Force-induced recruitment of cten along keratin network in epithelial cells.

The cytoskeleton provides structural integrity to cells and serves as a key component in mechanotransduction. Tensins are thought to provide a force-bearing linkage between integrins and the actin cytoskeleton; yet, direct evidence of tensin's role in mechanotransduction is lacking. We here report that local force application to epithelial cells using a micrometer-sized needle leads to rapid accumulation of cten (tensin 4), but not tensin 1, along a fibrous intracellular network. Surprisingly, cten-positive fibers are not actin fibers; instead, these fibers are keratin intermediate filaments. The dissociation of cten from tension-free keratin fibers depends on the duration of cell stretch, demonstrating that the external force favors maturation of cten-keratin network interactions over time and that keratin fibers retain remarkable structural memory of a cell's force-bearing state. These results establish the keratin network as an integral part of force-sensing elements recruiting distinct proteins like cten and suggest the existence of a mechanotransduction pathway via keratin network

Cantilever-based Resonant Gas Sensors with Integrated Recesses for Localized Sensing Layer Deposition

This work presents mass-sensitive hammerhead resonators with integrated recesses as a gas-phase chemical microsensor platform. Recesses are etched into the head region of the resonator to locally deposit chemically sensitive polymers by ink-jet printing. This permits the sensing films to be confined to areas that (a) are most effective in detecting mass loading and (b) are not strained during the in-plane vibrations of the resonator. As a result of the second point, even 5-μm thick polymer coatings on resonators with a 9-12 μm silicon thickness barely affect the Q-factor in air. This translates into higher frequency stability and ultimately higher sensor resolution compared to uniformly coated devices

On the Relative Sensitivity of Mass-sensitive Chemical Microsensors

In this work, the chemical sensitivity of mass-sensitive chemical microsensors with a uniform layer sandwich structure vibrating in their lateral or in-plane flexural modes is investigated. It is experimentally verified that the relative chemical sensitivity of such resonant microsensors is -to a first order- independent of the microstructure\u27s in-plane dimensions and the flexural eigenmode used, and only depends on the layer thicknesses and densities as well as the sorption properties of the sensing film. Important implications for the design of mass-sensitive chemical microsensors are discussed, whereby the designer can focus on the layer stack to optimize the chemical sensitivity and on the in-plane dimensions and mode shape to optimize the resonator\u27s frequency stability

Ferromagnetic resonance study of sputtered Co|Ni multilayers

We report on room temperature ferromagnetic resonance (FMR) studies of [$t$ Co$|2t$ Ni]$\times$N sputtered films, where $0.1 \leq t \leq 0.6$ nm. Two series of films were investigated: films with same number of Co$|$Ni bilayer repeats (N=12), and samples in which the overall magnetic layer thickness is kept constant at 3.6 nm (N=1.2/$t$). The FMR measurements were conducted with a high frequency broadband coplanar waveguide up to 50 GHz using a flip-chip method. The resonance field and the full width at half maximum were measured as a function of frequency for the field in-plane and field normal to the plane, and as a function of angle to the plane for several frequencies. For both sets of films, we find evidence for the presence of first and second order anisotropy constants, $K_1$ and $K_2$. The anisotropy constants are strongly dependent on the thickness $t$, and to a lesser extent on the total thickness of the magnetic multilayer. The Land\'e g-factor increases with decreasing $t$ and is practically independent of the multilayer thickness. The magnetic damping parameter $\alpha$, estimated from the linear dependence of the linewidth, $\triangle H$, on frequency, in the field in-plane geometry, increases with decreasing $t$. This behaviour is attributed to an enhancement of spin-orbit interactions with $t$ decreasing and in thinner films, to a spin-pumping contribution to the damping.Comment: 18 pages, 13 figure

Atomic scale investigation of Cr precipitation in copper

The early stage of the chromium precipitation in copper was analyzed at the atomic scale by Atom Probe Tomography (APT). Quantitative data about the precipitate size, 3D shape, density, composition and volume fraction were obtained in a Cu-1Cr-0.1Zr (wt.%) commercial alloy aged at 713K. Surprisingly, nanoscaled precipitates exhibit various shapes (spherical, plates and ellipsoid) and contain a large amount of Cu (up to 50%), in contradiction with the equilibrium Cu-Cr phase diagram. APT data also show that some impurities (Fe) may segregate along Cu/Cr interfaces. The concomitant evolution of the precipitate shape and composition as a function of the aging time is discussed. A special emphasis is given on the competition between interfacial and elastic energy and on the role of Fe segregation

Strain uses gap junctions to reverse stimulation of osteoblast proliferation by osteocytes

Identifying mechanisms by which cells of the osteoblastic lineage communicate in vivo is complicated by the mineralised matrix that encases osteocytes, and thus, vital mechanoadaptive processes used to achieve load‐bearing integrity remain unresolved. We have used the coculture of immunomagnetically purified osteocytes and primary osteoblasts from both embryonic chick long bone and calvariae to examine these mechanisms. We exploited the fact that purified osteocytes are postmitotic to examine both their effect on proliferation of primary osteoblasts and the role of gap junctions in such communication. We found that chick long bone osteocytes significantly increased basal proliferation of primary osteoblasts derived from an identical source (tibiotarsi). Using a gap junction inhibitor, 18β‐glycyrrhetinic acid, we also demonstrated that this osteocyte‐related increase in osteoblast proliferation was not reliant on functional gap junctions. In contrast, osteocytes purified from calvarial bone failed to modify basal proliferation of primary osteoblast, but long bone osteocytes preserved their proproliferative action upon calvarial‐derived primary osteoblasts. We also showed that coincubated purified osteocytes exerted a marked inhibitory action on mechanical strain–related increases in proliferation of primary osteoblasts and that this action was abrogated in the presence of a gap junction inhibitor. These data reveal regulatory differences between purified osteocytes derived from functionally distinct bones and provide evidence for 2 mechanisms by which purified osteocytes communicate with primary osteoblasts to coordinate their activity

Ripretinib Versus Sunitinib in Patients With Advanced Gastrointestinal Stromal Tumor After Treatment With Imatinib (INTRIGUE): A Randomized, Open-Label, Phase III Trial.

PURPOSE: Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib is a switch-control TKI approved for advanced GIST after prior treatment with three or more TKIs, including imatinib. We compared efficacy and safety of ripretinib versus sunitinib in patients with advanced GIST who were previously treated with imatinib (INTRIGUE, ClinicalTrials.gov identifier: NCT03673501). PATIENTS AND METHODS: Random assignment was 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off) and stratified by KIT/platelet-derived growth factor α mutation and imatinib intolerance. The primary end point was progression-free survival (PFS) by independent radiologic review using modified Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included objective response rate by independent radiologic review, safety, and patient-reported outcome measures. RESULTS: Overall, 453 patients were randomly assigned to ripretinib (intention-to-treat [ITT], n = 226; KIT exon 11 ITT, n = 163) or sunitinib (ITT, n = 227; KIT exon 11 ITT, n = 164). Median PFS for ripretinib and sunitinib (KIT exon 11 ITT) was 8.3 and 7.0 months, respectively (hazard ratio, 0.88; 95% CI, 0.66 to 1.16; P = .36); median PFS (ITT) was 8.0 and 8.3 months, respectively (hazard ratio, 1.05; 95% CI, 0.82 to 1.33; nominal P = .72). Neither was statistically significant. Objective response rate was higher for ripretinib versus sunitinib in the KIT exon 11 ITT population (23.9% v 14.6%, nominal P = .03). Ripretinib was associated with a more favorable safety profile, fewer grade 3/4 treatment-emergent adverse events (41.3% v 65.6%, nominal P < .0001), and better scores on patient-reported outcome measures of tolerability. CONCLUSION: Ripretinib was not superior to sunitinib in terms of PFS. However, meaningful clinical activity, fewer grade 3/4 treatment-emergent adverse events, and improved tolerability were observed with ripretinib

Cancellous bone and theropod dinosaur locomotion. Part I—an examination of cancellous bone architecture in the hindlimb bones of theropods

This paper is the first of a three-part series that investigates the architecture of cancellous (‘spongy’) bone in the main hindlimb bones of theropod dinosaurs, and uses cancellous bone architectural patterns to infer locomotor biomechanics in extinct non-avian species. Cancellous bone is widely known to be highly sensitive to its mechanical environment, and has previously been used to infer locomotor biomechanics in extinct tetrapod vertebrates, especially primates. Despite great promise, cancellous bone architecture has remained little utilized for investigating locomotion in many other extinct vertebrate groups, such as dinosaurs. Documentation and quantification of architectural patterns across a whole bone, and across multiple bones, can provide much information on cancellous bone architectural patterns and variation across species. Additionally, this also lends itself to analysis of the musculoskeletal biomechanical factors involved in a direct, mechanistic fashion. On this premise, computed tomographic and image analysis techniques were used to describe and analyse the three-dimensional architecture of cancellous bone in the main hindlimb bones of theropod dinosaurs for the first time. A comprehensive survey across many extant and extinct species is produced, identifying several patterns of similarity and contrast between groups. For instance, more stemward non-avian theropods (e.g. ceratosaurs and tyrannosaurids) exhibit cancellous bone architectures more comparable to that present in humans, whereas species more closely related to birds (e.g. paravians) exhibit architectural patterns bearing greater similarity to those of extant birds. Many of the observed patterns may be linked to particular aspects of locomotor biomechanics, such as the degree of hip or knee flexion during stance and gait. A further important observation is the abundance of markedly oblique trabeculae in the diaphyses of the femur and tibia of birds, which in large species produces spiralling patterns along the endosteal surface. Not only do these observations provide new insight into theropod anatomy and behaviour, they also provide the foundation for mechanistic testing of locomotor hypotheses via musculoskeletal biomechanical modelling

Two New Loci for Body-Weight Regulation Identified in a Joint Analysis of Genome-Wide Association Studies for Early-Onset Extreme Obesity in French and German Study Groups

Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85610 x 10(-8) in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84 x 10(-7)), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at similar to 1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults