A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Geometry- and rate-dependent adhesive failure of micropatterned surfaces

The dynamic nature of adhesive interface failure remains poorly understood, especially when the contact between the two surfaces is localized in microscopic points of adhesion. Here, we explore the dynamic failure of adhesive interfaces composed of a large number of micron-sized pillars against glass. Surprisingly, we find a large influence of the microcontact geometry; ordered arrays of these pillars exhibit significantly stronger adhesive properties than equivalent surfaces in which the pillars are disordered. This can be understood with a simple geometric argument that accounts for the number of adhesive bonds that needs to be broken simultaneously to propagate the crack front. Moreover, the adhesive strength in both cases depends largely on the velocity with which the surfaces are separated. This rate dependence is explained on the basis of a semi-phenomenological model that describes macroscopic failure as a consequence of microscopic bond-rupture events. Our results suggest that the dynamics of adhesive failure, in the limit explored here, is predominantly stress-driven and highly sensitive to local geometry effects

Stress enhancement in the delayed yielding of colloidal gels

Networks of aggregated colloidal particles are solidlike and can sustain an applied shear stress while exhibiting little or no creep; however, ultimately they will catastrophically fail. We show that the time delay for this yielding decreases in two distinct exponential regimes with applied stress. This behavior is universal and found for a variety of colloidal gel systems. We present a bond-rupture model that quantitatively describes this behavior and highlights the role of mesoscopic structures. Our result gives new insight into the nature of yielding in these soft solid materials

Structures, stresses, and fluctuations in the delayed failure of colloidal gel

Sample-spanning networks of aggregated colloidal particles have a finite stiffness and deform elastically when subjected to a small shear stress. After some period of creep, these gels ultimately suffer catastrophic failure. This delayed yielding is governed by the association and dissociation dynamics of interparticle bonds and the strand structure of the gel. We derive a model which connects the kinetics of the colloids to the erosion of the strand structure and ultimately to macroscopic failure. Importantly, this model relates time-to-failure of the gel to an applied static stress. Model predictions are in quantitative agreement with experiments. It is predicted that the strand structure, characterized by its mesh size and strand coarseness, has a significant impact on delay time. Decreasing the mesh size or increasing the strand thickness makes colloidal gels more resilient to delayed yielding. The quench and flow history of gels modifies their microstructures. Our experiments show that a slow quenching increases the delay time due to the coarsening of the strands; by contrast, preshear reduces the delay time, which we explain by the increased mesh size as a result of shear-induced fracture of strands

A physical cross-linking process of cellulose nanofibril gels with shear-controlled fibril orientation

Cellulose nanofibrils constitute the smallest fibrous components of wood, with a width of approximately 4 nm and a length in the micrometer range. They consist of aligned linear cellulose chains with crystallinity exceeding 60%, rendering stiff, high-aspect-ratio rods. These properties are advantageous in the reinforcement components of composites. Cross-linked networks of fibrils can be used as templates into which a polymer enters. In the semi-concentrated regime (i.e. slightly above the overlap concentration), carboxy methylated fibrils dispersed in water have been physically cross-linked to form a volume-spanning network (a gel) by reducing the pH or adding salt, which diminishes the electrostatic repulsion between fibrils. By applying shear during or after this gelation process, we can orient the fibrils in a preferred direction within the gel, for the purpose of fully utilizing the high stiffness and strength of the fibrils as reinforcement components. Using these gels as templates enables precise control of the spatial distribution and orientation of the dispersed phase of the composites, optimizing the potentially very large reinforcement capacity of the nanofibrils