The ABCs of MHC

The major histocompatibility complex (MHC) contains the most diverse genes known in vertebrates. These genes encode cell‐surface molecules that play a central role in controlling immunological activity and, as a consequence, in tissue rejection, autoimmunity, and immune responses to infectious diseases. In vertebrates, there are many different MHC genes, most with many alleles. This is true for all primates studied thus far. Multiple loci and alleles allow for an increased peptide‐binding repertoire; their variety has a profound impact on an organism's ability to battle constantly evolving pathogens. The argument that infectious disease is a driving force for MHC variability is supported by observations that most of the allelic variation centers on the amino acid residues that directly interact with foreign peptides. However, while MHC diversity could be maintained through heterozygote advantage, frequency‐dependent selection, or both, the direct evidence that natural selection enhances diversity is limited. Indeed, it is not wholly clear whether selection operates only with respect to disease resistance or if behavioral and biological mechanisms also contribute to the extreme variation that has been observed for many species. Furthermore, reproductive behavior and biology may also help to maintain genetic variability at MHC loci.     

The ABCs of artificial antigen presentation

Artificial antigen presentation aims to accelerate the establishment of therapeutic cellular immunity. Artificial antigen-presenting cells (AAPCs) and their cell-free substitutes are designed to stimulate the expansion and acquisition of optimal therapeutic features of T cells before therapeutic infusion, without the need for autologous antigen-presenting cells. Compelling recent advances include fibroblast AAPCs that process antigens, magnetic beads that are antigen specific, novel T-cell costimulatory combinations, the augmentation of therapeutic potency of adoptively transferred T lymphocytes by interleukin-15, and the safe use of dendritic cell-derived exosomes pulsed with tumor antigen. Whereas the safety and potency of the various systems warrant further preclinical and clinical studies, these emerging technologies are poised to have a major impact on adoptive T-cell therapy and the investigation of T cell-mediated immunity.     

The ABCs of trans(porter) inhibition

Transporter proteins mediate the import of nutrients and the export of toxins across biological membranes. A new crystal structure of a bacterial ABC transporter reveals an unexpected mechanism for transporter inhibition by its transported substrate.     

Integrative analysis of the expression and prognosis for CENPs in ovarian cancer

Centromere proteins (CENPs) are nuclear proteins that are involved in centromere formation and chromosome segregation during mitosis. Some members of CENPs have been extensively studied in the initiation and development of cancers. However, the expression patterns and exact roles of CENPs in ovarian cancer (OC) have not been fully elucidated. In this study, we comprehensively assessed the genetic variation, expression patterns and prognostic value of CENPs in OC by several databases. The mRNA expression levels of CENPA/F/H/L/N/U/W were found to be significantly upregulated in OC and related to worse prognosis. Additionally, function enrichment analysis showed that CENPs were involved in DNA repair and cell division. Meanwhile, immune infiltration analysis elucidated that CENPs were associated with myeloid-derived suppressor cells (MDSCs) and major histocompatibility complex (MHC). These results suggested that CENPs might serve as potential diagnostic and prognostic markers and provide new insights for the development of CENPs-targeted therapeutics for ovarian cancer.     

The ABCs of molecular dynamics simulations on B-DNA, circa 2012

This article provides a retrospective on the ABC initiative in the area of all-atom molecular dynamics (MD) simulations including explicit solvent on all tetranucleotide steps of duplex B-form DNA duplex, ca. 2012. The ABC consortium has completed two phases of simulations, the most current being a set of 50-100 trajectories based on the AMBER ff99 force field together with the parmbsc0 modification. Some general perspectives on the field of MD on DNA and sequence effects on DNA structure are provided, followed by an overview our MD results, including a detailed comparison of the ff99/parmbsc0 results with crystal and NMR structures available for d(CGCGAATTCGCG). Some projects inspired by or related to the ABC initiative and database are also reviewed, including methods for the trajectory analyses, informatics of dealing with the large database of results, compressions of trajectories for efficacy of distribution, DNA solvation by water and ions, parameterization of coarse-grained models with applications and gene finding and genome annotation.     

The ABCs of granule-mediated cytotoxicity: new weapons in the arsenal

Granule exocytosis is the main pathway for the immune elimination of virus-infected cells and tumour cells by cytotoxic T lymphocytes and natural killer cells. After target-cell recognition, release of the cytotoxic granule contents into the immunological synapse formed between the killer cell and its target induces apoptosis. The granules contain two membrane-perturbing proteins, perforin and granulysin, and a family of serine proteases known as granzymes, complexed with the proteoglycan serglycin. In this review, I discuss recent insights into the mechanisms of granule-mediated cytotoxicity, focusing on how granzymes A, B and C and granulysin activate cell death through caspase-independent pathways.     

Axes,boundaries and coordinates: The ABCs of fly leg development

Recent studies of gene expression in the developing fruitfly leg support a model – Meinhardt's Boundary Model – which seems to contradict the prevailing paradigm for pattern formation in the imaginal discs of Drosophila – the Polar Coordinate Model. Reasoning from geometric first principles, this article examines the strengths and weaknesses of these hypotheses, plus some baffling phenomena that neither model can comfortably explain. The deeper question at issue is: how does the fly's genome encode the three-dimensional anatomy of the adult? Does it demarcate territories and boundaries (as in a geopolitical map) and then use those boundaries and their points of intersection as a scaffolding on which to erect the anatomy (the Boundary Model)? Or does it assign cellular fates within a relatively seamless coordinate system (the Polar Coordinate Model)? The existence of hybrid Cartesian-polar models shows that the alternatives may not be so clear-cut: a single organ might utilize different systems that are spatially superimposed or temporally sequential.