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Neutrophils are the first line of defense at the site of an infection. They encounter and kill microbes intracellularly upon phagocytosis or extracellularly by degranulation of antimicrobial proteins and the release of Neutrophil Extracellular Traps (NETs). NETs were shown to ensnare and kill microbes. However, their complete protein composition and the antimicrobial mechanism are not well understood. Using a proteomic approach, we identified 24 NET-associated proteins. Quantitative analysis of these proteins and high resolution electron microscopy showed that NETs consist of modified nucleosomes and a stringent selection of other proteins. In contrast to previous results, we found several NET proteins that are cytoplasmic in unstimulated neutrophils. We demonstrated that of those proteins, the antimicrobial heterodimer calprotectin is released in NETs as the major antifungal component. Absence of calprotectin in NETs resulted in complete loss of antifungal activity in vitro. Analysis of three different Candida albicans in vivo infection models indicated that NET formation is a hitherto unrecognized route of calprotectin release. By comparing wild-type and calprotectin-deficient animals we found that calprotectin is crucial for the clearance of infection. Taken together, the present investigations confirmed the antifungal activity of calprotectin in vitro and, moreover, demonstrated that it contributes to effective host defense against C. albicans in vivo. We showed for the first time that a proportion of calprotectin is bound to NETs in vitro and in vivo.

Super-resolution imaging of the dynamics of organelle structures in live cells is facilitated by blinking, far-red dyes. Imaging cellular structures and organelles in living cells by long time-lapse super-resolution microscopy is challenging, as it requires dense labeling, bright and highly photostable dyes, and non-toxic conditions. We introduce a set of high-density, environment-sensitive (HIDE) membrane probes, based on the membrane-permeable silicon-rhodamine dye HMSiR, that assemble in situ and enable long time-lapse, live-cell nanoscopy of discrete cellular structures and organelles with high spatiotemporal resolution. HIDE-enabled nanoscopy movies span tens of minutes, whereas movies obtained with labeled proteins span tens of seconds. Our data reveal 2D dynamics of the mitochondria, plasma membrane and filopodia, and the 2D and 3D dynamics of the endoplasmic reticulum, in living cells. HIDE probes also facilitate acquisition of live-cell, two-color, super-resolution images, expanding the utility of nanoscopy to visualize dynamic processes and structures in living cells.

The merozoite stage of the malaria parasite that infects erythrocytes and causes the symptoms of the disease is initially formed inside host hepatocytes. However, the mechanism by which hepatic merozoites reach blood vessels (sinusoids) in the liver and escape the host immune system before invading erythrocytes remains unknown. Here, we show that parasites induce the death and the detachment of their host hepatocytes, followed by the budding of parasite-filled vesicles (merosomes) into the sinusoid lumen. Parasites simultaneously inhibit the exposure of phosphatidylserine on the outer leaflet of host plasma membranes, which act as \"eat me\" signals to phagocytes. Thus, the hepatocyte-derived merosomes appear to ensure both the migration of parasites into the bloodstream and their protection from host immunity.

Bio-inspired functionally graded cellular materials (FGCM) have improved performance in energy absorption compared with a uniform cellular material (UCM). In this work, sheet-based and strut-based gyroid cellular structures with graded densities are designed and manufactured by stereo-lithography (SLA). For comparison, uniform structures are also designed and manufactured, and the graded structures are generated with different gradients. The mechanical behaviors of these structures under compressive loads are investigated. Furthermore, the anisotropy and effective elastic modulus of sheet-based and strut-based unit gyroid cellular structures are estimated by a numerical homogenization method. On the one hand, it is found from the numerical results that the sheet-based gyroid tends to be isotropic, and the elastic modulus of sheet-based gyroid is larger than the strut-based gyroid at the same volume fraction. On the other hand, the graded cellular structure has novel deformation and mechanical behavior. The uniform structure exhibits overall deformation and collapse behavior, whereas the graded cellular structure shows layer-by-layer deformation and collapse behavior. Furthermore, the uniform sheet-based gyroid is not only stiffer but also better in energy absorption capacity than the uniform strut-based gyroid structure. Moreover, the graded cellular structures have better energy absorption capacity than the uniform structures. These significant findings indicate that sheet-based gyroid cellular structure with graded densities have potential applications in various industrial applications, such as in crashworthiness.

Although metastasis is the leading cause of cancer-related death, it is not clear why some patients with localized cancer develop metastatic disease after complete resection of their primary tumor. Such relapses have been attributed to tumor cells that disseminate early and remain dormant for prolonged periods of time; however, little is known about the control of these disseminated tumor cells. Here, we have used a spontaneous mouse model of melanoma to investigate tumor cell dissemination and immune control of metastatic outgrowth. Tumor cells were found to disseminate throughout the body early in development of the primary tumor, even before it became clinically detectable. The disseminated tumor cells remained dormant for varying periods of time depending on the tissue, resulting in staggered metastatic outgrowth. Dormancy in the lung was associated with reduced proliferation of the disseminated tumor cells relative to the primary tumor. This was mediated, at least in part, by cytostatic CD8+ T cells, since depletion of these cells resulted in faster outgrowth of visceral metastases. Our findings predict that immune responses favoring dormancy of disseminated tumor cells, which we propose to be the seed of subsequent macroscopic metastases, are essential for prolonging the survival of early stage cancer patients and suggest that therapeutic strategies designed to reinforce such immune responses may produce marked benefits in these patients.

The prospect of improved quality of life and the increasingly younger age of patients benefiting from Total Hip Arthroplasty will soon lead to the landmark of 10 million interventions per year worldwide. More than 10% of these procedures lead to significant bone resorption, increasing the need for revision surgeries. Current research focuses on the development of hip implant designs to achieve a stiffness profile closer to the natural bone. Additive Manufacturing has emerged as a viable solution by offering promising results in the fabrication of implant architectures based on metallic cellular structures that have demonstrated their capacity to replicate bone behavior mechanically and biologically. Aiming to offer an up-to-date overview of titanium cellular structures in hip implants, for both acetabular and femoral components, produced by Additive Manufacturing, including its design intricacies and performance, this comprehensive review meticulously examines the historical development of hip implants, encompassing commercial solutions and innovative attempts. A broad view of the practical applications and transformative potential of hip implants incorporating cellular structures is presented, aiming to outline opportunities for innovation.

The application of passive safety technology in vehicles is generally through impact-absorbing structures. This technology has been widely applied to trains, planes, and cars to protect passengers from fatal accidents. Cellular structures are defined by a unit cell that combines material, space, and unit cell repetition to obtain a large structure. It is selected as the base structure of the impact energy absorber for its potentially high specific energy absorption (SEA). Such a structure poses a challenge in its manufacturing method. This study examines alternative manufacturing processes for cellular structures designed as impact absorbers, and then selects and develops an effective and efficient manufacturing method to produce these cellular structures. Several alternative manufacturing methods were chosen to exercise the use of a combined plaster molding technology and additive manufacturing for prototyping. Manufacturing process simulation studies were conducted using Altair Inspire Cast software to determine the success of the casting process. The final stage is to carry out the process of making cell structures and evaluating the results. This work results in an effective manufacturing process design to be implemented throughout the production stage. Furthermore, for mass production, mold patterns may be replaced by using injection molding.

The immense design freedom offered by additive manufacturing yields tremendous benefits, but it also raises the question of how to best go about designing components to exploit this design freedom. In early design phases, design tools need to utilize this freedom, but do so with low computational cost and with a good estimate of the final weight to correctly assess the part’s influence on the overall product design. This is especially important for aerospace designs. In this paper, a design methodology is devised for cellular structures to be manufactured using additive manufacturing techniques, specifically for such early design phases. This design methodology uses adaptive meshing techniques to design the topology of the cellular structure, after which the struts of that cellular structure are optimized separately to reduce the dimensionality of the problem. The method is demonstrated for a small generic bracket and an aircraft bracket design from the literature. For these problems, our method is fast enough to evaluate many thousands of design options. This results in identifying promising candidate designs for further detailed design work.

Many cell biological facts that can be found in dedicated scientific textbooks are based on findings originally made in humans and/or other mammals, including respective tissue culture systems. They are often presented as if they were universally valid, neglecting that many aspects differ—in part considerably—between the three major kingdoms of multicellular eukaryotic life, comprising animals, plants and fungi. Here, we provide a comparative cross-kingdom view on the basic cell biology across these lineages, highlighting in particular essential differences in cellular structures and processes between phyla. We focus on key dissimilarities in cellular organization, e.g. regarding cell size and shape, the composition of the extracellular matrix, the types of cell–cell junctions, the presence of specific membrane-bound organelles and the organization of the cytoskeleton. We further highlight essential disparities in important cellular processes such as signal transduction, intracellular transport, cell cycle regulation, apoptosis and cytokinesis. Our comprehensive cross-kingdom comparison emphasizes overlaps but also marked differences between the major lineages of the three kingdoms and, thus, adds to a more holistic view of multicellular eukaryotic cell biology.

This paper proposes a novel multiscale concurrent topology optimization for cellular structures with continuously varying microstructures in space to obtain a superior structural performance at an affordable computation cost. At microscale, multiple prototype microstructures are topologically optimized to represent all the microstructures within macrostructure by incorporating a numerical homogenization approach into a parametric level set method (PLSM), whose connectivity is guaranteed by a kinematical connective constraint approach. A shape interpolation technology is developed to map these optimized prototype microstructures and generate a series of nonuniform microstructures, which are considered as sample points and used to construct a kriging metamodel. The built kriging metamodel is then employed to predict the effective properties of all the nonuniform microstructures within macrostructure. At macroscale, the variable thickness sheet (VTS) method is employed to generate an overall free material distribution patterns using the predicted effective properties of all the nonuniform microstructures. With the help of shape interpolation technology, all the nonuniform microstructures within macrostructure are well connected with each other due to the similar topological features at their interfaces. Using the proposed method, the macrostructural topology as well as the locations and configurations of the spatially varying nonuniform microstructures can be simultaneously optimized to ensure a sufficiently large multiscale design space. Numerical examples are provided to demonstrate the validity and advantages of the proposed method.