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"Simpson, David"
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Striding With Economic Giants
Striding explores the modernization process by outlining the economics of agriculture, growth theories of economic development, and problems with growth.
During the last century, policy makers and the public acquired a considerable interest in economics. As a result, this heightened awareness enhanced the well-being of society.
In 1969, the Nobel Foundation initiated the new prize category of economic sciences and started awarding the prize annually. At the forefront of their field, prize winners have introduced many innovative ideas. Moreover, an evaluation of their ideas reveals valuable nuggets to enrich the professional lives of non-economists.
Drawing on publications written by the Laureates, Striding with Economic Giants presents the essence of their thoughts in easy-to-understand concepts for the business and academic communities. This book is perfect for business executives, public policy makers, and economics students.
It describes logic and experimental frameworks in mathematics, econometrics, behavior modeling, and game theory. Next, Striding presents microeconomic contributions, including production theory, theory of institutions, fundamental ideas of markets, and consumerism. Then, it reviews financial theory in capital markets, portfolio choice, and asset pricing.
The book spotlights contributions to the rule of law, public administration, and political science. It also highlights a growing understanding of human capital by tracing demographic trends and describing health, education, minority, and labor economics. Enhancements to macroeconomic theory are featured in economic mechanisms and cycles, managing the economy, and policy making.
Striding explores the modernization process by outlining the economics of agriculture, growth theories of economic development, and problems with growth. It illustrates contributions to international economics in trade, finance, and global public policy. Finally, the book showcases contributions to social justice in social equality, income redistribution, and climate change.
eBook
Selective extracellular vesicle-mediated export of an overlapping set of microRNAs from multiple cell types
Background
MicroRNAs (miRNAs) are a class of small RNA molecules that regulate expression of specific mRNA targets. They can be released from cells, often encapsulated within extracellular vesicles (EVs), and therefore have the potential to mediate intercellular communication. It has been suggested that certain miRNAs may be selectively exported, although the mechanism has yet to be identified. Manipulation of the miRNA content of EVs will be important for future therapeutic applications. We therefore wished to assess which endogenous miRNAs are enriched in EVs and how effectively an overexpressed miRNA would be exported.
Results
Small RNA libraries from HEK293T cells and vesicles before or after transfection with a vector for miR-146a overexpression were analysed by deep sequencing. A subset of miRNAs was found to be enriched in EVs; pathway analysis of their predicted target genes suggests a potential role in regulation of endocytosis. RT-qPCR in additional cell types and analysis of publicly available data revealed that many of these miRNAs tend to be widely preferentially exported. Whilst overexpressed miR-146a was highly enriched both in transfected cells and their EVs, the cellular:EV ratios of endogenous miRNAs were not grossly altered. MiR-451 was consistently the most highly exported miRNA in many different cell types. Intriguingly, Argonaute2 (Ago2) is required for miR-451 maturation and knock out of Ago2 has been shown to decrease expression of other preferentially exported miRNAs (eg miR-150 and miR-142-3p).
Conclusion
The global expression data provided by deep sequencing confirms that specific miRNAs are enriched in EVs released by HEK293T cells. Observation of similar patterns in a range of cell types suggests that a common mechanism for selective miRNA export may exist.
Journal Article
Quantitative profiling of lifespan-dependent cell-cell communication potential reveals dynamic ligand-receptor network shifts across mouse tissues
Cell-to-cell communication (CCC) is a tightly regulated process essential for tissue development and homeostasis, but can become dysregulated during ageing. While CCC is inherently complex and remains incompletely characterised, advances in single-cell RNA sequencing (scRNA-seq) have enabled large-scale, unbiased inference of intercellular interactions which offers broad-spectrum information that complements traditional protein-based assays. Unlike these targeted assays, transcriptomic approaches enable systematic inference and exploration of both known and potentially novel ligand-receptor (LR) interactions. In this study, we applied LIgand-receptor ANalysis frAmework (LIANA), which integrates multiple inference methods to derive consensus CCC predictions, to scRNA-seq data for four mouse organs (liver, lung, heart, and kidney), spanning key life stages: post-natal development, adulthood and ageing. Our analysis revealed dynamic, organ-specific CCC patterns characterised by both gains and losses of LR interactions over time, reflecting lifespan-dependent shifts in transcriptome-inferred intercellular communication potential. To quantify these shifts, we developed a two-phase comparative framework and introduced the Shrink and Expand (SE) score to capture directional changes in inferred LR interaction sets between any two biological states. Applying this framework generated a curated dataset of LR pairs and their predicted changes, capturing the repertoire of putative interactions across organs and states and enabling robust, interpretable comparisons of organ-specific and coinciding patterns of change across multiple organs. For instance, CD44 and ITGB1 were found to undergo highly dynamic changes across timepoints and organs, suggesting that they may act as central nodes in predicted age-dependent communication changes. This generalisable approach supports quantitative comparisons of inferred CCC across diverse states, including development, ageing, disease, or treatment conditions, and provides a resource for prioritising candidate interactions for drug target discovery for further experimental validation while exploring context-specific shifts in predicted intercellular communication.
Journal Article
Differential Expression of Urinary Exosomal MicroRNAs miR-21-5p and miR-30b-5p in Individuals with Diabetic Kidney Disease
Biomarkers for the identification of diabetic kidney disease (DKD) are needed as current tests lack sensitivity for detecting early kidney damage. MicroRNAs (miRNAs) are short, non-coding regulatory ribonucleic acid (RNA) molecules commonly found in urinary exosomes differentially expressed as renal function declines. We evaluated urinary exosomal miRNA expression in persons with type 2 diabetes mellitus and DKD (T2DKD). 87 human urinary exosomal miRNAs were profiled in a discovery cohort of patients with T2DKD (n = 14) and age and gender matched controls with type 2 diabetes mellitus and normal renal function (T2DNRF; n = 15). Independent validation of differentially expressed target miRNAs was performed in a second cohort with T2DKD (n = 22) and two control groups: T2DNRF (n = 15) and controls with chronic kidney disease (CCKD) and poor renal function without diabetes (n = 18). In the discovery cohort, urinary miR-21-5p, let-7e-5p and miR-23b-3p were significantly upregulated in T2DKD compared to T2DNRF (p < 0.05). Conversely, miR-30b-5p and miR-125b-5p expression was significantly lower in T2DKD (p < 0.05). Independent validation confirmed up-regulation of miR-21-5p in the replication cohort in T2DKD (2.13-fold, p = 0.006) and in CCKD (1.73-fold, p = 0.024). In contrast, miR-30b-5p was downregulated in T2DKD (0.82-fold, p = 0.006) and in CCKD (0.66-fold, p < 0.002). This study identified differential expression of miR-21-5p and miR-30b-5p in individuals with diabetic kidney disease and poor renal function. These miRNAs represent potential biomarkers associated with the pathogenesis of renal dysfunction.
Journal Article
Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases
Treatment of multiple sclerosis with natalizumab is complicated by rare occurrence of progressive multifocal leukoencephalopathy (PML). Between July, 2006, and November, 2009, there were 28 cases of confirmed PML in patients with multiple sclerosis treated with natalizumab. Assessment of these clinical cases will help to inform future therapeutic judgments and improve the outcomes for patients.
The risk of PML increases with duration of exposure to natalizumab over the first 3 years of treatment. No new cases occurred during the first two years of natalizumab marketing but, by the end of November, 2009, 28 cases had been confirmed, of which eight were fatal. The median treatment duration to onset of symptoms was 25 months (range 6–80 months). The presenting symptoms most commonly included changes in cognition, personality, and motor performance, but several cases had seizures as the first clinical event. Although PML has developed in patients without any previous use of disease-modifying therapies for multiple sclerosis, previous therapy with immunosuppressants might increase risk. Clinical diagnosis by use of MRI and detection of JC virus in the CSF was established in all but one case. Management of PML has routinely used plasma exchange (PLEX) or immunoabsorption to hasten clearance of natalizumab and shorten the period in which natalizumab remains active (usually several months). Exacerbation of symptoms and enlargement of lesions on MRI have occurred within a few days to a few weeks after PLEX, indicative of immune reconstitution inflammatory syndrome (IRIS). This syndrome seems to be more common and more severe in patients with natalizumab-associated PML than it is in patients with HIV-associated PML.
Diagnosis of natalizumab-associated PML requires optimised clinical vigilance, reliable and sensitive PCR testing of the JC virus, and broadened criteria for recognition of PML lesions by use of MRI, including contrast enhancement. Optimising the management of IRIS reactions will be needed to improve outcomes. Predictive markers for patients at risk for PML must be sought. It is crucial to monitor the risk incurred during use of natalizumab beyond 3 years.
Journal Article