Neutrophils are central players in the innate immune system. They generate neutrophil extracellular traps (NETs), which protect against invading pathogens but are also associated with the development of autoimmune and/or inflammatory diseases and thrombosis. Here, we report that lactoferrin, one of the components of NETs, translocated from the cytoplasm to the plasma membrane and markedly suppressed NETs release. Furthermore, exogenous lactoferrin shrunk the chromatin fibers found in released NETs, without affecting the generation of oxygen radicals, but this failed after chemical removal of the positive charge of lactoferrin, suggesting that charge-charge interactions between lactoferrin and NETs were required for this function. In a model of immune complex-induced NET formation in vivo, intravenous lactoferrin injection markedly reduced the extent of NET formation. These observations suggest that lactoferrin serves as an intrinsic inhibitor of NETs release into the circulation. Thus, lactoferrin may represent a therapeutic lead for controlling NETs release in autoimmune and/or inflammatory diseases.
Kidney failure is an important outcome for patients, clinicians, researchers, healthcare systems, payers, and regulators. However, no harmonized international consensus definitions of kidney failure and key surrogates of progression to kidney failure exist specifically for clinical trials. The International Society of Nephrology convened an international multistakeholder meeting to develop consensus on this topic. A core group, experienced in design, conduct, and outcome adjudication of clinical trials, developed a database of 64 randomized trials and the 163 included definitions relevant to kidney failure. Using an iterative process, a set of proposed consensus definitions were developed and subsequently vetted by the larger multi-stakeholder group of 83 participants representing 18 different countries. The
It is proposed that osteocytes embedded in the bone matrix have the ability to sense deformation and/or damage to the matrix and to feed these mechanical signals back to the adaptive bone remodeling process. When osteoblasts differentiate into osteocytes during the bone formation process, they change their morphology to a stellate form with many slender processes. This characteristic cell shape may underlie the differences in mechanosensitivity between the cell processes and cell body. To elucidate the mechanism of cellular response to mechanical stimulus in osteocytes, we investigated the site-dependent response to quantitatively controlled local mechanical stimulus in single osteocytes isolated from chick embryos, using the technique of calcium imaging. A mechanical stimulus was applied to a single osteocyte using a glass microneedle targeting a microparticle adhered to the cell membrane by modification with a monoclonal antibody OB7.3. Application of the local deformation induced calcium transients in the vicinity of the stimulated point and caused diffusive wave propagation of the calcium transient to the entire intracellular region. The rate of cell response to the stimulus was higher when applied to the cell processes than when applied to the cell body. In addition, a large deformation was necessary at the cell body to induce calcium transients, whereas a relatively small deformation was sufficient at the cell processes, suggesting that the mechanosensitivity of the cell processes was higher than that of the cell body. These results suggest that the cell shape with slender processes contributes to the site-dependent mechanosensitivity in osteocytes.
A detailed investigation has been carried out to determine the effect of local fiber array irregularities and controlling fiber distribution parameters on microscopic interfacial normal stress states for transversely-loaded unidirectional carbon fiber (CF)/epoxy composites. Linear elastic finite element analyses were carried out for two-dimensional image-based models composed of about 70 fibers. The relationship between the geometrical distribution of two adjacent fibers and the interfacial normal stresses (INSs) is 2 investigated for all fibers in different image-based models. Three boundary conditions for loading were selected: Case A involved cooling from the curing temperature (the difference in temperature was-155 K); Case B involved transverse loading of 75 MPa chosen as an example of macroscopic transverse fracture strength; and Case C involved both cooling from the curing temperature and transverse loading of 75 MPa. High compressive INSs due to the difference in the coefficients of thermal expansion are observed at the location of the shortest interfiber distance for Case A (cooling). High tensile INSs are observed at the location of the shortest interfiber distance and where the fiber alignment angle to the loading direction is small for Case B (loading). For Case C (cooling and loading), the high thermal residual compressive INSs and the high mechanical tensile INSs compensate each other, and the INSs at a short interfiber distance are much lower than those for Case B. These results clearly indicate the importance of the contribution of the thermal residual stresses to the transverse tensile failure initiation of CF/epoxy laminates.
We have studied the tensile behaviour of Bi2223 superconducting composite tapes at room temperature, and the influence of the tensile damages introduced at room temperature on the critical current Ic and the n values at 77 K. In the measurement of the Ic and n values, the overall composite with a gauge length 60 mm was divided into six elements with a gauge length of 10 mm in order to find the correlation of the Ic and n values of the overall composite to those of the local elements which constitute the composite. From the measured stress–strain curve of the composite and the calculated residual strain of the Bi2223 filaments, the intrinsic fracture strain of Bi2223 filaments was estimated to be 0.09–0.12%. When the applied strain was lower than the onset strain of the filament damage, the original Ic and n values were retained both in the overall composite and the elements. In this situation, while the overall voltage at the transition from superconductivity to normal conductivity of the composite was the sum of the voltages of the constituent elements, among all elements the overall voltage was affected more by the element with the lower Ic (higher voltage). The damage of the filaments arose first locally, resulting in a reduction of the Ic and n values in the corresponding local element, even though the other elements retained the original Ic and n values. In this situation, the voltage of the overall composite stemmed dominantly from that of the firstly damaged weakest element, and the overall Ic and n values were almost determined by the values of such an element. After the local element was fully damaged, the damage arose also in other elements, resulting in segmentation of the filaments. Thus, the Ic and n values were reduced in all elements. The correlation of Ic between the overall composite and the elements could be described comprehensively for non-damaged and damaged states from the voltage–current relation.
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