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Colonial lives across the British Empire : imperial careering in the long nineteenth century
This volume tells the stories of men and women who dwelt for extended periods in one colonial space before moving on to others, developing 'imperial careers'. Their histories constituted meaningful connections across the empire that facilitated the continual reformulation of imperial discourses and cultures.
Book
The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential
Key Points
Nociceptin/orphanin FQ (N/OFQ) is the first example of a peptide that was isolated by reverse pharmacology.
N/OFQ activates a G
i
-protein-coupled receptor, NOP, and this peptide–receptor system has been implicated in a diverse range of biological functions including (but not limited to) pain, reward/drug abuse, cardiovascular control and immune function.
Many peptide and non-peptide ligands are available. The main chemical classes of the current non-peptides are morphinans (for example, buprenorphine; mixed); aminoquinolines (for example, JTC-801; antagonist); benzimidazopiperidines (for example, J-113397; antagonist); aryl-piperidines (for example, SB-612111; antagonist); and spiropiperidines (for example, Ro64-6198; agonist).
Central NOP antagonists have, variably, antinociceptive (supraspinal), and antidepressant effects. Central NOP agonists have anti-opioid (supraspinal), antinociceptive (spinal), anxiolytic effects and produce bradycardia/hypotension.
Peripheral NOP agonists have antinociceptive, vasodilatory and aquaretic effects. They also produce bardycardia and hypotension, and inhibit bladder activity.
A small number of molecules are in clinical development: ZP120, a peptide in Phase I and II for congestive heart failure, and JTC-801, a non-peptide antagonist in Phase II for pain.
In this Review, Lambert describes the physiology and potential clinical applications of nociceptin/orphanin FQ and its receptor. This peptide–receptor system has been implicated in a wide range of biological functions such as pain, drug abuse, cardiovascular control and immunity.
Identification of the enigmatic nociceptin/orphanin FQ peptide (N/OFQ) in 1995 represented the first successful use of reverse pharmacology and led to deorphanization of the N/OFQ receptor (NOP). Subsequently, the N/OFQ–NOP system has been implicated in a wide range of biological functions, including pain, drug abuse, cardiovascular control and immunity. Although this could be considered a hurdle for the development of pharmaceuticals selective for a specific disease indication, NOP represents a viable drug target. This article describes potential clinical indications and highlights the current status of the very limited number of clinical trials.
Journal Article
Signalling pathways involved in urotensin II induced ventricular myocyte hypertrophy
Sustained pathologic myocardial hypertrophy can result in heart failure(HF); a significant health issue affecting a large section of the population worldwide. In HF there is a marked elevation in circulating levels of the peptide urotensin II(UII) but it is unclear whether this is a result of hypertrophy or whether the high levels contribute to the development of hypertrophy. The aim of this study is to investigate a role of UII and its receptor UT in the development of cardiac hypertrophy and the signalling molecules involved. Ventricular myocytes isolated from adult rat hearts were treated with 200nM UII for 48hours and hypertrophy was quantified from measurements of length/width (L/W) ratio. UII resulted in a change in L/W ratio from 4.53±0.10 to 3.99±0.06; (p<0.0001) after 48hours. The response is reversed by the UT-antagonist SB657510 (1μM). UT receptor activation by UII resulted in the activation of ERK1/2, p38 and CaMKII signalling pathways measured by Western blotting; these are involved in the induction of hypertrophy. JNK was not involved. Moreover, ERK1/2, P38 and CaMKII inhibitors completely blocked UII-induced hypertrophy. Sarcoplasmic reticulum (SR) Ca 2+ -leak was investigated in isolated myocytes. There was no significant increase in SR Ca 2+ -leak. Our results suggest that activation of MAPK and CaMKII signalling pathways are involved in the hypertrophic response to UII. Collectively our data suggest that increased circulating UII may contribute to the development of left ventricular hypertrophy and pharmacological inhibition of the UII/UT receptor system may prove beneficial in reducing adverse remodeling and alleviating contractile dysfunction in heart disease.
Journal Article
Knowledge and the future school : curriculum and social justice
\"Written at a time of uncertainty about the implications of the English government's curriculum policies, Knowledge and the Future School engages with the debate between the government and large sections of the educational community. It provides a forward-looking framework for head teachers, their staff and those training teachers to use when developing the curriculum of individual schools in the context of a national curriculum. While explaining recent ideas in the sociology of educational knowledge, the authors draw on Michael Young's earlier research to distinguish three models of the curriculum in terms of their assumptions about knowledge, referred to in this book as Future 1, Future 2 and Future 3. They link Future 3 to the idea of 'powerful knowledge' for all pupils as a curriculum principle for any school, arguing that the question of knowledge is intimately linked to the issue of social justice and that access to 'powerful knowledge' is a necessary starting point for the education of all pupils. Knowledge and the Future School offers a new way of thinking about the problems that head teachers, their staff and curriculum designers face. In charting a course for schools that goes beyond current debates, it provides a perspective that policy makers should not avoid\"-- Provided by publisher.
Book
Achieving Human Potential Through Geography Education: A Capabilities Approach to Curriculum Making in Schools
This article provides the theoretical underpinnings for an innovative international collaborative project in the field of geography education named GeoCapabilities. The project attempts to respond in new ways to enduring challenges facing geography teachers in schools. These include the need to find convincing expression of geography's contribution to the education of all young people and coping with the apparent divergence of geography in educational settings and its highly disparate expression as a research discipline in university departments. The project also hopes to contribute to the development of a framework for communicating the aims and purposes of geography in schools internationally, because here, too, there is great variety in definitions of national standards and even of disciplinary allegiances (including, e.g., the social studies, humanities, and biological sciences). GeoCapabilities does not seek to flatten such divergences, for one of geography's great strengths is its breadth. The long-term goal is to establish a secure platform for the international development of teachers' capacities as creative and disciplined innovators. The project encourages teachers to think beyond program delivery and implementation and to embrace their role as the curriculum makers.
Journal Article
Help your kids with geography : a unique step-by-step visual guide
\"Perplexed by plate tectonics? Confused by climates? Disorientated by demographics? Help Your Kids With Geography helps parents to get a grasp on what their children learn in geography class by exploring all these topics and more.\"--Publisher's description.
BOOK
Biased versus Partial Agonism in the Search for Safer Opioid Analgesics
Opioids such as morphine—acting at the mu opioid receptor—are the mainstay for treatment of moderate to severe pain and have good efficacy in these indications. However, these drugs produce a plethora of unwanted adverse effects including respiratory depression, constipation, immune suppression and with prolonged treatment, tolerance, dependence and abuse liability. Studies in β-arrestin 2 gene knockout (βarr2(−/−)) animals indicate that morphine analgesia is potentiated while side effects are reduced, suggesting that drugs biased away from arrestin may manifest with a reduced-side-effect profile. However, there is controversy in this area with improvement of morphine-induced constipation and reduced respiratory effects in βarr2(−/−) mice. Moreover, studies performed with mice genetically engineered with G-protein-biased mu receptors suggested increased sensitivity of these animals to both analgesic actions and side effects of opioid drugs. Several new molecules have been identified as mu receptor G-protein-biased agonists, including oliceridine (TRV130), PZM21 and SR–17018. These compounds have provided preclinical data with apparent support for bias toward G proteins and the genetic premise of effective and safer analgesics. There are clinical data for oliceridine that have been very recently approved for short term intravenous use in hospitals and other controlled settings. While these data are compelling and provide a potential new pathway-based target for drug discovery, a simpler explanation for the behavior of these biased agonists revolves around differences in intrinsic activity. A highly detailed study comparing oliceridine, PZM21 and SR–17018 (among others) in a range of assays showed that these molecules behave as partial agonists. Moreover, there was a correlation between their therapeutic indices and their efficacies, but not their bias factors. If there is amplification of G-protein, but not arrestin pathways, then agonists with reduced efficacy would show high levels of activity at G-protein and low or absent activity at arrestin; offering analgesia with reduced side effects or ‘apparent bias’. Overall, the current data suggests—and we support—caution in ascribing biased agonism to reduced-side-effect profiles for mu-agonist analgesics.
Journal Article
Opioid immunomodulation – an enigma?
[...]a retrospective analysis suggested patients presenting for breast cancer surgery had better survival with paravertebral block compared to those who received general anesthesia [5]. With respect to immune function classical opioids (like the archetypal clinical ligand, morphine) have been shown to inhibit the activity of a wide range of immune cells. [...]using mice that were knock out for MOP receptor it was shown that immune function is not critically regulated by tone at this receptor [20]. The NOP receptor can be modulated in situations mimicking clinical immune challenge, for example in vitro sepsis [30]. [...]we have shown that some immune cells can produce and release the native peptide agonist for NOP, Nociceptin/Orphanin FQ (N/OFQ) [31]. [...]differences between human and experimental animal data and time courses of action make this target also controversial. There is an interesting series of papers showing that some opioids can interact with TLR4 receptors; not all and enantioselectivity is not the same as for classical opioid receptors. [...]this response is naloxone sensitive; the sensitivity is weak [19, 33, 34].
Journal Article
Growth and morphogenesis of the gastropod shell
Gastropod shell morphologies are famously diverse but generally share a common geometry, the logarithmic coil. Variations on this morphology have been modeled mathematically and computationally but the developmental biology of shell morphogenesis remains poorly understood. Here we characterize the organization and growth patterns of the shell-secreting epithelium of the larval shell of the basket whelk Tritia (also known as Ilyanassa). Despite the larval shell’s relative simplicity, we find a surprisingly complex organization of the shell margin in terms of rows and zones of cells. We examined cell division patterns with EdU incorporation assays and found two growth zones within the shell margin. In the more anterior aperture growth zone, we find that inferred division angles are biased to lie parallel to the shell edge, and these divisions occur more on the margin’s left side. In the more posterior mantle epithelium growth zone, inferred divisions are significantly biased to the right, relative to the anterior–posterior axis. These growth zones, and the left–right asymmetries in cleavage patterns they display, can explain the major modes of shell morphogenesis at the level of cellular behavior. In a gastropod with a different coiling geometry, Planorbella sp., we find similar shell margin organization and growth zones as Tritia, but different left–right asymmetries than we observed in the helically coiled shell of Tritia. These results indicate that differential growth patterns in the mantle edge epithelium contribute to shell shape in gastropod shells and identify cellular mechanisms that may vary to generate shell diversity in evolution.
Journal Article