causes age-related degeneration of peripheral sensory nerves. Senescent neurons are neurons with arrested cell cycle that have undergone cellular senescence but remain in the tissue and play various biological roles. To understand the accumulation of senescent neurons in the DRG during aging, we aimed to elucidate the mechanism that induces cellular senescence in DRG neurons and the role of senescent DRG neurons.
