Overactivation of Notch1 Signaling Induces Ectopic Hair Cells in the Mouse Inner Ear in an Age-Dependent Manner

Background: During mouse inner ear development, Notch1 signaling first specifies sensory progenitors, and subsequently controls progenitors to further differentiate into either hair cells (HCs) or supporting cells (SCs). Overactivation of NICD (Notch1 intracellular domain) at early embryonic stages leads to ectopic HC formation. However, it remains unclear whether such an effect can be elicited at later embryonic or postnatal stages, which has important implications in mouse HC regeneration by reactivation of Notch1 signaling. Methodology/Principal Findings: We performed comprehensive in vivo inducible overactivation of NICD at various developmental stages. In CAG CreER+; Rosa26-NICD loxp/+ mice, tamoxifen treatment at embryonic day 10.5 (E10.5) generated ectopic HCs in the non-sensory regions in both utricle and cochlea, whereas ectopic HCs only appeared in the utricle when tamoxifen was given at E13. When tamoxifen was injected at postnatal day 0 (P0) and P1, no ectopic HCs were observed in either utricle or cochlea. Interestingly, Notch1 signaling induced new HCs in a non-cell-autonomous manner, because the new HCs did not express NICD. Adjacent to the new HCs were cells expressing the SC marker Sox10 (either NICD+ or NICDnegative). Conclusions/Significance: Our data demonstrate that the developmental stage determines responsiveness of embryonic otic precursors and neonatal non-sensory epithelial cells to NICD overactivation, and that Notch 1 signaling in the wild type, postnatal inner ear is not sufficient for generating new HCs. Thus, our genetic mouse model is suitable to test additiona

Treatment of axial spondyloarthritis with biologic and targeted synthetic DMARDs: British Society for Rheumatology guideline scope

Pharmacological management has advanced considerably since the 2015 British Society for Rheumatology axial spondyloarthritis (axSpA) guideline to incorporate new classes of biologic DMARDs (bDMARDs, including biosimilars), targeted synthetic DMARDs (tsDMARDs) and treatment strategies such as drug tapering. The aim of this guideline is to provide an evidence-based update on pharmacological management of adults with axSpA (including AS and non-radiographic axSpA) using b/tsDMARDs. This guideline is aimed at health-care professionals in the UK who care directly for people with axSpA, including rheumatologists, rheumatology specialist nurses, allied health professionals, rheumatology specialty trainees and pharmacists; people living with axSpA; and other stakeholders, such as patient organizations and charities

Bmp4 Is Essential for the Formation of the Vestibular Apparatus that Detects Angular Head Movements

Angular head movements in vertebrates are detected by the three semicircular canals of the inner ear and their associated sensory tissues, the cristae. Bone morphogenetic protein 4 (Bmp4), a member of the Transforming growth factor family (TGF-β), is conservatively expressed in the developing cristae in several species, including zebrafish, frog, chicken, and mouse. Using mouse models in which Bmp4 is conditionally deleted within the inner ear, as well as chicken models in which Bmp signaling is knocked down specifically in the cristae, we show that Bmp4 is essential for the formation of all three cristae and their associated canals. Our results indicate that Bmp4 does not mediate the formation of sensory hair and supporting cells within the cristae by directly regulating genes required for prosensory development in the inner ear such as Serrate1 (Jagged1 in mouse), Fgf10, and Sox2. Instead, Bmp4 most likely mediates crista formation by regulating Lmo4 and Msx1 in the sensory region and Gata3, p75Ngfr, and Lmo4 in the non-sensory region of the crista, the septum cruciatum. In the canals, Bmp2 and Dlx5 are regulated by Bmp4, either directly or indirectly. Mechanisms involved in the formation of sensory organs of the vertebrate inner ear are thought to be analogous to those regulating sensory bristle formation in Drosophila. Our results suggest that, in comparison to sensory bristles, crista formation within the inner ear requires an additional step of sensory and non-sensory fate specification

Executive Summary: The 2025 British Society for Rheumatology guideline for the treatment of axial spondyloarthritis with biologic and targeted synthetic DMARDs

CC BY 4.0 (Creative Commons Attribution

The 2025 British Society for Rheumatology guideline for the treatment of axial spondyloarthritis with biologic and targeted synthetic DMARDs

CC BY‑NC‑ND 4.0 (open access

An Investigation of the Concept of Designer Style and its Relevance to the Design of CAD Systems

Underlying the notion of style is the basic premise that all designers are not the same and that the manner in which any designer works through a design problem towards a proposed solution may be qualitatively different from other designers. If, through this work, this is shown to be the case and the concept of designer style can be meaningfully discussed then any model of the design process and any system or product relating to this model must allow for such variations at the level of the group or individual. This is the starting point of this investigation of the concept of designer styles

Impact of Advancement in Technology, False Conclusion of Real Estate Bubble, Record Low Mortgage Delinquency, Irresponsible Media, U.S. Economic Policy Disaster: Evidence Supporting Eddison Walters Risk Expectation Theory of The Global Financial Crisis of 2007 and 2008

Data analysis in recent studies by the current researcher presented evidence suggesting the existence of a real estate bubble preceding the Global Financial Crisis of 2007 and 2008 was a false conclusion. Data analysis from Walters (2019) resulted in 194.041 Mean Dependent Variable, 0.989 Adjusted R-square, 5.908 Square Error of Regression, and 488.726 Sum-of-Square Residual, from nonlinear regression analysis with the independent variable of &amp;ldquo;advancement in technology&amp;rdquo;, which proved to be the most significant factor causing the dependent variable of &amp;ldquo;home purchase price&amp;rdquo; to increase preceding the Global Financial Crisis of 2007 and 2008. Based on the findings of data analysis in Walters (2019), the researcher concluded the data confirmed the assertion agreed upon by Alan Greenspan and Ben Bernanke, it was impossible to have a real estate bubble, while citing the Efficient Market Hypothesis in 2005. Subsequent to 2005, alternative attempts to explain the existence of a real estate bubble were made by both former Chairmen of the Federal Reserve Board. Subprime lending and low interest rates were ruled out as the cause of the Global Financial Crisis of 2007 and 2008 in Walters (2019). As a result of the findings from Walters (2019), further investigation to gain an understanding of the impact of how the rapid adaption of advancement in technology influence on the rapid increase in home purchase price preceding the Global Financial Crisis of 2007 and 2008 is required. The purpose of this study is to gain an understanding of the role the rapid adaption of advancement in technology played in the mortgage industry and real estate industry in the United States, and the influence on to the rapid increase in home purchase prices preceding the Global Financial Crisis of 2007 and 2008 as a result of the changes. Insight into the rapid transformation of the mortgage industry and the real estate industry in the United States, and the role the transformation played in the crisis is a critical factor to understanding the impact of advancement in technology on the real estate market in the United States preceding the Global Financial Crisis of 2007 and 2008. Failure to consider the impact of rapid adaption of advancement in technology on the mortgage industry and real estate industry, and the transformation of the real estate market preceding the Global Financial Crisis 2007 and 2008, was a significant error which led to the false conclusion of the existence of a real estate bubble. An understanding of how the rapid transformation of the real estate market as a result of advancement in technology in the United States preceding the Global Financial Crisis of 2007 and 2008, will provide the critical knowledge to evaluate mistakes leading to the false conclusion of a real estate bubble preceding the crisis. The information gained from the current study will help avoid a future financial crisis of the same magnitude.</jats:p

Evidence From Data Analysis, Fifteen Developed Countries and the United States Home Prices Increase Between 1990 to 2006 Result of Advancement In Technology, Worldwide Economic Collapse and Great Recession Result of False Information by Media and Economic Policy Failures: Walters Real Estate Bubble Impossibility Price Transparency Theory, Real Estate Bubble Is Impossible, An End to Economic Policies Based on False Information

Based on the findings of the current study, policymakers must take a hard look at the media and themselves, because the world can no longer blame the subprime mortgage industry for causing the Global Financial Crisis of 2007 and 2008. The public must demand answers from the media and policymakers explaining how an economic crisis that could have been avoided resulted in the collapse of the global economy. The lack of evidence supporting the theory of a financial bubble and a real estate bubble called for further investigation of factors leading to the Global Financial Crisis of 2007 and 2008. Evidence presented from data analysis in Walters (2018) suggested no financial bubble existed in developed or developing countries around the world, preceding the Global Financial Crisis of 2007 and 2008. Based on data analysis in Walters (2018) the evidence also suggested, the lasting effect of economic policies in response to the Global Financial Crisis of 2007 and 2008 for both developed and developing countries around the world, had no significant impact on the financial sector but pointed to a lack of economic growth. The findings raised significant questions about the existence of a real estate bubble in both developed and developing countries. Evidence from data analysis presented in Walters and Djokic (2019) suggested the existence of a real estate bubble in the United States real estate market preceding the Global Financial Crisis of 2007 and 2008 was a false conclusion. Data analysis in Walters (2019) resulted in, 0.989 Adjusted R-square, 194.041 Mean Dependent Variable, 5.908 Square Error of Regression, 488.726 Sum-of- Square Residual, and 0.00000 Probability (F-statistic), for correlation between the independent variable representing advancement in technology, and the dependent variable representing home purchase price in the United States preceding the Global Financial Crisis of 2007 and 2008. The findings in Walters (2019) concluded the rapid increase in home purchase price in the United States real estate market, was due to increased demand for homes from the adaptation of advancement in technology in the real estate and mortgage industries. The current study expanded the investigation of the growth in home purchase price to fifteen developed countries around the world, building on the findings of previous research by the current researcher. The researcher in the current study concluded, the existence of significant and near-perfect correlation in many cases, between the dependent variable representing growth in home purchase price, and the independent variable representing advancement in technology. The analysis was based on data analyzed from fifteen developed countries around the world, which was collected between 1990 and 2006. The data analysis included home purchase price data from, Canada, United Kingdom, Denmark, Finland, France, Italy, New Zealand, Sweden, Netherlands, Australia, Ireland, Belgium, Norway, Spain, and Portugal. Data preceding the Global Financial Crisis of 2007 and 2008 were analyzed in the current study. The researcher in the current study concluded the existence of overwhelming evidence suggesting advancement in technology was responsible for the rapid increase in home prices in developed countries around the world preceding the Global Financial Crisis of 2007 and 2008. The result of data analysis in the current study provided further confirmation of the accuracy of former Federal Reserve Board Chairmen, Alan Greenspan and Ben Bernanke 2005 assessment which concluded, the occurrence of a real estate bubble developing was impossible due to the Efficient Market Hypothesis, before reversing course subsequent their assertion in 2005 (Belke &amp;amp; Wiedmann, 2005; Starr,2012). The result of the current study provided additional evidence supporting Eddison Walters Risk Expectation Theory of The Global Financial Crisis of 2007 and 2008. The result from data analysis also confirmed the need for the adaptation of Eddison Walters Modern Economic Analysis Theory. As a result of the findings in the current study, the researcher concluded the development of a real estate bubble is impossible where there exists real estate price transparency, as is the case in most developed and developing countries. The researcher presented Walters Real Estate Bubble Impossibility Price Transparency Theory based on the findings. False information of a real estate bubble and predictions of a real estate crash disseminated through the mainstream media and social media can be a destructive force with a disastrous effect on the economy around the world. The failure by the media to hold themselves and policymakers to a higher standard resulted in the Global Financial Crisis of 2007 and 2008. The result of the failure by the media was a worldwide economic crisis and the Great Recession that followed the Global Financial Crisis of 2007 and 2008. Lessons learned from the Global Financial Crisis of 2007 and 2008 can assist in preventing another economic crisis in the future.</jats:p

Operational Research

A brief, introductory talk on a subject, such as this, will naturally be expected to start with a definition. In this, I must frankly admit to some difficulty, as I do not know of any really satisfactory definition of operational research. This, however, is nothing to be abashed at. It is usually easy enough to be clear about a field of study when you are in the centre of it; the boundaries, however, are commonly diffuse—and it is with boundaries that definitions are concerned. This difficulty of precise definition can be found even with quite well-established fields such as physics or, dare I suggest, the actuarial profession.I shall therefore be content to quote a phrase which is commonly applied to operational research, really more a description than a definition, and shall then try to expand and explain the salient points incorporated in it.</jats:p

Increase in Consumer Debt Preceding Crisis Due to Advancement in Technology, Further Evidence Supporting the Idea No Real Estate Bubble Existed Preceding Crisis Presented by Eddison Walters Risk Expectation Theory of the Global Financial Crisis of 2007 and 2008: The Case for Eddison Walters Modern Economic Analysis Theory

The researcher called for economic research to consider the potential effect of advancement in technology on analysis of economic data in Eddison Walters Modern Economic Analysis Theory in the future represented a paradigm shift in economic analysis that will significantly reduce the potential for error due to data distortion in the future. The foundation of the world&amp;#39;s economy is based on the sharing of information, yet very little attention has been given to the effect of technology advancement in the analysis of data. The researcher of the current study highlighted the critical nature of sharing information to the development of the world&amp;rsquo;s economy in the past, as well as the critical nature of sharing information to the world&amp;rsquo;s economy today. Advancement in technology has drastically improved the sharing of information and has led to the globalized economy. The lack of evidence supporting the widely accepted theory of the Global Financial Crisis of 2007 and 2008 prompted the investigation by the current researcher aimed at gaining insight into economic factors that were responsible for conditions contributing to the Global Financial Crisis of 2007 and 2008. Walters (2018) presented evidence suggesting no financial bubble existed before the Global Financial Crisis of 2007 and 2008. The study resulted in the development of &amp;ldquo;Eddison Walters Risk Expectation Theory of The Global Financial Crisis of 2007 and 2008&amp;rdquo;. The theory presented an alternative explanation for the financial crisis. The researcher called for additional investigation to gain insight into the nature of the cause of the Global Financial Crisis of 2007 and 2008. Further investigation in Walters (2019) provided evidence supporting the idea, technological advancement led to the rapid growth in home prices before the Global Financial Crisis of 2007 and 2008. The result from the analysis of data in Walters (2019) revealed the following, 0.989 Adjusted R-square, 194.041 Mean Dependent Variable, 5.908 Square Error of Regression, and 488.726 Sum-of-Square Residual, from nonlinear regression analysis. The dependent variable in the study was, &amp;ldquo;home purchase price&amp;rdquo; and the independent variable was, &amp;ldquo;advancement in technology&amp;rdquo;. The current study continued the investigation into factors that were described in the literature which set the conditions leading to the Global Financial Crisis of 2007 and 2008. Gaining insight into the effect of technological advancement on the significant increase in consumer debt prior to the Global Financial Crisis will significantly contribute to the understanding of the economic environment before the Global Financial Crisis of 2007 and 2008. Insight into the effect of advancement in technology on the increase in consumer lending prior to the Global Financial Crisis of 2007 and 2008, will significantly contribute to the understanding of the Global Financial Crisis of 2007 and 2008.</jats:p