Soft Spheres Make More Mesophases

We use both mean-field methods and numerical simulation to study the phase diagram of classical particles interacting with a hard-core and repulsive, soft shoulder. Despite the purely repulsive interaction, this system displays a remarkable array of aggregate phases arising from the competition between the hard-core and shoulder length scales. In the limit of large shoulder width to core size, we argue that this phase diagram has a number of universal features, and classify the set of repulsive shoulders that lead to aggregation at high density. Surprisingly, the phase sequence and aggregate size adjusts so as to keep almost constant inter-aggregate separation.Comment: 4 pages, 2 included figure

The influence of T cell development on pathogen specificity and autoreactivity

T cells orchestrate adaptive immune responses upon activation. T cell activation requires sufficiently strong binding of T cell receptors on their surface to short peptides derived from foreign proteins bound to protein products of the major histocompatibility (MHC) gene products, which are displayed on the surface of antigen presenting cells. T cells can also interact with peptide-MHC complexes, where the peptide is derived from host (self) proteins. A diverse repertoire of relatively self-tolerant T cell receptors is selected in the thymus. We study a model, computationally and analytically, to describe how thymic selection shapes the repertoire of T cell receptors, such that T cell receptor recognition of pathogenic peptides is both specific and degenerate. We also discuss the escape probability of autoimmune T cells from the thymus.Comment: 12 pages, 7 figure

Bacterial Biofilm Material Properties Enable Removal and Transfer by Capillary Peeling

Biofilms, surface‐attached communities of bacterial cells, are a concern in health and in industrial operations because of persistent infections, clogging of flows, and surface fouling. Extracellular matrices provide mechanical protection to biofilm‐dwelling cells as well as protection from chemical insults, including antibiotics. Understanding how biofilm material properties arise from constituent matrix components and how these properties change in different environments is crucial for designing biofilm removal strategies. Here, using rheological characterization and surface analyses of Vibrio cholerae biofilms, it is discovered how extracellular polysaccharides, proteins, and cells function together to define biofilm mechanical and interfacial properties. Using insight gained from our measurements, a facile capillary peeling technology is developed to remove biofilms from surfaces or to transfer intact biofilms from one surface to another. It is shown that the findings are applicable to other biofilm‐forming bacterial species and to multiple surfaces. Thus, the technology and the understanding that have been developed could potentially be employed to characterize and/or treat biofilm‐related infections and industrial biofouling problems

Non-Hookean statistical mechanics of clamped graphene ribbons

Thermally fluctuating sheets and ribbons provide an intriguing forum in which to investigate strong violations of Hooke's Law: large distance elastic parameters are in fact not constant, but instead depend on the macroscopic dimensions. Inspired by recent experiments on free-standing graphene cantilevers, we combine the statistical mechanics of thin elastic plates and large-scale numerical simulations to investigate the thermal renormalization of the bending rigidity of graphene ribbons clamped at one end. For ribbons of dimensions $W\times L$ (with $L\geq W$), the macroscopic bending rigidity $\kappa_R$ determined from cantilever deformations is independent of the width when $W<\ell_\textrm{th}$, where $\ell_\textrm{th}$ is a thermal length scale, as expected. When $W>\ell_\textrm{th}$, however, this thermally renormalized bending rigidity begins to systematically increase, in agreement with the scaling theory, although in our simulations we were not quite able to reach the system sizes necessary to determine the fully developed power law dependence on $W$. When the ribbon length $L > \ell_p$, where $\ell_p$ is the $W$-dependent thermally renormalized ribbon persistence length, we observe a scaling collapse and the beginnings of large scale random walk behavior

Effects of thymic selection of the T cell repertoire on HLA-class I associated control of HIV infection

Without therapy, most people infected with human immunodeficiency virus (HIV) ultimately progress to AIDS. Rare individuals (‘elite controllers’) maintain very low levels of HIV RNA without therapy, thereby making disease progression and transmission unlikely. Certain HLA class I alleles are markedly enriched in elite controllers, with the highest association observed for HLA-B57 (ref. 1). Because HLA molecules present viral peptides that activate CD8+ T cells, an immune-mediated mechanism is probably responsible for superior control of HIV. Here we describe how the peptide-binding characteristics of HLA-B57 molecules affect thymic development such that, compared to other HLA-restricted T cells, a larger fraction of the naive repertoire of B57-restricted clones recognizes a viral epitope, and these T cells are more cross-reactive to mutants of targeted epitopes. Our calculations predict that such a T-cell repertoire imposes strong immune pressure on immunodominant HIV epitopes and emergent mutants, thereby promoting efficient control of the virus. Supporting these predictions, in a large cohort of HLA-typed individuals, our experiments show that the relative ability of HLA-B alleles to control HIV correlates with their peptide-binding characteristics that affect thymic development. Our results provide a conceptual framework that unifies diverse empirical observations, and have implications for vaccination strategies.Mark and Lisa Schwartz FoundationNational Institutes of Health (U.S.) (Director’s Pioneer award)Philip T. and Susan M. Ragon FoundationJane Coffin Childs Memorial Fund for Medical ResearchBill & Melinda Gates FoundationNational Institute of Allergy and Infectious Diseases (U.S.)National Institutes of Health (U.S.) (contract no. HHSN261200800001E)National Institutes of Health (U.S.). Intramural Research ProgramNational Cancer Institute (U.S.)Center for Cancer Research (National Cancer Institute (U.S.)

Spectroscopic Study of Solvent Effects on the Electronic Absorption Spectra of Flavone and 7-Hydroxyflavone in Neat and Binary Solvent Mixtures

The solvatochromic characteristics of flavone and 7-hydroxyflavone were investigated in neat and binary solvent mixtures. The spectral shifts of these solutes were correlated with the Kamlet and Taft parameters (α, β and π*) using linear solvation energy relationships. The multiparametric analysis indicates that both specific hydrogen bond donor ability and non-specific dipolar interactions of the solvents play an important role in absorption maxima of flavone in pure solvents. The hydrogen bond acceptor ability of the solvent was the main parameter affecting the absorption maxima of 7-hydroxyflavone. The simulated absorption spectra using a TD-DFT method were in good agreement with the experimental ones for both flavones. Index of preferential solvation was calculated as a function of solvent composition. Preferential solvation by ethanol was detected in cyclohexane-ethanol and acetonitrile-ethanol mixtures for flavone and in acetonitrile-ethanol mixtures for 7-hydroxyflavone. These results indicate that intermolecular hydrogen bonds between solute and solvent are responsible for the non-linear variation of the solvatochromic shifts on the mole fraction of ethanol in the analyzed binary mixtures

Leveraging ligand affinity and properties: discovery of novel benzamide-type cereblon binders for the design of PROTACs

Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomide are the most common cereblon (CRBN) recruiters in proteolysis-targeting chimera (PROTAC) design. However, these CRBN ligands induce the degradation of IMiD neosubstrates and are inherently unstable, degrading hydrolytically under moderate conditions. In this work, we simultaneously optimized physiochemical properties, stability, on-target affinity, and off-target neosubstrate modulation features to develop novel nonphthalimide CRBN binders. These efforts led to the discovery of conformationally locked benzamide-type derivatives that replicate the interactions of the natural CRBN degron, exhibit enhanced chemical stability, and display a favorable selectivity profile in terms of neosubstrate recruitment. The utility of the most potent ligands was demonstrated by their transformation into potent degraders of BRD4 and HDAC6 that outperform previously described reference PROTACs. Together with their significantly decreased neomorphic ligase activity on IKZF1/3 and SALL4, these ligands provide opportunities for the design of highly selective and potent chemically inert proximity-inducing compounds

Thymic Selection of T-Cell Receptors as an Extreme Value Problem

T lymphocytes (T cells) orchestrate adaptive immune responses upon activation. T-cell activation requires sufficiently strong binding of T-cell receptors on their surface to short peptides (p) derived from foreign proteins, which are bound to major histocompatibility gene products (displayed on antigen-presenting cells). A diverse and self-tolerant T-cell repertoire is selected in the thymus. We map thymic selection processes to an extreme value problem and provide an analytic expression for the amino acid compositions of selected T-cell receptors (which enable its recognition functions).National Institutes of Healt

The versatile and strategic O-carbamate directed metalation group in the synthesis of aromatic molecules

The aryl O-carbamate (ArOAm) group is among the strongest of the directed metalation groups (DMGs) in directed ortho metalation (DoM) chemistry, especially in the form Ar-OCONEt$_2$. Since the last comprehensive review of metalation chemistry involving ArOAms (published more than 30 years ago), the field has expanded significantly. For example, it now encompasses new substrates, solvent systems, and metalating agents, while conditions have been developed enabling metalation of ArOAm to be conducted in a green and sustainable manner. The ArOAm group has also proven to be effective in the anionic ortho-Fries (AoF) rearrangement, Directed remote metalation (DreM), iterative DoM sequences, and DoM-halogen dance (HalD) synthetic strategies and has been transformed into a diverse range of functionalities and coupled with various groups through a range of cross-coupling (CC) strategies. Of ultimate value, the ArOAm group has demonstrated utility in the synthesis of a diverse range of bioactive and polycyclic aromatic compounds for various applications