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"Jones, Phill"
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A Multicompartment Vascular Model for Inferring Baseline and Functional Changes in Cerebral Oxygen Metabolism and Arterial Dilation
Functional hemodynamic responses are the composite results of underlying variations in cerebral oxygen consumption and the dilation of arterial vessels after neuronal activity. The development of biophysically based models of the cerebral vasculature allows the separation of the neuro-metabolic and neuro-vascular influences on measurable hemodynamic signals such as functional magnetic resonance imaging or optical imaging. We describe a multicompartment model of the vascular and oxygen transport dynamics associated with stimulus-driven neuronal activation. Our model offers several unique features compared with previous formulations such as the ability to estimate baseline blood flow, volume, and oxygen consumption from functional data. In addition, we introduce a capillary compliance model, arterial and venous oxygen permeability, and model the dynamics of extravascular tissue oxygenation. We apply this model to multimodal optical spectroscopic and laser speckle imaging of the rat somato-sensory cortex during nine conditions of whisker stimulation. By fitting the model using a psuedo-Bayesian framework to incorporate multimodal observations, we estimate baseline blood flow to be 94 (±15) mL/100 g min and baseline oxygen consumption to be 6.7 (±1.3) mL O2/100 gmin. We calculate parametric, linear increases in arterial dilation (R2 = 0.96) and CMRo2 (R2 = 0.87) responses over the nine conditions. Other parameters estimated by the model include vascular transit time and volume reserve, oxygen content, saturation, diffusivity rate constants, and partial pressure of oxygen in the vascular compartments and in the extravascular tissue. Finally, we compare this model to earlier work and find that the multicompartment model more accurately describes the observed oxygenation changes when compared with a single compartment version.
Journal Article
Instability in the Middle East: structural causes and uneven modernisation 1950-2012
Middle Eastern instability is manifest externally in many ways: by crises afflicting governing regimes, the rise of political Islam, terrorism, revolution, civil war, increased migration, and the collapse of many states. This book examines the roots of this instability using a theoretically original and empirically supported historical-sociological comparative analysis. Countering common interpretations of postcolonial Middle Eastern development, Instability in the Middle East focuses on the highly uneven and unsynchronized pace of change in individual sociodemographic, economic, and political dimensions of modernization. Drawing on the theory of multiple modernities, Cerný investigates the broader cultural, religious, and international political context of uneven modernization in the Middle East and tests his model using a time series of dozens of indicators over the past fifty years, revealing a long-term trend of cumulative change across the region.
eBook
Reciprocal relationship between APP positioning relative to the membrane and PS1 conformation
Background
Several familial Alzheimer disease (FAD) mutations within the transmembrane region of the amyloid precursor protein (APP) increase the Aβ
42/40
ratio without increasing total Aβ production. In the present study, we analyzed the impact of FAD mutations and γ-secretase modulators (GSMs) that alter the Aβ
42/40
ratio on APP C-terminus (CT) positioning relative to the membrane, reasoning that changes in the alignment of the APP intramembranous domain and presenilin 1 (PS1) may impact the PS1/γ-secretase cleavage site on APP.
Results
By using a Förster resonance energy transfer (FRET)-based technique, fluorescent lifetime imaging microscopy (FLIM), we show that Aβ
42/40
ratio-modulating factors which target either APP substrate or PS1/γ-secretase affect proximity of the APP-CT to the membrane and change PS1 conformation.
Conclusions
Thus, we propose that there is a reciprocal relationship between APP-CT positioning relative to the membrane and PS1 conformation, suggesting that factors that modulate either APP positioning in the membrane or PS1 conformation could be exploited therapeutically.
Journal Article
The genetic code
This book tracks the key experiments and discoveries that set in motion efforts to crack the code and explores the many ways humans have applied knowledge of the genetic code to alter gene activity.
Book
US courts struggle with new patent infringement standards
The lesson from
Festo
is that during patent prosecution, what you say (or don't say) and what you do (or don't do) will be used against you.
Journal Article
Instability in the Middle East
Middle Eastern instability is manifest externally in many ways: by crises afflicting governing regimes, the rise of political Islam, terrorism, revolution, civil war, increased migration, and the collapse of many states. This book examines the roots of this instability using a theoretically original and empirically supported historical sociological comparative analysis. Up till now interpretations of the development of the post-colonial Middle East have been dominated by two opposing theses. The first views the region as backward, unchanging and rigid, the second as undergoing excessively rapid transformation. This book offers an alternative perspective focusing on the highly uneven and unsynchronised pace of change in individual dimensions of Middle Eastern modernisation. What we are seeing is (1) rapid socio-demographic change (a sharp increase in the population and the proportion of young people, rapid urbanisation, and the expansion of the media and education), (2) slower and unstable economic change (dependency on oil exports, high unemployment), and (3) slow or regressive political change (erosion of the capacity to govern, the absence of democratisation and liberalisation). The theoretical model employed emerged from a critical reading of theories of modernisation and a concept of multiple modernities that also allows for an interrogation of the broader cultural, religious and international political context of uneven modernisation in the Middle East. This model is then tested empirically using the time series (1960–2010) of dozens of indicators covering the demographic, social, economic and political dimensions of the modernisation process.In general the book does not concentrate on externally monitorable political actors and their rivalries, as so often is the case. Instead, it focuses on the political rivalries of deep, long-term cumulative demographic, social and economic change taking place beneath the surface. It looks at changes that are not simply taking place in individual countries of the Middle East, but since the end of the Second World War have affected the entire region and are responsible for the emergence of a Middle East completely different to that to which we were accustomed for many decades.
eBook