Thermo-mechanical analysis of additively manufactured hybrid extrusion dies with conformal cooling channels

Profile overheating and surface defects during hot aluminum extrusion can occur when seeking higher productivity rates at increased ram speed velocities. The incorporation of cooling channels in the die-design allows overcoming this process limitation by keeping the profile temperature below the melting point of the alloy used [1]. Selective laser melting (SLM) of conformal cooling channels provides, in contrast to conventional manufacturing techniques, the opportunity to place the cooling circuit inside the mandrel of a porthole-die in a well-defined position to the critical bearing region [2]. In the framework of this study, a preliminary numerical investigation on the extrusion process under the assumption of liquid nitrogen cooling is analysed. The results show, that by combining conformal cooling channels with liquid nitrogen as a cooling media high cooling rates, which are well beyond the state of the art of conventional dies, can be achieved. In a hybrid extrusion die set-up, a part of the mandrel, that is additively manufactured, is either joined [3] or directly selective leaser melted onto the conventionally manufactured parts [4]. For a proper implementation in the extrusion process, material testing of the welded joint are needed. Thus, in the current study, tensile tests performed at room temperature for hybrid specimens, partially consisting of conventionally processed tool steel 1.2343 and partially additively manufactured 1.2709, will be presented. Moreover, four different heat treatment sequences of the hybrid specimens will be discussed. In addition, for each configuration, micro-structural images are taken to investigate failure at the bonding region. Finally, an optimal manufacturing sequence for a hybrid die with the described material combination is proposed

Control of S phase duration: a replication capacity model with E2F transcription at its heart

DNA replication capacity, the maximal amount of DNA a cell can synthesize at any given time during S phase, is controlled by E2F-dependent transcription. Controlling replication capacity limits the replication rate and provides a robust mechanism to keep replication fork speed within an optimal range whilst ensuring timely completion of genome duplication

Cell cycle control in cancer

Cancer is a group of diseases in which cells divide continuously and excessively. Cell division is tightly regulated by multiple evolutionarily conserved cell cycle control mechanisms, to ensure the production of two genetically identical cells. Cell cycle checkpoints operate as DNA surveillance mechanisms that prevent the accumulation and propagation of genetic errors during cell division. Checkpoints can delay cell cycle progression or, in response to irreparable DNA damage, induce cell cycle exit or cell death. Cancer-associated mutations that perturb cell cycle control allow continuous cell division chiefly by compromising the ability of cells to exit the cell cycle. Continuous rounds of division, however, create increased reliance on other cell cycle control mechanisms to prevent catastrophic levels of damage and maintain cell viability. New detailed insights into cell cycle control mechanisms and their role in cancer reveal how these dependencies can be best exploited in cancer treatment

MORPH: A Reference Architecture for Configuration and Behaviour Self-Adaptation

An architectural approach to self-adaptive systems involves runtime change of system configuration (i.e., the system's components, their bindings and operational parameters) and behaviour update (i.e., component orchestration). Thus, dynamic reconfiguration and discrete event control theory are at the heart of architectural adaptation. Although controlling configuration and behaviour at runtime has been discussed and applied to architectural adaptation, architectures for self-adaptive systems often compound these two aspects reducing the potential for adaptability. In this paper we propose a reference architecture that allows for coordinated yet transparent and independent adaptation of system configuration and behaviour

Thermal stability and aggregation of sulfolobus solfataricus b-glycosidase are dependent upon the N-e-methylation of specific lysyl residues: critical role of in vivo post-translational modifications.

Methylation in vivo is a post-translational modification observed in several organisms belonging to eucarya, bacteria, and archaea. Although important implications of this modification have been demonstrated in several eucaryotes, its biological role in hyperthermophilic archaea is far from being understood. The aim of this work is to clarify some effects of methylation on the properties of β-glycosidase from Sulfolobus solfataricus, by a structural comparison between the native, methylated protein and its unmethylated counterpart, recombinantly expressed in Escherichia coli. Analysis by Fourier transform infrared spectroscopy indicated similar secondary structure contents for the two forms of the protein. However, the study of temperature perturbation by Fourier transform infrared spectroscopy and turbidimetry evidenced denaturation and aggregation events more pronounced in recombinant than in native β-glycosidase. Red Nile fluorescence analysis revealed significant differences of surface hydrophobicity between the two forms of the protein. Unlike the native enzyme, which dissociated into SDS-resistant dimers upon exposure to the detergent, the recombinant enzyme partially dissociated into monomers. By electrospray mapping, the methylation sites of the native protein were identified. A computational analysis of β-glycosidase three-dimensional structure and comparisons with other proteins from S. solfataricus revealed analogies in the localization of methylation sites in terms of secondary structural elements and overall topology. These observations suggest a role for the methylation of lysyl residues, located in selected domains, in the thermal stabilization of β-glycosidase from S. solfataricu

Determinants of obesity in Italian adults : the role of taste sensitivity, food liking, and food neophobia

Recent evidence has suggested that factors related to sensory perception may explain excess weight. The objective of this study was to consider multiple aspects while investigating the phenomenon of obesity. One goal was to compare taste acuity (taste threshold and density of fungiform papillae) in both normal weight and obese subjects. Thresholds for 4 basic tastes and the fat stimulus were investigated. A second research goal was to study the relationship between food neophobia and food liking according to the body mass index and taste sensitivity. The results showed that obese subjects seem to have higher threshold values and a reduced number of fungiform papillae than do normal weight subjects. Food neophobia did not vary with nutritional status, whereas differences were found for food liking, with obese subjects showing significantly higher liking ratings for high energy dense products compared with normal weight subjects

In silico approach for the definition of radiomirnomic signatures for breast cancer differential diagnosis

Personalized medicine relies on the integration and consideration of specific characteristics of the patient, such as tumor phenotypic and genotypic profiling. BACKGROUND: Radiogenomics aim to integrate phenotypes from tumor imaging data with genomic data to discover genetic mechanisms underlying tumor development and phenotype. METHODS: We describe a computational approach that correlates phenotype from magnetic resonance imaging (MRI) of breast cancer (BC) lesions with microRNAs (miRNAs), mRNAs, and regulatory networks, developing a radiomiRNomic map. We validated our approach to the relationships between MRI and miRNA expression data derived from BC patients. We obtained 16 radiomic features quantifying the tumor phenotype. We integrated the features with miRNAs regulating a network of pathways specific for a distinct BC subtype. RESULTS: We found six miRNAs correlated with imaging features in Luminal A (miR-1537, -205, -335, -337, -452, and -99a), seven miRNAs (miR-142, -155, -190, -190b, -1910, -3617, and -429) in HER2+, and two miRNAs (miR-135b and -365-2) in Basal subtype. We demonstrate that the combination of correlated miRNAs and imaging features have better classification power of Luminal A versus the different BC subtypes than using miRNAs or imaging alone. CONCLUSION: Our computational approach could be used to identify new radiomiRNomic profiles of multi-omics biomarkers for BC differential diagnosis and prognosis

Sustained E2F-Dependent Transcription Is a Key Mechanism to Prevent Replication-Stress-Induced DNA Damage

Recent work established DNA replication stress as a crucial driver of genomic instability and a key event at the onset of cancer. Post-translational modifications play an important role in the cellular response to replication stress by regulating the activity of key components to prevent replication-stress-induced DNA damage. Here, we establish a far greater role for transcriptional control in determining the outcome of replication-stress-induced events than previously suspected. Sustained E2F-dependent transcription is both required and sufficient for many crucial checkpoint functions, including fork stalling, stabilization, and resolution. Importantly, we also find that, in the context of oncogene-induced replication stress, where increased E2F activity is thought to cause replication stress, E2F activity is required to limit levels of DNA damage. These data suggest a model in which cells experiencing oncogene-induced replication stress through deregulation of E2F-dependent transcription become addicted to E2F activity to cope with high levels of replication stress

Microglia in prion diseases: Angels or demons?

Prion diseases are rare transmissible neurodegenerative disorders caused by the accumulation of a misfolded isoform (PrPSc) of the cellular prion protein (PrPC) in the central nervous system (CNS). Neuropathological hallmarks of prion diseases are neuronal loss, astrogliosis, and enhanced microglial proliferation and activation. As immune cells of the CNS, microglia participate both in the maintenance of the normal brain physiology and in driving the neuroinflammatory response to acute or chronic (e.g., neurodegenerative disorders) insults. Microglia involvement in prion diseases, however, is far from being clearly understood. During this review, we summarize and discuss controversial findings, both in patient and animal models, suggesting a neuroprotective role of microglia in prion disease pathogenesis and progression, or\u2014conversely\u2014a microglia-mediated exacerbation of neurotoxicity in later stages of disease. We also will consider the active participation of PrPC in microglial functions, by discussing previous reports, but also by presenting unpublished results that support a role for PrPC in cytokine secretion by activated primary microglia

Enhancing workflow-nets with data for trace completion

The growing adoption of IT-systems for modeling and executing (business) processes or services has thrust the scientific investigation towards techniques and tools which support more complex forms of process analysis. Many of them, such as conformance checking, process alignment, mining and enhancement, rely on complete observation of past (tracked and logged) executions. In many real cases, however, the lack of human or IT-support on all the steps of process execution, as well as information hiding and abstraction of model and data, result in incomplete log information of both data and activities. This paper tackles the issue of automatically repairing traces with missing information by notably considering not only activities but also data manipulated by them. Our technique recasts such a problem in a reachability problem and provides an encoding in an action language which allows to virtually use any state-of-the-art planning to return solutions