Multi-Objective Optimization of a Vehicle Body by Combining Gradient-based Methods and Vehicle Concept Modelling

Abstract In the automotive field, size optimization procedures can be combined with concept modelling approaches, in order to design a vehicle Body-In-White (BIW) model with optimal static and dynamic performances already in the early design stages. However, this specific optimization problem, with hundreds of design variables, limited design space and often conflicting objectives, makes the choice of the appropriate optimization method really difficult. The aim of this paper is to show an industrial case study, where two different implementations of the classical gradient-based (GB) method are used in combination with a technique for vehicle body concept modelling to achieve a multi-objective BIW optimization of a passenger car

What Matters Most to Patients and Rheumatologists? A Discrete Choice Experiment in Rheumatoid Arthritis

Introduction: To determine patient and rheumatologist preferences for rheumatoid arthritis (RA) treatment attributes in Spain and to evaluate their attitude towards shared decision-making (SDM). Methods: Observational, descriptive, exploratory and cross-sectional study based on a discrete choice experiment (DCE). To identify the attributes and their levels, a literature review and two focus groups (patients [P] = 5; rheumatologists [R] = 4) were undertaken. Seven attributes with 2–4 levels were presented in eight scenarios. Attribute utility and relative importance (RI) were assessed using a conditional logit model. Patient preferences for SDM were assessed using an ad hoc questionnaire. Results: Ninety rheumatologists [52.2% women; mean years of experience 18.1 (SD: 9.0); seeing an average of 24.4 RA patients/week (SD: 15.3)] and 137 RA patients [mean age: 47.5 years (SD: 10.7); 84.0% women; mean time since diagnosis of RA: 14.2 years (SD: 11.8) and time in treatment: 13.2 years (SD: 11.2), mean HAQ score 1.2 (SD: 0.7)] participated in the study. In terms of RI, rheumatologists and RA patients viewed: time with optimal QoL: R: 23.41%/P: 35.05%; substantial symptom improvement: R: 13.15%/P: 3.62%; time to onset of treatment action: R: 16.24%/P: 13.56%; severe adverse events: R: 10.89%/P: 11.20%; mild adverse events: R: 4.16%/P: 0.91%; mode of administration: R: 25.23%/P: 25.00%; and added cost: R: 6.93%/P: 10.66%. Nearly 73% of RA patients were involved in treatment decision-making to a greater or lesser extent; however, 27.4% did not participate at all. Conclusion: Both for rheumatologists and patients, the top three decision-making drivers are time with optimal quality, treatment mode of administration and time to onset of action, although in different ranking order. Patients were willing to be more involved in the treatment decision-making process

MicroRNA and other non-coding RNAs in Epstein–Barr virus-associated cancers

Simple Summary Epstein-Barr virus (EBV) is associated with a variety of malignancies. In this review, we discuss EBV-encoded microRNAs and ncRNAs and consider how their detection could aid in the diagnosis, prognostication, and monitoring of treatment in patients with EBV-associated malignancies, including classical Hodgkin's lymphoma (cHL), Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), nasopharyngeal carcinoma (NPC), and gastric carcinoma (GC). EBV is a direct causative agent in around 1.5% of all cancers. The oncogenic properties of EBV are related to its ability to activate processes needed for cellular proliferation, survival, migration, and immune evasion. The EBV latency program is required for the immortalization of infected B cells and involves the expression of non-coding RNAs (ncRNAs), including viral microRNAs. These ncRNAs have different functions that contribute to virus persistence in the asymptomatic host and to the development of EBV-associated cancers. In this review, we discuss the function and potential clinical utility of EBV microRNAs and other ncRNAs in EBV-associated malignancies. This review is not intended to be comprehensive, but rather to provide examples of the importance of ncRNAs

Short and long term surface chemistry and wetting behaviour of stainless steel with 1D and 2D periodic structures induced by bursts of femtosecond laser pulses

We investigate the short and long term wettability of laser textured stainless steel samples in order to better understand the interplay between surface topography and chemistry. Very different 1D and 2D periodic as well as non-periodic surface patterns were produced by exploiting the extreme flexibility of a setup consisting of five rotating birefringent crystals, which allows generating bursts of up to 32 femtosecond laser pulses with fixed intra-burst delay of 1.5 ps. The change of the surface morphology as a function of the pulse splitting, the burst polarization state and the fluence was systematically studied. The surface topography was characterized by SEM and AFM microscopy. The laser textured samples exhibited, initially, superhydrophilic behaviour which, during exposure to ambient air, turned into superhydrophobic with an exponential growth of the static contact angle. The dynamic contact angle measurements revealed a water adhesive character which was explained by XPS analyses of the surfaces that showed an increase of hydrocarbons and more oxidized metal species with the aging. The characteristic water adhesiveness and superhydrophobicity of laser textured surfaces can be exploited for no loss droplet reversible transportation or harvesting

Burkitt lymphoma beyond MYC translocation: N-MYC and DNA methyltransferases dysregulation

Background: The oncogenic transcription factor MYC is pathologically activated in many human malignancies. A paradigm for MYC dysregulation is offered by Burkitt lymphoma, where chromosomal translocations leading to Immunoglobulin gene-MYC fusion are the crucial initiating oncogenic events. However, Burkitt lymphoma cases with no detectable MYC rearrangement but maintaining MYC expression have been identified and alternative mechanisms can be involved in MYC dysregulation in these cases. Methods: We studied the microRNA profile of MYC translocation-positive and MYC translocation-negative Burkitt lymphoma cases in order to uncover possible differences at the molecular level. Data was validated at the mRNA and protein level by quantitative Real-Time polymerase chain reaction and immunohistochemistry, respectively. Results: We identified four microRNAs differentially expressed between the two groups. The impact of these microRNAs on the expression of selected genes was then investigated. Interestingly, in MYC translocation-negative cases we found over-expression of DNA-methyl transferase family members, consistent to hypo-expression of the hsa-miR-29 family. This finding suggests an alternative way for the activation of lymphomagenesis in these cases, based on global changes in methylation landscape, aberrant DNA hypermethylation, lack of epigenetic control on transcription of targeted genes, and increase of genomic instability. In addition, we observed an over-expression of another MYC family gene member, MYCN that may therefore represent a cooperating mechanism of MYC in driving the malignant transformation in those cases lacking an identifiable MYC translocation but expressing the gene at the mRNA and protein levels. Conclusions: Collectively, our results showed that MYC translocation-positive and MYC translocation-negative Burkitt lymphoma cases are slightly different in terms of microRNA and gene expression. MYC translocation-negative Burkitt lymphoma, similarly to other aggressive B-cell non Hodgkin's lymphomas, may represent a model to understand the intricate molecular pathway responsible for MYC dysregulation in cancer

Development and Validation of “Hazard O’Clock”: A Home Hazard and Disaster Awareness Game

The Philippines is the fourth most disaster-prone country in the world due to its location in the Pacific Ring of Fire and Pacific Typhoon Belt. When it comes to these disasters, children below the age of 18 are considered to be among the most vulnerable. This study aimed to develop a mobile game about Disaster Risk Reduction and Management (DRRM) in the home setting that can be used as a teaching aid for children. The information integrated into the game was from different resources made by various government agencies. The Analysis, Design, Development, Implementation, and Evaluation (ADDIE) model was used in the development of the game, and game development educators and STEM educators evaluated it. Using a 5-point Likert scale survey, the game’s quality and appropriateness were evaluated for the following categories: Instructional Content, Functional Suitability, Performance Efficiency, and Usability. For each category, the mean score ratings were 4.43, 4.43, 4.80, and 4.60 respectively. Overall, the game received a rating of 4.52 indicating that it is Very Appropriate for its purpose. The research findings have shown that the game, Hazard O’Clock, could be used as a teaching aid for DRRM

The Origin of X-ray Emission in the Gamma-ray emitting Narrow-Line Seyfert 1 1H 0323+342

We present the results of X-ray spectral and timing analyses of the closest gamma-ray emitting narrow-line Seyfert 1 ($\gamma$-NLS1) galaxy, 1H 0323+342. We use observations from a recent, simultaneous XMM-Newton/NuSTAR campaign. As in radio-quiet NLS1s, the spectrum reveals a soft excess at low energies ($\lesssim2$ keV) and reflection features such as a broad iron K emission line. We also find evidence of a hard excess at energies above $\sim35$ keV that is likely a consequence of jet emission. Our analysis shows that relativistic reflection is statistically required, and using a combination of models that includes the reflection model relxill for the broadband spectrum, we find an inclination of $i=63^{+7}_{-5}$ degrees, which is in tension with much lower values inferred by superluminal motion in radio observations. We also find a flat ($q=2.2\pm0.3$) emissivity profile, implying that there is more reflected flux than usual being emitted from the outer regions of the disk, which in turn suggests a deviation from the thin disk model assumption. We discuss possible reasons for this, such as reflection off of a thick accretion disk geometry.Comment: Accepted for publication in MNRAS. 11 pages, 9 figures; references adde

Putative role of circulating human papillomavirus DNA in the development of primary squamous cell carcinoma of the middle rectum: A case report

Here we present the case of a patient affected by rectal squamous cell carcinoma in which we demonstrated the presence of Human Papillomavirus (HPV) by a variety of techniques. Collectively, the virus was detected not only in the tumor but also in some regional lymph nodes and in non-neoplastic mucosa of the upper tract of large bowel. By contrast, it was not identifiable in its common sites of entry, namely oral and ano-genital region. We also found HPV DNA in the plasma-derived exosome. Next, by in vitro studies, we confirmed the capability of HPV DNA-positive exosomes, isolated from the supernatant of a HPV DNA positive cell line (CaSki), to transfer its DNA to human colon cancer and normal cell lines. In the stroma nearby the tumor mass we were able to demonstrate the presence of virus DNA in the stromal compartment, supporting its potential to be transferred from epithelial cells to the stromal ones. Thus, this case report favors the notion that human papillomavirus DNA can be vehiculated by exosomes in the blood of neoplastic patients and that it can be transferred, at least in vitro, to normal and neoplastic cells. Furthermore, we showed the presence of viral DNA and RNA in pluripotent stem cells of non-tumor tissue, suggesting that after viral integration (as demonstrated by p16 and RNA in situ hybridization positivity), stem cells might have been activated into cancer stem cells inducing neoplastic transformation of normal tissue through the inactivation of p53, p21, and Rb. It is conceivable that the virus has elicited its oncogenic effect in this specific site and not elsewhere, despite its wide anatomical distribution in the patient, for a local condition of immune suppression, as demonstrated by the increase of T-regulatory (CD4/CD25/FOXP3 positive) and T-exhausted (CD8/PD-1positive) lymphocytes and the M2 polarization (high CD163/CD68 ratio) of macrophages in the neoplastic microenvironment. It is noteworthy that our findings depicted a static picture of a long-lasting dynamic process that might evolve in the development of tumors in other anatomical sites

The Reactome pathway knowledgebase

Reactome (http://www.reactome.org) is a manually curated open-source open-data resource of human pathways and reactions. The current version 46 describes 7088 human proteins (34% of the predicted human proteome), participating in 6744 reactions based on data extracted from 15 107 research publications with PubMed links. The Reactome Web site and analysis tool set have been completely redesigned to increase speed, flexibility and user friendliness. The data model has been extended to support annotation of disease processes due to infectious agents and to mutation

Epigenetic Alteration of the Cancer-Related Gene TGFBI in B Cells Infected with Epstein–Barr Virus and Exposed to Aflatoxin B1: Potential Role in Burkitt Lymphoma Development

Burkitt lymphoma (BL) is a malignant B cell neoplasm that accounts for almost half of pediatric cancers in sub-Saharan African countries. Although the BL endemic prevalence is attributable to the combination of Epstein–Barr virus (EBV) infection with malaria and environmental carcinogens exposure, such as the food contaminant aflatoxin B1 (AFB1), the molecular determinants underlying the pathogenesis are not fully understood. Consistent with the role of epigenetic mechanisms at the interface between the genome and environment, AFB1 and EBV impact the methylome of respectively leukocytes and B cells specifically. Here, we conducted a thorough investigation of common epigenomic changes following EBV or AFB1 exposure in B cells. Genome-wide DNA methylation profiling identified an EBV–AFB1 common signature within the TGFBI locus, which encodes for a putative tumor suppressor often altered in cancer. Subsequent mechanistic analyses confirmed a DNA-methylation-dependent transcriptional silencing of TGFBI involving the recruitment of DNMT1 methyltransferase that is associated with an activation of the NF-κB pathway. Our results reveal a potential common mechanism of B cell transformation shared by the main risk factors of endemic BL (EBV and AFB1), suggesting a key determinant of disease that could allow the development of more efficient targeted therapeutic strategies