2,164 research outputs found
No. 617 Stuart Ruckman
No full textTranscript (12, 40 pages) of two interviews by Matt Driscoll with Stuart Ruckman on April 9, 2010, and July 7, 2011Ruckman (b. 1966) was born in Salt Lake City, Utah. Stuart shares how his family, particularly his father, played a significant role in introducing him to the outdoors. Some of his initial explorations included a hike to the top of Mount Olympus when he was five years old, backpacking trips in the Wasatch and Uinta Mountains, and a successful summit attempt on the Grand Teton when he was twelve. Stuart discovered technical rock climbing due to the influence of his older brother Bret, five years Stuart\u27s senior. Bret learned under Dennis Turville, a well-respected Salt Lake climbing instructor. Stuart shares his observations on the Salt Lake climbing community of the late 1970s and 1980s, noting the intimacy of the community, while also pointing out the significant influence of a handful of climbers, including Merrill Bitter, Les Ellison, and Brian Smoot. He briefly describes the proliferation of new-route development in the Wasatch during his first decade in climbing. In collaboration with his brother Bret, Stuart published comprehensive guidebooks on climbing in the Wasatch Mountains. Stuart\u27s contributions as a first-ascensionist and co-author of Rock Climbing the Wasatch Range attest to his lasting impact on Utah climbing. Interview is part of the Outdoor Recreation History Project. Interviewer: Matt Driscol
A study of morphological and compositional influence on bioartificial hepatic microenvironments within electrospun polycaprolactone scaffolds
No full textLiver disease is a leading cause of death throughout the world and has seen rising mortality
rates since the 1970s in contrast to other leading causes of death such as cardiovascular
disease and cancer. A quarter of the global population is predicted to have non-alcoholic fatty
liver disease (NAFLD) and are at risk of developing chronic conditions such as fibrosis and
hepatocellular carcinoma (HCC). There currently exist no approved pharmaceutical
therapeutics for the treatment of liver disease and disease management is particularly
complex to negotiate. End-stage liver disease presents a significant threat to life and the only
cure is to replace the chronically damaged liver with a transplant. To ease the burden on liver
disease patients and health workers, it is necessary to find pharmaceutical and regenerative
therapies that can effectively hinder disease progression. Reaching such treatments implies
the use of in-vitro methods to produce liver models for testing target and drug molecules, for
the expansion of cells with regenerative capacity and for bioartificial liver devices. In-vitro
hepatocyte culture methods have progressed in recent decades from standard 2D tissue
culture to 3D organoids and scaffolded cultures which provide a biomimetic environment and
elicit phenotypic responses from hepatocytes in-vitro. This thesis has sought to optimise
electrospun polycaprolactone (PCL) scaffolds for the culture of hepatocytes, with a focus on
morphology and composition, through three methods: 1) assessment of the influence of
electrospun PCL fibre diameter and morphology on hepatocyte culture 2) the inclusion of rat
liver extracellular matrix (rLECM) into hybrid PCL:rLECM scaffolds 3) the inclusion of human
liver ECM (hLECM) into hybrid PCL:hLECM scaffolds with a comparison of donor-to-donor
variance. All fabricated scaffolds were subject to physical and chemical analyses and cultured
with an immortalised hepatic cell line (HepG2) or Primary Mouse Hepatocytes (PMHs). The
biological influence of the scaffolds on cell cultures was assessed through proliferation
analysis, immunohistochemistry and RT-qPCR gene expression analysis of cultured cells. Our
results show that fibre morphology affects the attachment, morphology and proliferation of
hepatocytes. The architecture of the cells upon the scaffolds also shows to affect cell function
through significant upregulation of key hepatic phenotypic markers on scaffolds with higher
porosity. Incorporation of both rLECM and hLECM into electrospun scaffolds with
morphological consistency has been demonstrated. rLECM at concentrations of 5 w/w% and
10 w/w% shows to significantly increase the proliferative activity of HepG2 cultures. The
incorporation of hLECM at a 1 w/w% concentration demonstrated variable proliferative activity
of HepG2 between tissue donors whilst functional gene expression is maintained across
donors. Biological differences between the immortalised cell line (HepG2) and Primary Mouse
Hepatocytes are reflected in functional response differences observed upon different scaffold
microenvironments. These studies show that the morphology and composition of electrospun
polycaprolactone scaffolds can have a measurable impact on hepatocyte cultures and our
methods hold potential for the development of utile in-vitro hepatic microenvironments
John Stuart Mill’s projected science of society: 1827-1848
No full textThe purpose of the thesis is to examine John Stuart Mill’s political thought from
about 1827 to 1848 as an exercise in intellectual history. It focuses, first, on Mill’s view,
formulated by the late 1830s, that contemporary society was ‘civilized’, and second, on
his project of a science of society, which he aspired to develop in the late 1830s and
early 1840s.
By the late 1830s, Mill came to the view that his contemporary society was a
‘commercial society or civilization’, dominated by the middle, commercial class. The
first part of my thesis, constituted by Chapters 2-4, discusses the way in which Mill
formed his notion of civilization, and what he meant by the term ‘civilization’. Mill paid
attention to the implications of the rise of the middle class, and regarded such
phenomena of contemporary society as the corruption of the commercial spirit and
excessive social conformity as an inevitable consequence of the rise of the middle class.
The second part of the thesis, constituted by Chapters 5-9, examines Mill’s
projected science of society. In the late 1830s and early 1840s, Mill attempted to
develop a new science of society whose subject-matter was the nature and prospects of
commercial, civilized society. This aspiration culminated in A System of Logic,
published in 1843. In examining Mill’s projected science, I pay particular attention to
the fact that he conceived new sciences of history and of the formation of character,
both of which were indispensable in his project, although he failed to give a complete
account of these sciences. My thesis shows that the implications of his interest both in
history and in the formation of character are more significant than Mill scholars have
assumed
REpeated AutoLogous Infusions of STem cells In Cirrhosis (REALISTIC):a multicentre, phase II, open-label, randomised controlled trial of repeated autologous infusions of granulocyte colony-stimulating factor (GCSF) mobilised CD133+ bone marrow stem cells in patients with cirrhosis. A study protocol for a randomised controlled trial
No full textINTRODUCTION: Liver disease mortality and morbidity are rapidly rising and liver transplantation is limited by organ availability. Small scale human studies have shown that stem cell therapy is safe and feasible and has suggested clinical benefit. No published studies have yet examined the effect of stem cell therapy in a randomised controlled trial and evaluated the effect of repeated therapy.METHODS AND ANALYSIS: Patients with liver cirrhosis will be randomised to one of three trial groups: group 1: Control group, Standard conservative management; group 2 treatment: granulocyte colony-stimulating factor (G-CSF; lenograstim) 15 µg/kg body weight daily on days 1-5; group 3 treatment: G-CSF 15 µg/kg body weight daily on days 1-5 followed by leukapheresis, isolation and aliquoting of CD133+ cells. Patients will receive an infusion of freshly isolated CD133+ cells immediately and frozen doses at days 30 and 60 via peripheral vein (0.2×10(6) cells/kg for each of the three doses). Primary objective is to demonstrate an improvement in the severity of liver disease over 3 months using either G-CSF alone or G-CSF followed by repeated infusions of haematopoietic stem cells compared with standard conservative management. The trial is powered to answer two hypotheses of each treatment compared to control but not powered to detect smaller expected differences between the two treatment groups. As such, the overall α=0.05 for the trial is split equally between the two hypotheses. Conventionally, to detect a relevant standardised effect size of 0.8 point reduction in Model for End-stage Liver Disease score using two-sided α=0.05(overall α=0.1 split equally between the two hypotheses) and 80% power requires 27 participants to be randomised per group (81 participants in total).ETHICS AND DISSEMINATION: The trial is registered at Current Controlled Trials on 18 November 2009 (ISRCTN number 91288089, EuDRACT number 2009-010335-41). The findings of this trial will be disseminated to patients and through peer-reviewed publications and international presentations.</p
Redemption in the work of Francis Stuart
No full textThe idea of redemption is central to an understanding of the work
of Francis Stuart. Through an examination of its development and
expression, it is possible to demonstrate the integrity of his work and
its distinctive qualities. Such a demonstration is necessary because
Stuart's writing has been subjected to comparatively little scholarly
inquiry, although reviews of his work, especially that produced since
1949, suggest that it is impressive and important.
First, a general background to Stuart's work, a discussion of the
special problems associated with reading it, and a summary of his corpus
is provided. This indicates that the idea of redemption is important to
his earliest writing. The state of redemption is shown to be a
necessary apotheosis for Stuart's outcast heroes; it involves spiritual
suffering through which may be found a sense of reintegration and a
higher reality. This is expressed through interrelated themes such as
those of gambler, artist and ordinary man; mystic and criminal; sacred
and profane love; and spirituality and the mundane. The nature of the
redemptive experience is further elaborated by distinctive, complex
motifs, especially the hare, the ark and the woman-Christ. Their
recurrence provides an important element in the unity of Stuart's work.
Because Stuart's idea of the outcast raises important biographical
questions, an examination of the relationship between Stuart's life and
his work is made. Finally, the way in which the idea of redemption
exists in the language structures of Stuart's novels is examined, with
especial reference to his most recent work, The High Consistory. The
thesis shows that the development of the these of redemption
demonstrates the integrity of Stuart's work
Defining the functional role of laminin isoforms in the regulation of the adult hepatic progenitor cell
No full textDuring chronic and severe acute liver injury, regeneration is thought to occur through
hepatic progenitor cells (HPCs). Understanding the regulation of HPCs may offer
therapeutic opportunities to enhance liver regeneration. HPCs are associated with an
increase in laminins in the extracellular matrix. Laminins are heterotrimeric proteins,
composed of an alpha, beta and gamma chain. There are 5 alpha chains with different
distributions and functions, but the relative contributions of these in HPC-mediated
liver regeneration are not known. My aims were to describe the laminin alpha chains
associated with the HPC response and to define the functional effects of specific
laminin chains on HPCs.
I examined the laminin alpha chains in two mouse models of HPC activation: a
transgenic model using conditional deletion of Mdm2 in hepatocytes, and a dietary
model using 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). The laminin alpha 5
(Lama5) chain is significantly upregulated in both models and forms a basement
membrane which surrounds the progenitor cells. I have also demonstrated Lama5
expression in the ductular reaction seen in human liver disease. Using primary mouse
cell cultures, I have shown that Lama5 is produced predominantly by the HPCs
themselves, rather than by stellate cells. The HPCs express the cell surface receptor
alpha-6 beta-1 integrin, a binding partner of Lama5.
I then studied the functional effects of matrix on cell behaviour in vitro using
recombinant laminins and a line of spontaneously immortalised mouse HPCs.
Compared to other laminin chains, Lama5 selectively promotes HPC adhesion and
spreading. These effects are partially blocked by antibodies against beta-1 integrin.
Lama5 also significantly enhances HPC migration, resulting in an increase in cell
migration. Furthermore, only Lama5 enhances HPC survival in serum-free medium,
with an increase in cell viability. Culturing HPCs on HPCs maintained in culture on
plastic synthesise Lama5 chain. Knock-down of endogenous Lama5 production
using siRNA results in reduced proliferation and increased hepatocytic
differentiation, with increased albumin production.
I then studied the effects in vivo using transgenic Cre-lox mouse strains that allow
conditional knock-out of either laminin alpha 5 or beta-1 integrin in HPCs. The
effects of gene deletion were examined in healthy mice and two dietary models of
HPC activation: the DDC diet and a choline-deficient, ethionine-supplemented
(CDE) diet. Although these experiments were limited by a low number of
experimental animals and low recombination rates, there was a suggestion of
impaired HPC expansion associated with loss of laminin alpha 5. There was also a
significant increase in hepatocellular injury and fibrosis in response to the DDC diet
seen with loss of laminin alpha 5 expression.
Laminin alpha 5-containing matrix is deposited around HPCs during liver
regeneration and supports progenitor cell attachment, migration and maintenance of
an undifferentiated phenotype. This work identifies a novel target for enhancing liver
regeneration
Cell therapy for chronic liver disease
No full textThere is a growing literature of clinical studies of bone marrow (BM) cell therapy for
liver cirrhosis. At present, the optimum choice of cell type(s) and the mechanism(s)
of effect remain undefined. Cells of the monocyte-macrophage lineage have key roles
in the development and resolution of liver fibrosis. Therefore, I tested the therapeutic
effects of these cells in the context of experimental murine liver fibrosis.
The effects of unmanipulated, syngeneic macrophages, their specific BM precursors
and unfractionated (whole) BM cells were examined in the iterative carbon
tetrachloride model of liver fibrosis. BM-derived macrophage (BMM) delivery
resulted in early chemokine upregulation with the hepatic recruitment of
endogenous macrophages and neutrophils. These cells delivered matrix
metalloproteinases-13 and -9 respectively, into the hepatic scar. The effector cell
infiltrate was accompanied by increased levels of the anti-inflammatory cytokine IL-10. A reduction in hepatic myofibroblasts was followed by reduced fibrosis detected
4 weeks after macrophage infusion. Serum albumin levels were elevated at this time.
Upregulation of the liver progenitor cell mitogen TWEAK preceded expansion of the
progenitor cell compartment. BMM delivery increased hepatic expression of
cytokines with reparative effects (including colony stimulating factor-1, insulin-like
growth factor-1 and vascular endothelial growth factor). In contrast to the effects of
differentiated macrophages, liver fibrosis was not significantly improved by the
application of macrophage precursors and was exacerbated by whole BM. BMMs did
not affect liver fibrosis or regeneration in the 1% DDC model of biliary disease.
These effects were only detected following the intraportal delivery of BM cells. The
peripheral (tail) vein administration of BMMs, either singly or repeatedly did not
recapitulate the therapeutic phenotype. This was investigated by in vivo tracking of
BMMs constitutively expressing green fluorescent protein (GFP). The peripheral
administration route resulted in the early (1 hour) accumulation of BMMs within the
pulmonary system. This was followed by delayed hepatic engraftment, which was
also numerically reduced (<30%) compared with intraportal administration.
Macrophage cell therapy improves clinically relevant parameters in experimental
chronic liver injury. Paracrine signalling to endogenous cells amplifies the effect. The
benefits from this single, defined cell type suggest clinical potential
Trade bookbinding in the British Isles, 1660-1800 by Stuart Bennett
No full textreviewA review of "Trade Bookbinding in the British Isles, 1660-1800" by Stuart Bennett
Reading Stuart Elden’s The Birth of Territory
No full textThe Birth of Territory is an outstanding scholarly achievement, a book ‘of remarkable depth and breadth’, as noted by Alec Murphy in his comment, a book that already promises to become a ‘classic’ in geography, together with very few others published in the past decades. But Elden's book is also a difficult one to position within mainstream human geography. Its genealogical engagement with multiple sources/texts in various historical and linguistic contexts is far reaching, and it has very few precedents in the discipline—since it is deliberately inspired by the Cambridge school of contextual history, and the German tradition of Begriffsgeschichte, conceptual history. The Birth of Territory is also methodologically challenging, as its account of territory is carved out of a clear selection of ‘presences and absences’ operated by the author that, like all work of this kind, is open to criticism in relation to the strategies of inclusion/exclusion (of texts, concepts, people) adopted. What follows is a brief account of an Author meets Critics panel on The Birth of Territory held at the AAG Conference held in Tampa in April 2014
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