Characterisation of the responses, and possible mechanisms behind, spontaneous phasic activity in the isolated guinea pig bladder

Spontaneous and volume induced phasic activity in the isolated guinea pig bladder is generated and modulated by a complex interaction of opposing excitatory and inhibitory stimuli. Although the exact nature and location of these mechanisms are not known, they represent local mechanisms inherent to the wall of the bladder. It has been suggested that phasic activity represents a component of afferent activity involved in the generation of sensation. Evaluation of the effects of the M3 specific muscarinic antagonist 4-DAMP have identified cholinergic mechanisms involved in the generation of pacemaker activity that are sensitive to the effects of M3 antagonism. It is therefore suggested that antimuscarinics exert their clinical effects upon sensation through this mechanism.The intrinsic characteristics of spontaneous, phasic activity in response to volume have also revealed a period of inhibition following volume reduction termed the inhibitory phase. This is dependant upon the magnitude and duration of volume increase prior to decrease and is regulated by a distinct mechanism comprising of a combination of excitatory and inhibitory stimuli co-ordinated by ganglia. It can manipulated by anticholinergic medication, nicotinic antagonists and purinergic agonists suggesting its underlying generation and regulation to be complex.The actions of hexamethonium and pancuronium upon phasic activity have suggested the presence of non-ganglionic nicotinic receptors involved in the modulation of spontaneous and volume induced activity; in addition to the role of ganglia in co-ordinating the return of activity during the inhibitory phase.Purinoceptors were found to display a varied and complex response, both on pacemaker activity and upon the inhibitory phase. Both excitatory and inhibitory receptors were present; however, individual subtypes seemed to display a differing degree of functional relevance between low and high volume. Though P2X and P2Y may have excitatory and inhibitory effects respectively, the overall effect of purinergic receptor stimulation upon phasic activity is inhibitory.The data obtained during the course of these experiments illustrate the mechanisms involved in the generation and co-ordination of spontaneous activity to be complex. It highlights novel mechanisms through which acetylcholine and adenosine triphosphate may be exerting an effect, and may account for the therapeutic actions of anticholinergic medications. It also highlights potential mechanisms which may act as further therapeutic targets in the development of newer drugs for the treatment of OAB

It\u27s All Dark But He\u27s Not Afraid: Translations of Stories by Ingvar Ambjornsen

This thesis consists of English translations of two short stories by the Norwegian novelist, essayist and short-story writer Ingvar Ambjornsen, with an introduction in which special problems and challenges associated with the individual stories, and with the two languages in general, are discussed. The two stories translated are Into the Mountain (original title: Bergtatt ) and The Cherry Tree (original title: Kirsebaertreet ). Both are taken from Ambjornsen\u27s 2005 collection Delvis til stede

The actin binding proteins cortactin and HS1 are dispensable for platelet actin nodule and megakaryocyte podosome formation

A dynamic, properly organised actin cytoskeleton is critical for the production and haemostatic function of platelets. The Wiskott Aldrich Syndrome protein (WASp) and Actin-Related Proteins 2 & 3 Complex (Arp2/3 complex) are critical mediators of actin polymerisation and organisation in many cell types. In platelets and megakaryocytes, these proteins have been shown to be important for proper platelet production and function. The cortactin family of proteins (Cttn & HS1) are known to regulate WASp-Arp2/3-mediated actin polymerisation in other cell types and so here we address the role of these proteins in platelets using knockout mouse models. We generated mice lacking Cttn and HS1 in the megakaryocyte/platelet lineage. These mice had normal platelet production, with platelet number, size and surface receptor profile comparable to controls. Platelet function was also unaffected by loss of Cttn/HS1 with no differences observed in a range of platelet function assays including aggregation, secretion, spreading, clot retraction or tyrosine phosphorylation. No effect on tail bleeding time or in thrombosis models was observed. In addition, platelet actin nodules, and megakaryocyte podosomes, actin-based structures known to be dependent on WASp and the Arp2/3 complex, formed normally. We conclude that despite the importance of WASp and the Arp2/3 complex in regulating F-actin dynamics in many cells types, the role of cortactin in their regulation appears to be fulfilled by other proteins in platelets

Overactive bladder syndrome in the ageing population

Overactive bladder syndrome (OAB) is a common problem in the older age group that can seriously effect quality of life. It raises challenges in the assessment and treatment of the patient with attention needed to be given to the presence of co-existent disease, cognition, patient motivation and the potential negative effects of pharmacological treatment. Though with the correct approach a substantial amount patients should derive some benefit

Curriculum innovation:reflection on MSci Integrated Masters with Industrial Experience

An emerging curriculum innovation within UK Higher Education is MSci Integrated Masters with Industrial Experience. However, we know little about how such programmes may be designed based on feedback and insights from its three main stakeholders: employers, students, and academics. In this paper we reflect on our ongoing work for curriculum development and evaluation, focusing on the MSci Computer Science at Lancaster University. We report on 15 interviews with employers offering placements, MSci students, and academics supervising them. We focus on the critical issue of matching interests and competencies across the three stakeholders to construct industry placements, while allowing for the negotiation of their mutual benefits. Findings also highlight stakeholders’ perceived placement’s challenges and ways of addressing them. We conclude with several suggestions for the MSci curriculum development including mechanisms for managing stakeholders’ expectations, recognising companies’ contributions, strengthening academics’ engagement during placements, and ensuring effective matching process among companies providing placements, students and academics

Bottom-Up Forcing And The Decline of Steller Sea Lions (Eumetopias jubatus) In Alaska: Assessing The Ocean Climate Hypothesis

Declines of Steller sea lion ( Eumetopias jubatus) populations in the Aleutian Islands and Gulf of Alaska could be a consequence of physical oceanographic changes associated with the 1976–77 climate regime shift. Changes in ocean climate are hypothesized to have affected the quantity, quality, and accessibility of prey, which in turn may have affected the rates of birth and death of sea lions. Recent studies of the spatial and temporal variations in the ocean climate system of the North Pacific support this hypothesis. Ocean climate changes appear to have created adaptive opportunities for various species that are preyed upon by Steller sea lions at mid-trophic levels. The east–west asymmetry of the oceanic response to climate forcing after 1976–77 is consistent with both the temporal aspect (populations decreased after the late 1970s) and the spatial aspect of the decline (western, but not eastern, sea lion populations decreased). These broad-scale climate variations appear to be modulated by regionally sensitive biogeographic structures along the Aleutian Islands and Gulf of Alaska, which include a transition point from coastal to open-ocean conditions at Samalga Pass westward along the Aleutian Islands. These transition points delineate distinct clusterings of different combinations of prey species, which are in turn correlated with differential population sizes and trajectories of Steller sea lions. Archaeological records spanning 4000 yr further indicate that sea lion populations have experienced major shifts in abundance in the past. Shifts in ocean climate are the most parsimonious underlying explanation for the broad suite of ecosystem changes that have been observed in the North Pacific Ocean in recent decades. [ABSTRACT FROM AUTHOR] Copyright of Fisheries Oceanography is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder\u27s express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.

Torsional Force Microscopy of Van der Waals Moir\'es and Atomic Lattices

In a stack of atomically-thin Van der Waals layers, introducing interlayer twist creates a moir\'e superlattice whose period is a function of twist angle. Changes in that twist angle of even hundredths of a degree can dramatically transform the system's electronic properties. Setting a precise and uniform twist angle for a stack remains difficult, hence determining that twist angle and mapping its spatial variation is very important. Techniques have emerged to do this by imaging the moir\'e, but most of these require sophisticated infrastructure, time-consuming sample preparation beyond stack synthesis, or both. In this work, we show that Torsional Force Microscopy (TFM), a scanning probe technique sensitive to dynamic friction, can reveal surface and shallow subsurface structure of Van der Waals stacks on multiple length scales: the moir\'es formed between bilayers of graphene and between graphene and hexagonal boron nitride (hBN), and also the atomic crystal lattices of graphene and hBN. In TFM, torsional motion of an AFM cantilever is monitored as the it is actively driven at a torsional resonance while a feedback loop maintains contact at a set force with the surface of a sample. TFM works at room temperature in air, with no need for an electrical bias between the tip and the sample, making it applicable to a wide array of samples. It should enable determination of precise structural information including twist angles and strain in moir\'e superlattices and crystallographic orientation of VdW flakes to support predictable moir\'e heterostructure fabrication.Comment: 28 pages, 14 figures including supplementary material

Chemotaxis: a feedback-based computational model robustly predicts multiple aspects of real cell behaviour

The mechanism of eukaryotic chemotaxis remains unclear despite intensive study. The most frequently described mechanism acts through attractants causing actin polymerization, in turn leading to pseudopod formation and cell movement. We recently proposed an alternative mechanism, supported by several lines of data, in which pseudopods are made by a self-generated cycle. If chemoattractants are present, they modulate the cycle rather than directly causing actin polymerization. The aim of this work is to test the explanatory and predictive powers of such pseudopod-based models to predict the complex behaviour of cells in chemotaxis. We have now tested the effectiveness of this mechanism using a computational model of cell movement and chemotaxis based on pseudopod autocatalysis. The model reproduces a surprisingly wide range of existing data about cell movement and chemotaxis. It simulates cell polarization and persistence without stimuli and selection of accurate pseudopods when chemoattractant gradients are present. It predicts both bias of pseudopod position in low chemoattractant gradients and-unexpectedly-lateral pseudopod initiation in high gradients. To test the predictive ability of the model, we looked for untested and novel predictions. One prediction from the model is that the angle between successive pseudopods at the front of the cell will increase in proportion to the difference between the cell's direction and the direction of the gradient. We measured the angles between pseudopods in chemotaxing Dictyostelium cells under different conditions and found the results agreed with the model extremely well. Our model and data together suggest that in rapidly moving cells like Dictyostelium and neutrophils an intrinsic pseudopod cycle lies at the heart of cell motility. This implies that the mechanism behind chemotaxis relies on modification of intrinsic pseudopod behaviour, more than generation of new pseudopods or actin polymerization by chemoattractant

Urological cancer care pathways: development and use in the context of systematic reviews and clinical practice guidelines

Background: Making healthcare treatment decisions is a complex process involving a broad stakeholder base including patients, their families, health professionals, clinical practice guideline developers and funders of healthcare. Methods: This paper presents a review of a methodology for the development of urological cancer care pathways (UCAN care pathways), which reflects an appreciation of this broad stakeholder base. The methods section includes an overview of the steps in the development of the UCAN care pathways and engagement with clinical content experts and patient groups. Results: The development process is outlined, the uses of the urological cancer care pathways discussed and the implications for clinical practice highlighted. The full set of UCAN care pathways is published in this paper. These include care pathways on localised prostate cancer, locally advanced prostate cancer, metastatic prostate cancer, hormone-resistant prostate cancer, localised renal cell cancer, advanced renal cell cancer, testicular cancer, penile cancer, muscle invasive and metastatic bladder cancer and non-muscle invasive bladder cancer. Conclusion: The process provides a useful framework for improving urological cancer care through evidence synthesis, research prioritisation, stakeholder involvement and international collaboration. Although the focus of this work is urological cancers, the methodology can be applied to all aspects of urology and is transferable to other clinical specialties.11 page(s