45 research outputs found
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
Diaryltriazenes as antibacterial agents against methicillin resistant Staphylococcus aureus (MRSA) and Mycobacterium smegmatis
Diaryltriazene derivatives were synthesized and evaluated for their antimicrobial properties. Initial experiments showed some of these compounds to have activity against both methicillin-resistant strains of Staphylococus aureus (MRSA) and Mycobacterium smegmatis, with MICs of 0.02 and 0.03 μg/mL respectively. Those compounds with potent anti-staphylococcal and anti-mycobacterial activity were not found to act as growth inhibitors of mammalian cell lines or yeast. Furthermore, we demonstrated that one of the most active anti-MRSA diaryltriazene derivatives was subject to very low frequencies of resistance at <10−9. Whole genome sequencing of resistant isolates identified mutations in the enzyme that lysylates phospholipids. This could result in the modification of phospholipid metabolism and consequently the characteristics of the staphylococcal cell membrane, ultimately modifying the sensitivity of these pathogens to triazene challenge. Our work has therefore extended the potential range of triazenes, which could yield novel antimicrobials with low levels of resistance
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 (with ), the macroscopic bending rigidity
determined from cantilever deformations is independent of the width
when , where is a thermal length scale,
as expected. When , 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
. When the ribbon length , where is the -dependent
thermally renormalized ribbon persistence length, we observe a scaling collapse
and the beginnings of large scale random walk behavior
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
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.)
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
Anti-mycobacterial activity of 1,3-diaryltriazenes.
<p>The rapid generation and spread of the drug resistant tuberculosis has led to an ongoing demand for novel compounds for therapeutic use. Identification and study of compounds with the ability to inhibit Mycobacterium tuberculosis is of paramount importance. For this reason, a library of substituted 1,3-diaryltriazenes based on the acting component of the anti-trypanosomal drug, diminazene aceturate was created and evaluated for its potential as anti-tubercular agent. Several compounds were identified with sub-micro molar inhibitory concentrations against M. tuberculosis and other clinically relevant mycobacterial species such as Mycobacterium bovis, Mycobacterium avium and Mycobacterium ulcerans. Although the library of the compounds showed a considerable acute cytotoxicity, a genotoxicity could not be observed. Finally, the triazene 14 was selected with the best biological properties (IC50 = 3.26 μM, NI50 = 24.22 μM, SI = 7.44). The compound 14 showed the ability to inhibit the growth of intracellular replicating and multi-drug resistant M. tuberculosis. The results suggest the molecule to be an interesting scaffold for further study and optimization.</p></p