Complexity in surfaces of densest packings for families of polyhedra

Packings of hard polyhedra have been studied for centuries due to their mathematical aesthetic and more recently for their applications in fields such as nanoscience, granular and colloidal matter, and biology. In all these fields, particle shape is important for structure and properties, especially upon crowding. Here, we explore packing as a function of shape. By combining simulations and analytic calculations, we study three 2-parameter families of hard polyhedra and report an extensive and systematic analysis of the densest packings of more than 55,000 convex shapes. The three families have the symmetries of triangle groups (icosahedral, octahedral, tetrahedral) and interpolate between various symmetric solids (Platonic, Archimedean, Catalan). We find that optimal (maximum) packing density surfaces that reveal unexpected richness and complexity, containing as many as 130 different structures within a single family. Our results demonstrate the utility of thinking of shape not as a static property of an object in the context of packings, but rather as but one point in a higher dimensional shape space whose neighbors in that space may have identical or markedly different packings. Finally, we present and interpret our packing results in a consistent and generally applicable way by proposing a method to distinguish regions of packings and classify types of transitions between them.Comment: 16 pages, 8 figure

SLAM Family Receptors and Autoimmunity

The immune system is responsible for the defense against a wide array of pathogens but without responding to each individual’s (self) antigens. Autoimmune diseases are characterized by a loss of tolerance to self antigens that leads to the appearance of autoreactive lymphocytes. The main factors that contribute to the development of autoimmunity are genetic susceptibility and infection. Disease susceptibility is the result of the combined action of multiple genes. It has been shown that certain gene polymorphisms can influence the establishment of self-tolerance. The human immune system is a complex machinery involving numerous proteins. Cell-surface proteins expressed by leukocytes are of particular relevance due not only to their participation in the network of interactions that regulate the innate and adaptive immune responses, but also to their potential as excellent targets for diagnostic and therapeutic interventions (Diaz-Ramos et al., 2011). These molecules deliver signals that modulate leukocyte development, activation, survival, clonal expansion, and important effector functions. Some of these cell-surface signaling molecules have the capacity to activate lymphocytes and other leukocytes, while others function as downmodulators of immune responses, playing a key role in the establishment of tolerance to self antigens. Thus, it is not surprising that many of the allelic variants associated with autoimmunity identified, to date, correspond to leukocyte cell-surface molecules (Maier & Hafler, 2009). In this review we will discuss recent observations that point to a key role of signaling lymphocyte activation molecule family (SLAMF) receptors in the development of autoimmunity

Divergent traits and ligand-binding properties of the cytomegalovirus CD48 gene family

The genesis of gene families by the capture of host genes and their subsequent duplication is a crucial process in the evolution of large DNA viruses. CD48 is a cell surface molecule that interacts via its N-terminal immunoglobulin (Ig) domain with the cell surface receptor 2B4 (CD244), regulating leukocyte cytotoxicity.We previously reported the presence of five CD48 homologs (vCD48s) in two related cytomegaloviruses, and demonstrated that one of them, A43, binds 2B4 and acts as a soluble CD48 decoy receptor impairing NK cell function. Here, we have characterized the rest of these vCD48s. We show that they are highly glycosylated proteins that display remarkably distinct features: divergent biochemical properties, cellular locations, and temporal expression kinetics. In contrast to A43, none of them interacts with 2B4. Consistent with this, molecular modeling of the N-terminal Ig domains of these vCD48s evidences notable changes as compared to CD48, suggesting that they interact with alternative targets. Accordingly, we demonstrate that one of them, S30, tightly binds CD2, a crucial T- and NK-cell adhesion and costimulatory molecule. Thus, our findings show how a key host immune receptor gene captured by a virus can be subsequently remodeled to evolve new immunoevasins with altered binding properties

Novel role of 3'UTR-embedded Alu elements as facilitators of processed pseudogene genesis and host gene capture by viral genomes

Since the discovery of the high abundance of Alu elements in the human genome, the interest for the functional significance of these retrotransposons has been increasing. Primate Alu and rodent Alu-like elements are retrotransposed by a mechanism driven by the LINE1 (L1) encoded proteins, the same machinery that generates the L1 repeats, the processed pseudogenes (PPs), and other retroelements. Apart from free Alu RNAs, Alus are also transcribed and retrotranscribed as part of cellular gene transcripts, generally embedded inside 3' untranslated regions (UTRs). Despite different proposed hypotheses, the functional implication of the presence of Alus inside 3'UTRs remains elusive. In this study we hypothesized that Alu elements in 3'UTRs could be involved in the genesis of PPs. By analyzing human genome data we discovered that the existence of 3'UTR-embedded Alu elements is overrepresented in genes source of PPs. In contrast, the presence of other retrotransposable elements in 3'UTRs does not show this PP linked overrepresentation. This research was extended to mouse and rat genomes and the results accordingly reveal overrepresentation of 3'UTR-embedded B1 (Alu-like) elements in PP parent genes. Interestingly, we also demonstrated that the overrepresentation of 3'UTR-embedded Alus is particularly significant in PP parent genes with low germline gene expression level. Finally, we provide data that support the hypothesis that the L1 machinery is also the system that herpesviruses, and possibly other large DNA viruses, use to capture host genes expressed in germline or somatic cells. Altogether our results suggest a novel role for Alu or Alu-like elements inside 3'UTRs as facilitators of the genesis of PPs, particularly in lowly expressed genes. Moreover, we propose that this L1-driven mechanism, aided by the presence of 3'UTR-embedded Alus, may also be exploited by DNA viruses to incorporate host genes to their viral genomes

Ly9 (CD229) Cell-Surface Receptor is Crucial for the Development of Spontaneous Autoantibody Production to Nuclear Antigens

The Signaling Lymphocyte Activation Molecule Family (SLAMF) genes, which encode cell-surface receptors that modulate innate and adaptive immune responses, lay within a genomic region of human and mouse chromosome 1 that confers a predisposition for the development of systemic lupus erythematosus (SLE). Herein, we demonstrate that the SLAMF member Ly9 arises as a novel receptor contributing to the reinforcement of tolerance. Specifically, Ly9-deficient mice spontaneously developed features of systemic autoimmunity such as the production of anti-nuclear antibodies (ANA), -dsDNA, and -nucleosome autoantibodies, independently of genetic background [(B6.129) or (BALB/c.129)]. In aged (10- to 12-month-old) Ly9−/− mice key cell subsets implicated in autoimmunity were expanded, e.g., T follicular helper (Tfh) as well as germinal center (GC) B cells. More importantly, in vitro functional experiments showed that Ly9 acts as an inhibitory receptor of IFN-γ producing CD4+ T cells. Taken together, our findings reveal that the Ly9 receptor triggers cell intrinsic safeguarding mechanisms to prevent a breach of tolerance, emerging as a new non-redundant inhibitory cell-surface receptor capable of disabling autoantibody responses

SAP-Dependent and -Independent Regulation of Innate T Cell Development Involving SLAMF Receptors

Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) plays an essential role in the immune system mediating the function of several members of the SLAM family (SLAMF) of receptors, whose expression is essential for T, NK, and B-cell responses. Additionally, the expression of SAP in double-positive thymocytes is mandatory for natural killer T (NKT) cells and, in mouse, for innate CD8+ T cell development. To date, only two members of the SLAMF of receptors, Slamf1 and Slamf6, have been shown to positively cooperate during NKT cell differentiation in mouse. However, it is less clear whether other members of this family may also participate in the development of these innate T cells. Here, we show that Slamf[1 + 6]−/− and Slamf[1 + 5 + 6]−/−B6 mice have ~70% reduction of NKT cells compared to wild-type B6 mice. Unexpectedly, the proportion of innate CD8+ T cells slightly increased in the Slamf[1 + 5 + 6]−/−, but not in the Slamf[1 + 6]−/− strain, suggesting that Slamf5 may function as a negative regulator of innate CD8+ T cell development. Accordingly, Slamf5−/− B6 mice showed an exclusive expansion of innate CD8+ T cells, but not NKT cells. Interestingly, the SAP-independent Slamf7−/− strain showed an expansion of both splenic innate CD8+ T cells and thymic NKT cells. On the other hand, and similar to what was recently shown in Slamf3−/− BALB/c mice, the proportions of thymic promyelocytic leukemia zinc finger (PLZFhi) NKT cells and innate CD8+ T cells significantly increased in the SAP-independent Slamf8−/− BALB/c strain. In summary, these results show that NKT and innate CD8+ T cell development can be regulated in a SAP-dependent and -independent fashion by SLAMF receptors, in which Slamf1, Slamf6, and Slamf8 affect development of NKT cells, and that Slamf5, Slamf7, and Slamf8 affect the development of innate CD8+ T cells

Slamf6 negatively regulates autoimmunity

The nine SLAM family (Slamf) receptors are positive or negative regulators of adaptive and innate immune responses, and of several autoimmune diseases. Here we report that the transfer of Slamf6-/- B6 CD4+ T cells into co-isogenic bm12 mice causes SLE-like autoimmunity with elevated levels of autoantibodies. In addition, significantly higher percentages of Tfh cells and IFN-γ-producing CD4+ cells, as well as GC B cells were observed. Interestingly, the expression of the Slamf6-H1 isoform in Slamf6-/- CD4+ T cells did not induce this lupus-like phenotype. By contrast, Slamf1-/- or Slamf5-/- CD4+ T cells caused the same pathology as WT CD4+ T cells. As the transfer of Slamf [1+6]-/- or Slamf [1+5+6]-/- CD4+ T cells induced WT levels of autoantibodies, the presence of Slamf1 was requisite for the induction of increased levels of autoantibodies by Slamf6-/- CD4+ T cells. We conclude that Slamf6 functions as an inhibitory receptor that controls autoimmune responses