Multi-scale strain-stiffening of semiflexible bundle networks

Bundles of polymer filaments are responsible for the rich and unique mechanical behaviors of many biomaterials, including cells and extracellular matrices. In fibrin biopolymers, whose nonlinear elastic properties are crucial for normal blood clotting, protofibrils self-assemble and bundle to form networks of semiflexible fibers. Here we show that the extraordinary strain-stiffening response of fibrin networks is a direct reflection of the hierarchical architecture of the fibrin fibers. We measure the rheology of networks of unbundled protofibrils and find excellent agreement with an affine model of extensible wormlike polymers. By direct comparison with these data, we show that physiological fibrin networks composed of thick fibers can be modeled as networks of tight protofibril bundles. We demonstrate that the tightness of coupling between protofibrils in the fibers can be tuned by the degree of enzymatic intermolecular crosslinking by the coagulation Factor XIII. Furthermore, at high stress, the protofibrils contribute independently to the network elasticity, which may reflect a decoupling of the tight bundle structure. The hierarchical architecture of fibrin fibers can thus account for the nonlinearity and enormous elastic resilience characteristic of blood clots.Comment: 27 pages including 8 figures and Supplementary Dat

Redundancy and cooperativity in the mechanics of compositely crosslinked filamentous networks

The actin cytoskeleton in living cells has many types of crosslinkers. The mechanical interplay between these different crosslinker types is an open issue in cytoskeletal mechanics. We develop a framework to study the cooperativity and redundancy in the mechanics of filamentous networks with two types of crosslinkers: crosslinkers that allow free rotations of filaments and crosslinkers that do not. The framework consists of numerical simulations and an effective medium theory on a percolating triangular lattice. We find that the introduction of angle-constraining crosslinkers significantly lowers the filament concentrations required for these networks to attain mechanical integrity. This cooperative effect also enhances the stiffness of the network and suppresses non-affine deformations at a fixed filament concentration. We further find that semiflexible networks with only freely-rotating crosslinks are mechanically very similar to compositely crosslinked flexible networks with both networks exhibiting the same scaling behavior. We show that the network mechanics can either be redundant or cooperative depending on the relative energy scale of filament bending to the energy stored in the angle-constraining crosslinkers, and the relative concentration of crosslinkers. Our results may have implications for understanding the role of multiple crosslinkers even in a system without bundle formation or other structural motifs.Comment: 21 pages, 5 figure

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection

Circulating TNF Receptors Are Significant Prognostic Biomarkers for Idiopathic Membranous Nephropathy

<div><p>Idiopathic membranous nephropathy (iMN) is a common cause of nephrotic syndrome in adults. A biomarker to accurately indicate the severity of iMN and predict long-term prognosis is insufficient. Here, we evaluated the clinical significance of circulating tumor necrosis factor receptors (cTNFRs) as prognostic biomarkers of iMN with nephrotic syndrome. A total of 113 patients with biopsy-proven iMN and 43 healthy volunteers were enrolled in this study. Ninety patients with iMN had nephrotic range proteinuria. Levels of cTNFRs were measured by using serum samples collected at the time of initial diagnosis. Levels of cTNFRs were higher in the patients with nephrotic syndrome than in those with subnephrotic range proteinuria or in the healthy volunteers (<i>P</i> for trend <0.001). Estimated glomerular filtration rate and proteinuria tended to worsen as the cTNFRs levels increased. Having a cTNFR1 level within the highest tertile was a significant risk factor for renal progression after adjustment, in comparison with the other tertiles (hazard ratio [HR], 3.39; 95% confidence interval [95% CI], 1.48–7.78; <i>P</i> = 0.004). The cTNFR2 level within the highest tertile also significantly increased the risk of renal progression (HR, 3.29; 95% CI, 1.43–7.54; <i>P</i> = 0.005). Renal tubular TNFRs expression was associated with cTNFRs level. However, the cTNFRs levels were not associated with autoantibody against phospholipase A₂ receptor reactivity/levels or treatment response. This study demonstrated that cTNFRs levels at the time of initial diagnosis could predict renal progression in patients with iMN.</p></div