Effective Mechanical Properties of AlSi7Mg Additively Manufactured Cubic Lattice Structures

Lattice structures, whose manufacturing has been enabled by additive technologies, are gaining growing popularity in all the fields where lightweighting is imperative. Since the complexity of the lattice geometries stretches the technological boundaries even of additive processes, the manufactured structures can be significantly different from the nominal ones, in terms of expected dimensions but also of defects. Therefore, the successful use of lattices needs the combined optimization of their design, structural modeling, build orientation, and setup. The article reports the results of quasi-static compression tests performed on BCCxyz lattices manufactured in a AlSi7Mg alloy using additive manufacturing. The results are compared with numerical simulations using two different approaches. The findings show the influence of the relative density on stiffness, strength, and on the energy absorption properties of the lattice. The correlation with the technological feasibility points out credible improvements in the choice of a unit cell with fewer manufacturing issues, lower density, and possibly equal mechanical properties

weight reduction by topology optimization of an engine subframe mount designed for additive manufacturing production

Abstract Additive Manufacturing (AM) technologies are getting more and more strategic for different purposes in many industrial fields. Among the most outstanding are part prototyping, single part to small batch production, relatively reduced manufacturing times and investments costs, reduced material consumption, and innovative and efficient shapes. The considerable advantages these technologies offer, compared to subtractive ones, make additive manufacturing a potentially industry-leading process in almost all domains - from aeronautics to the medical industry. Under these circumstances, the inspiration given by topology optimization tools can lead to feasible industrial parts, with fewer constraints in comparison to traditional manufacturing processes. The paper presents the development and the results obtained using topology optimization and design for AM technology on an automotive part: an engine mount sub-frame component for a rear middle engine sports car. The final design enables a significant weight reduction

Structural biology of STAT3 and its implications for anticancer therapies development

Transcription factors are proteins able to bind DNA and induce the transcription of specific genes. Consequently, they play a pivotal role in multiple cellular pathways and are frequently over-expressed or dysregulated in cancer. Here, we will focus on a specific “signal transducer and activator of transcription” (STAT3) factor that is involved in several pathologies, including cancer. For long time, the mechanism by which STAT3 exerts its cellular functions has been summarized by a three steps process: (1) Protein phosphorylation by specific kinases, (2) dimerization promoted by phosphorylation, (3) activation of gene expression by the phosphorylated dimer. Consequently, most of the inhibitors reported in literature aimed at blocking phosphorylation and dimerization. However, recent observations reopened the debate and the entire functional mechanism has been revisited stimulating the scientific community to pursue new inhibition strategies. In particular, the dimerization of the unphosphorylated species has been experimentally demonstrated and specific roles proposed also for these dimers. Despite difficulties in the expression and purification of the full length STAT3, structural biology investigations allowed the determination of atomistic structures of STAT3 dimers and several protein domains. Starting from this information, computational methods have been used both to improve the understanding of the STAT3 functional mechanism and to design new inhibitors to be used as anticancer drugs. In this review, we will focus on the contribution of structural biology to understand the roles of STAT3, to design new inhibitors and to suggest new strategies of pharmacological intervention

Dynamic Modal Correlation of an Automotive Rear Subframe, with Particular Reference to the Modelling of Welded Joints

This paper presents a comparison between the experimental investigation and the Finite Element (FE) modal analysis of an automotive rear subframe. A modal correlation between the experimental data and the forecasts is performed. The present numerical model constitutes a predictive methodology able to forecast the experimental dynamic behaviour of the structure. The actual structure is excited with impact hammers and the modal response of the subframe is collected and evaluated by the PolyMAX algorithm. Both the FE model and the structural performance of the subframe are defined according to the Ferrari S.p.A. internal regulations. In addition, a novel modelling technique for welded joints is proposed that represents an extension of ACM2 approach, formulated for spot weld joints in dynamic analysis. Therefore, the Modal Assurance Criterion (MAC) is considered the optimal comparison index for the numerical-experimental correlation. In conclusion, a good numerical-experimental agreement from 50 Hz up to 500 Hz has been achieved by monitoring various dynamic parameters such as the natural frequencies, the mode shapes, and frequency response functions (FRFs) of the structure that represent a validation of this FE model for structural dynamic applications

On the Technological Feasibility of additively manufactured self-supporting AlSi10Mg lattice structures

The capability to design and manufacture metal lattice structures is today one of the most promising targets of Powder Bed Fusion technologies. Not only additively manufactured lattices offer great lightweighting possibilities, but they open the way to tailored and graded mechanical response. To best capitalize on this opportunity, research effort is first needed to assess the feasibility of reticular structures and to quantify the expected deviations from the nominal geometry, as a function of the cell topology and dimensions. Notwithstanding the inherent suitability of additive processes to complex shapes, this paper proposes a more exact definition of the technological boundaries for body-centred cubic lattices, showing to what extent specific dimensional ratios, as well as a self-supporting cell structure, can be favourable to minimize thedeviation from the nominal reticulum in terms of dimensions, density and presence of defects

Mitochondrial Plasticity Promotes Resistance to Sorafenib and Vulnerability to STAT3 Inhibition in Human Hepatocellular Carcinoma

The multi-kinase inhibitor sorafenib is a primary treatment modality for advanced-stage hepatocellular carcinoma (HCC). However, the therapeutic benefits are short-lived due to innate and acquired resistance. Here, we examined how HCC cells respond to sorafenib and adapt to continuous and prolonged exposure to the drug. Sorafenib-adapted HCC cells show a profound reprogramming of mitochondria function and marked activation of genes required for mitochondrial protein translation and biogenesis. Mitochondrial ribosomal proteins and components of translation and import machinery are increased in sorafenib-resistant cells and sorafenib-refractory HCC patients show similar alterations. Sorafenib-adapted cells also exhibited increased serine 727 phosphorylated (pSer727) STAT3, the prevalent form in mitochondria, suggesting that STAT3 might be an actionable target to counteract resistance. Consistently, a small-molecule STAT3 inhibitor reduces pSer727, reverts mitochondrial alterations, and enhances the response to sorafenib in resistant cells. These results sustain the importance of mitochondria plasticity in response to sorafenib and identify a clinically actionable strategy for improving the treatment efficacy in HCC patients

MicroRNA-424 impairs ubiquitination to activate STAT3 and promote prostate tumor progression.

Mutations and deletions in components of ubiquitin ligase complexes that lead to alterations in protein turnover are important mechanisms in driving tumorigenesis. Here we describe an alternative mechanism involving upregulation of the microRNA miR-424 that leads to impaired ubiquitination and degradation of oncogenic transcription factors in prostate cancers. We found that miR-424 targets the E3 ubiquitin ligase COP1 and identified STAT3 as a key substrate of COP1 in promoting tumorigenic and cancer stem-like properties in prostate epithelial cells. Altered protein turnover due to impaired COP1 function led to accumulation and enhanced basal and cytokine-induced activity of STAT3. We further determined that loss of the ETS factor ESE3/EHF is the initial event that triggers the deregulation of the miR-424/COP1/STAT3 axis. COP1 silencing and STAT3 activation were effectively reverted by blocking of miR-424, suggesting a possible strategy to attack this key node of tumorigenesis in ESE3/EHF-deficient tumors. These results establish miR-424 as an oncogenic effector linked to noncanonical activation of STAT3 and as a potential therapeutic target

Epigenetic Control of Mitochondrial Fission Enables Self-Renewal of Stem-like Tumor Cells in Human Prostate Cancer

Cancer stem cells (CSCs) contribute to disease progression and treatment failure in human cancers. The balance among self-renewal, differentiation, and senescence determines the expansion or progressive exhaustion of CSCs. Targeting these processes might lead to novel anticancer therapies. Here, we uncover a novel link between BRD4, mitochondrial dynamics, and self-renewal of prostate CSCs. Targeting BRD4 by genetic knockdown or chemical inhibitors blocked mitochondrial fission and caused CSC exhaustion and loss of tumorigenic capability. Depletion of CSCs occurred in multiple prostate cancer models, indicating a common vulnerability and dependency on mitochondrial dynamics. These effects depended on rewiring of the BRD4-driven transcription and repression of mitochondrial fission factor (Mff). Knockdown of Mff reproduced the effects of BRD4 inhibition, whereas ectopic Mff expression rescued prostate CSCs from exhaustion. This novel concept of targeting mitochondrial plasticity in CSCs through BRD4 inhibition provides a new paradigm for developing more effective treatment strategies for prostate cancer