The influence of heat treatment on the microstructural, mechanical and corrosion behaviour of cold sprayed SS 316L coatings

The present study evaluates the response of cold sprayed SS 316L coatings on mild steel substrate to aqueous corrosion in a 0.1 N HNO3 solution as determined using polarization tests. The corrosion behaviour of the SS 316L coating was studied not only in the as-coated condition, but also after heat treatment at 400, 800 and 1,100 °C. Heat treatment reduced the porosity, improved inter-splat bonding, increased the elastic modulus and more importantly increased the corrosion resistance of the cold sprayed SS 316L coating

Socioeconomic inequalities in early adulthood disrupt the immune transcriptomic landscape via upstream regulators

Disparities in socio-economic status (SES) predict many immune system-related diseases, and previous research documents relationships between SES and the immune cell transcriptome. Drawing on a bioinformatically-informed network approach, we situate these findings in a broader molecular framework by examining the upstream regulators of SES-associated transcriptional alterations. Data come from the National Longitudinal Study of Adolescent to Adult Health (Add Health), a nationally representative sample of 4543 adults in the United States. Results reveal a network—of differentially expressed genes, transcription factors, and protein neighbors of transcription factors—that shows widespread SES-related dysregulation of the immune system. Mediational models suggest that body mass index (BMI) plays a key role in accounting for many of these associations. Overall, the results reveal the central role of upstream regulators in socioeconomic differences in the molecular basis of immunity, which propagate to increase risk of chronic health conditions in later-life

Socioeconomic inequalities in molecular risk for chronic diseases observed in young adulthood

Many common chronic diseases of aging are negatively associated with socioeconomic status (SES). This study examines whether inequalities can already be observed in the molecular underpinnings of such diseases in the 30s, before many of them become prevalent. Data come from the National Longitudinal Study of Adolescent to Adult Health (Add Health), a large, nationally representative sample of US subjects who were followed for over two decades beginning in adolescence. We now have transcriptomic data (mRNA-seq) from a random subset of 4,543 of these young adults. SES in the household-of-origin and in young adulthood were examined as covariates of a priori -defined mRNA-based disease signatures and of specific gene transcripts identified de novo . An SES composite from young adulthood predicted many disease signatures, as did income and subjective status. Analyses highlighted SES-based inequalities in immune, inflammatory, ribosomal, and metabolic pathways, several of which play central roles in senescence. Many genes are also involved in transcription, translation, and diverse signaling mechanisms. Average causal-mediated effect models suggest that body mass index plays a key role in accounting for these relationships. Overall, the results reveal inequalities in molecular risk factors for chronic diseases often decades before diagnoses and suggest future directions for social signal transduction models that trace how social circumstances regulate the human genome

Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition

Understanding the emerging models of adaptive resistance is key to overcoming cancer chemotherapy failure. Using human breast cancer explants, in vitro cell lines, mouse in vivo studies and mathematical modelling, here we show that exposure to a taxane induces phenotypic cell state transition towards a favoured transient CD44HiCD24Hi chemotherapy-tolerant state. This state is associated with a clustering of CD44 and CD24 in membrane lipid rafts, leading to the activation of Src Family Kinase (SFK)/hemopoietic cell kinase (Hck) and suppression of apoptosis. The use of pharmacological inhibitors of SFK/Hck in combination with taxanes in a temporally constrained manner, where the kinase inhibitor is administered post taxane treatment, but not when co-administered, markedly sensitizes the chemotolerant cells to the chemotherapy. This approach of harnessing chemotherapy-induced phenotypic cell state transition for improving antitumour outcome could emerge as a translational strategy for the management of cancer

Multiple product positioning : a note on incorporating effects of synergy

Includes bibliographical references (p. 21-22)

Attack-defense marketing strategies : a full equilibrium analysis based on response function models

Includes bibliographical references (p. 23)

Pre-emptive product positioning in regulated markets : objectives and strategies

Bibliography: p. [4]

Product positioning strategies for segment pre-emption

Bibliography: p. 25-26

Metabolic network analysis and its application in understanding the biology of aging

A fundamental aim of life science is to understand the functioning of an organism and draw system-level connections between its genotype and behavior. Among the most significant types of interaction networks, cellular metabolism is a well-established descriptor of the phenotype of an organism. It relies on thousands of enzymatic reactions that are often represented as a dense and enmeshed web of biochemical conversions. Inspecting the metabolic network in its entirety is crucial in attaining a holistic understanding of the underlying biological mechanism. Colossal research efforts in the post-genomic era have enabled the curation of metabolic networks of entire organisms. Concurrently, advancements in computational strategies and algorithms have led to the inception of countless tools that utilize the essential information in genome-scale metabolic models to attain valuable insights into the physiology of an organism. Constraint-based modeling is a widely used and tested technique to model the metabolic network. Flux balance analysis (FBA) is the most popular constraint-based approach to predict intracellular metabolic flux distributions and network capabilities in genome-scale models. They are modeled on two fundamental assumptions. Firstly, that the cellular metabolism operates at a homeostatic condition, and secondly, that the cell typically organizes its metabolism to optimize a particular cellular objective. However, these assumptions significantly impair the applicability of the traditional flux balance analysis. Where the prediction accuracy is insufficient, additional constraints from omics data sources assist in obtaining biologically relevant inference. In this work, we showcase the addition of transcriptomic data to gain a profound understanding of the early events in the progression of Alzheimer’s disease model Caenorhabditis elegans. Transgenically expressing human amyloid-beta recapitulated the phenotypic disease response in the worms. Our analyses of the contextualized genome-scale metabolic network curated with the integration of experimentally derived gene expression data implicated metabolic alterations in Tricarboxylic Acid (TCA) cycle following low-level amyloid-beta expression. Along with metabolomic and enzymatic assays, we show repression in alpha-Ketoglutarate dehydrogenase. Identification of metabolic dysfunction as an early event is paramount in formulating mitigating efforts. Formulating a metabolic objective for use in constraint-based modeling is hazy, particularly for complex multicellular organisms. In addressing such concerns, we developed a computational algorithm, ∆FBA (delta–FBA), that focuses on the differences in the metabolic distribution between a pair of conditions. By formulating the mathematical problem to optimize for maximal consistency between the inferred flux alterations and integrated gene expression changes, ∆FBA predicts metabolic rewiring as an effect of genetic or environmental perturbations. We validated our strategy in a wide range of single-gene deletion knockouts and environmental modifications in Escherichia coli, where ∆FBA outperforms similar methods. Furthermore, our findings of metabolic changes in human diabetic subjects show the robustness of ∆FBA. Akin to metabolism, aging is a complex biological process that necessitates a system-level analysis in unraveling its etiology and progression. Despite numerous efforts, the aging process in humans is far from being completely understood. The Genotype-Tissue Expression (GTEx) project represents an invaluable repository of information that is ideal for studying human aging by examining the differences in the gene expression of over seven hundred individuals. Our bioinformatics and metabolic network analysis of the transcriptome associated human aging with conserved hallmarks of aging. Additionally, we show that the temporal changes in gene expression significantly contribute to the aging process. Our findings suggest that persistent moderators of cell fate and early repressors of cellular energetics could play a pivotal role in the progression of the aging process, one that culminates in accelerated decline

Supplemental appendices to defensive marketing strategies : an equilibrium analysis based on decoupled response function models

Includes biblilographical references