Efficient Experimental and Data-Centered Workflow for Microstructure-Based Fatigue Data – Towards a Data Basis for Predictive AI Models

Background Early fatigue mechanisms for various materials are yet to be unveiled for the (very) high-cycle fatigue (VHCF) regime. This can be ascribed to a lack of available data capturing initial fatigue damage evolution, which continues to adversely affect data scientists and computational modeling experts attempting to derive microstructural dependencies from small sample size data and incomplete feature representations. Objective The aim of this work is to address this lack and to drive the digital transformation of materials such that future virtual component design can be rendered more reliable and more efficient. Achieving this relies on fatigue models that comprehensively capture all relevant dependencies. Methods To this end, this work proposes a combined experimental and data post-processing workflow to establish multimodal fatigue crack initiation and propagation data sets efficiently. It evolves around fatigue testing of mesoscale specimens to increase damage detection sensitivity, data fusion through multimodal registration to address data heterogeneity, and image-based data-driven damage localization. Results A workflow with a high degree of automation is established, that links large distortion-corrected microstructure data with damage localization and evolution kinetics. The workflow enables cycling up to the VHCF regime in comparatively short time spans, while maintaining unprecedented time resolution of damage evolution. Resulting data sets capture the interaction of damage with microstructural features and hold the potential to unravel a mechanistic understanding. Conclusions The proposed workflow lays the foundation for future data mining and data-driven modeling of microstructural fatigue by providing statistically meaningful data sets extendable to a wide range of materials

Liver cancer cells are sensitive to Lanatoside C induced cell death independent of their PTEN status

Background Hepatocellular carcinoma is the second deadliest cancer with limited treatment options. Loss of PTEN causes the P13K/Akt pathway to be hyperactive which contributes to cell survival and resistance to therapeutics in various cancers, including the liver cancer. Hence molecules targeting this pathway present good therapeutic strategies for liver cancer. Hypothesis It was previously reported that Cardiac glycosides possessed antitumor activity by inducing apoptosis of multiple cancer cells through oxidative stress. However, whether Cardiac glycoside Lanatoside C can induce oxidative stress in liver cancer cells and induce cell death both in vitro and in vivo remains unknown. Methods Cell viability was measured by SRB assay. Cell death analysis was investigated by propidium iodide staining with flow cytometry and PARP cleavage. DCFH-DA staining and cytometry were used for intracellular ROS measurement. Protein levels were analyzed by western blot analysis. Antitumor activity was investigated on mice xenografts in vivo. Results In this study, we found that Cardiac glycosides, particularly Lanatoside C from Digitalis ferruginea could significantly inhibit PTEN protein adequate Huh7 and PTEN deficient Mahlavu human liver cancer cell proliferation by the induction of apoptosis and G2/M arrest in the cells. Lanatoside C was further shown to induce oxidative stress and alter ERK and Akt pathways. Consequently, JNK1 activation resulted in extrinsic apoptotic pathway stimulation in both cells while JNK2 activation involved in the inhibition of cell survival only in PTEN deficient cells. Furthermore, nude mice xenografts followed by MRI showed that Lanatoside C caused a significant decrease in the tumor size. In this study apoptosis induction by Lanatoside C was characterized through ROS altered ERK and Akt pathways in both PTEN adequate epithelial and deficient mesenchymal liver cancer cells. Conclusion The results indicated that Lanatoside C could be contemplated in liver cancer therapeutics, particularly in PTEN deficient tumors. This is due to Lanatoside C's stress inducing action on ERK and Akt pathways through differential activation of JNK1 and JNK2 by GSK3β. © 2015 Elsevier GmbH. © 2016 Elsevier GmbH. All rights reserved

Distribution of Spoligotyping Defined Genotypic Lineages among Drug-Resistant Mycobacterium tuberculosis Complex Clinical Isolates in Ankara, Turkey

Background: Investigation of genetic heterogeneity and spoligotype-defined lineages of drug-resistant Mycobacterium tuberculosis clinical isolates collected during a three-year period in two university hospitals and National Tuberculosis Reference and Research Laboratory in Ankara, Turkey. Methods and Findings: A total of 95 drug-resistant M. tuberculosis isolates collected from three different centers were included in this study. Susceptibility testing of the isolates to four major antituberculous drugs was performed using proportion method on Löwenstein–Jensen medium and BACTEC 460-TB system. All clinical isolates were typed by using spoligotyping and IS6110-restriction fragment length polymorphism (RFLP) methods. Seventy-three of the 95 (76.8%) drug resistant M. tuberculosis isolates were isoniazid-resistant, 45 (47.4%) were rifampicin-resistant, 32 (33.7%) were streptomycinresistant and 31 (32.6%) were ethambutol-resistant. The proportion of multidrug-resistant isolates (MDR) was 42.1%. By using spoligotyping, 35 distinct patterns were observed; 75 clinical isolates were grouped in 15 clusters (clustering rate of 79%) and 20 isolates displayed unique patterns. Five of these 20 unique patterns corresponded to orphan patterns in th

Combined transcriptomic-(1)H NMR metabonomic study reveals yhat monoethylhexyl phthalate stimulates adipogenesis and glyceroneogenesis in human adipocytes

Adipose tissue is a major storage site for lipophilic environmental contaminants. The environmental metabolic disruptor hypothesis postulates that some pollutants can promote obesity or metabolic disorders by activating nuclear receptors involved in the control of energetic homeostasis. In this context, monoethylhexyl phthalate (MEHP) is of particular concern since it was shown to activate the peroxisome proliferator-activated receptor γ (PPARγ) in 3T3-L1 murine preadipocytes. In the present work, we used an untargeted, combined transcriptomic-(1)H NMR-based metabonomic approach to describe the overall effect of MEHP on primary cultures of human subcutaneous adipocytes differentiated in vitro. MEHP stimulated rapidly and selectively the expression of genes involved in glyceroneogenesis, enhanced the expression of the cytosolic phosphoenolpyruvate carboxykinase, and reduced fatty acid release. These results demonstrate that MEHP increased glyceroneogenesis and fatty acid reesterification in human adipocytes. A longer treatment with MEHP induced the expression of genes involved in triglycerides uptake, synthesis, and storage; decreased intracellular lactate, glutamine, and other amino acids; increased aspartate and NAD, and resulted in a global increase in triglycerides. Altogether, these results indicate that MEHP promoted the differentiation of human preadipocytes to adipocytes. These mechanisms might contribute to the suspected obesogenic effect of MEHP

Extended-Spectrum-Beta-Lactamases, AmpC Beta-Lactamases and Plasmid Mediated Quinolone Resistance in Klebsiella spp. from Companion Animals in Italy

We report the genetic characterization of 15 Klebsiella pneumoniae (KP) and 4 isolates of K. oxytoca (KO) from clinical cases in dogs and cats and showing extended-spectrum cephalosporin (ESC) resistance. Extended spectrum beta-lactamase (ESBL) and AmpC genes, plasmid-mediated quinolone resistance (PMQR) and co-resistances were investigated. Among KP isolates, ST101 clone was predominant (8/15, 53%), followed by ST15 (4/15, 27%). ST11 and ST340, belonging to Clonal Complex (CC)11, were detected in 2012 (3/15, 20%). MLST on KP isolates corresponded well with PFGE results, with 11 different PFGE patterns observed, including two clusters of two (ST340) and four (ST101) indistinguishable isolates, respectively. All isolates harbored at least one ESBL or AmpC gene, all carried on transferable plasmids (IncR, IncFII, IncI1, IncN), and 16/19 were positive for PMQR genes (qnr family or aac(6')-Ib-cr). The most frequent ESBL was CTX-M-15 (11/19, 58%), detected in all KP ST101, in one KP ST15 and in both KP ST340. blaCTX-M-15 was carried on IncR plasmids in all but one KP isolate. All KP ST15 isolates harbored different ESC resistance genes and different plasmids, and presented the non-transferable blaSHV-28 gene, in association with blaCTX-M-15, blaCTX-M-1 (on IncR, or on IncN), blaSHV-2a (on IncR) or blaCMY-2 genes (on IncI1). KO isolates were positive for blaCTX-M-9 gene (on IncHI2), or for the blaSHV-12 and blaDHA-1 genes (on IncL/M). They were all positive for qnr genes, and one also for the aac(6')-Ib-cr gene. All Klebsiella isolates showed multiresistance towards aminoglycosides, sulfonamides, tetracyclines, trimethoprim and amphenicols, mediated by strA/B, aadA2, aadB, ant (2")-Ia, aac(6')-Ib, sul, tet, dfr and cat genes in various combinations. The emergence in pets of multidrug-resistant Klebsiella with ESBL, AmpC and PMQR determinants, poses further and serious challenges in companion animal therapy and raise concerns for possible bi-directional transmission between pets and humans, especially at household level

Physical characterisation of an alginate/lysozyme nano-laminate coating and its evaluation on ‘coalho’ cheese shelf life

This work aimed at the characterisation of a nanolaminate coating produced by the layer-by-layer methodology and its evaluation on the preservation of ‘Coalho’ cheese. Initially, five alternate layers of alginate and lysozyme were assembled in an aminolysed/charged polyethylene terephthalate (A/C PET) and physically characterised by UV/VIS spectroscopy, contact angle, water vapour (WVTR) and oxygen (OTR) transmission rates and scanning electron microscopy. Afterwards, the same methodology was used to apply the nano-laminate coating in ‘Coalho’ cheese and its shelf life was evaluated during 20 days in terms of mass loss, pH, lipid peroxidation, titratable acidity and microbial count. UV/VIS spectroscopy and contact angle analyses confirmed the layers’ deposition and the successful assembly of nano-laminate coating on A/C PET surface. The coating presented WVTR and OTR values of 1.03×10−3 and 1.28× 10−4 g m−2 s−1, respectively. After 20 days, coated cheese showed lower values of mass loss, pH, lipidic peroxidation, microorganisms’ proliferation and higher titratable acidity in comparison with uncoated cheese. These results suggest that gas barrier and antibacterial properties of alginate/lysozyme nanocoating can be used to extend the shelf life of ‘Coalho’ cheese.The author Bartolomeu G. de S. Medeiros is recipient of a scholarship from Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES-Brazil). The author Marthyna P. Souza is recipient of a scholarship from Fundacao de Amparo a Ciencia e Tecnologia do Estado de Pernambuco (FACEPE, Brazil) and was recipient of a scholarship from Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES/PDEE-Brazil). The authors Ana C. Pinheiro, Ana I. Bourbon and Miguel A. Cerqueira are recipients of a fellowship (SFRH/BD/48120/2008, SFRH/BD/73178/2010 and SFRH/BPD/72753/2010, respectively), supported by Fundacao para a Ciencia e Tecnologia, POPH-QREN and FSE (FCT, Portugal). Maria G. Carneiro-da-Cunha express is gratitude to the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) for research grant. The present work was supported by CAPES/PROCAD/NF/1415/2007. The support of EU Cost Action FA0904 is gratefully acknowledged

Impact of rituximab biosimilars on overall survival in diffuse large B-cell lymphoma: a Dutch population-based study

In 2017, the European Medicines Agency approved rituximab biosimilars (R-biosimilars) for treatment of diffuse large B-cell lymphoma (DLBCL). Thereafter, the Netherlands was one of the first countries to implement R-biosimilars, given lower costs compared with rituximab originator (R-originator). This study's objective was to investigate whether overall survival (OS) of patients with DLBCL receiving R-biosimilars is similar to patients treated with R-originator. DLBCL patients >18 years, diagnosed between 2014 and 2018, who received at least 1 cycle of rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) were identified in the Netherlands Cancer Registry. Patients were categorized into R-originator or R-biosimilars groups based on data from a central repository of the Dutch medicinal drug market. The primary end point was 3-year OS, defined as the time between diagnosis and all-cause death. By the end of 2018, 91% of purchased rituximab were biosimilars. In total, 4429 patients were identified with 876 in the R-biosimilars group and 3553 in the R-originator group. Patients in the R-biosimilars group less frequently received >6 cycles of R-CHOP compared with patients treated with R-originator (24% vs 30%, P = .003). The 3-year OS did not differ between patients treated with R-originator or R-biosimilars (73% vs 73%, P = .855). This was confirmed with a multivariable Cox regression analysis accounting for sex, age, International Prognostic Index score, and number of R-CHOP cycles. In conclusion, the 3-year OS is similar for patients treated with CHOP in combination with R-originator or R-biosimilars and, therefore, favors the use of R-biosimilars in DLBCL treatment management.Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

How chromosomal inversions reorient the evolutionary process

Inversions are structural mutations that reverse the sequence of a chromosome segment and reduce the effective rate of recombination in the heterozygous state. They play a major role in adaptation, as well as in other evolutionary processes such as speciation. Although inversions have been studied since the 1920s, they remain difficult to investigate because the reduced recombination conferred by them strengthens the effects of drift and hitchhiking, which in turn can obscure signatures of selection. Nonetheless, numerous inversions have been found to be under selection. Given recent advances in population genetic theory and empirical study, here we review how different mechanisms of selection affect the evolution of inversions. A key difference between inversions and other mutations, such as single nucleotide variants, is that the fitness of an inversion may be affected by a larger number of frequently interacting processes. This considerably complicates the analysis of the causes underlying the evolution of inversions. We discuss the extent to which these mechanisms can be disentangled, and by which approach