5,015 research outputs found
Low Affinity GPCRs for Metabolic Intermediates: Challenges for Pharmacologists
The discovery that a number of metabolites and metabolic intermediates can act through G protein-coupled receptors has attracted great interest in the field and has led to new therapeutic targets for diseases such as hypertension, type 2 diabetes, inflammation, and metabolic syndrome. However, the low apparent affinity of these ligands for their cognate receptors poses a number of challenges for pharmacologists interested in investigating receptor structure, function or physiology. Furthermore, the endogenous ligands matched to their receptors have other, well established metabolic roles and thus selectivity is difficult to achieve. This review discusses some of the issues researchers face when working with these receptors and highlights the ways in which a number of these obstacles have been overcome
Photoactivatable metal complexes : from theory to applications in biotechnology and medicine
This short review highlights some of the exciting new experimental and theoretical developments in the field of photoactivatable metal complexes and their applications in biotechnology and medicine. The examples chosen are based on some of the presentations at the Royal Society Discussion Meeting in June 2012, many of which are featured in more detail in other articles in this issue. This is a young field. Even the photochemistry of well-known systems such as metal–carbonyl complexes is still being elucidated. Striking are the recent developments in theory and computation (e.g. time-dependent density functional theory) and in ultrafast-pulsed radiation techniques which allow photochemical reactions to be followed and their mechanisms to be revealed on picosecond/nanosecond time scales. Not only do some metal complexes (e.g. those of Ru and Ir) possess favourable emission properties which allow functional imaging of cells and tissues (e.g. DNA interactions), but metal complexes can also provide spatially controlled photorelease of bioactive small molecules (e.g. CO and NO)—a novel strategy for site-directed therapy. This extends to cancer therapy, where metal-based precursors offer the prospect of generating excited-state drugs with new mechanisms of action that complement and augment those of current organic photosensitizers
The APOBEC3 genes and their role in cancer: insights from human papillomavirus
The interaction between human papillomaviruses (HPV) and the apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC)3 (A3) genes has garnered increasing attention in recent years, with considerable efforts focused on understanding their apparent roles in both viral editing and in HPV-driven carcinogenesis. Here we review these developments and highlight several outstanding questions in the field. We consider whether editing of the virus and mutagenesis of the host are linked, or whether both are essentially separate events, coincidentally mediated by a common, or distinct A3 enzymes. We discuss the viral mechanisms and cellular signalling pathways implicated in A3 induction in virally-infected cells, examine which of the A3 enzymes might play the major role in HPV-associated carcinogenesis and in the development of therapeutic resistance. We consider the parallels between A3 induction in HPV-infected cells and what might be causing aberrant A3 activity in HPV-independent cancers such as those arising in the bladder, lung and breast. Finally, we discuss the implications of ongoing A3 activity in tumours under treatment and the therapeutic opportunities that this may present
Changing the mindset:An innovative work-based learning programme within an English higher education institution
This paper aims to explore and critically analyse the perceptions and experiences of academics in relation to the design and delivery of an innovative Work Based Learning (WBL) programme within an English higher education institution (HEI). These perceptions were gathered through semi-structured interviews and subjected to discourse analysis. Consequently, the key themes which have emerged are: (i) the intensity of the learning experience, (ii) the tensions and pressures amongst academics delivering the programme, for example an expectation that academics „get it right first time‟, and (iii) learning support for students. The paper concludes with recommendations for future policy and research
Working with the patient and clinical community to deliver clinical research in cystic fibrosis. James Lind CF Phase II
This is a protocol which sets out the aims, objectives and commitments of the second phase of the James Lind Alliance Priority Setting Partnership in Cystic Fibrosis and the basic roles and responsibilities of the partners therein.
The James Lind Alliance Priority Setting Partnership in cystic fibrosis was carried out in 2016 using a robust and widely accepted methodology to develop the top 10 questions for clinical research in CF, through discussions with both the clinical and patient community.
We now aim to explore four of the top ten questions from this process and develop them into a series of testable hypotheses for clinical research. Where the hypothesis will be tested in a clinical trial, we will develop a PICO question for each hypothesis (Population, Intervention, Comparator & Outcome).
We will use online surveys and focus groups to achieve our aim
Interactome comparison of human embryonic stem cell lines with the inner cell mass and trophectoderm
Networks of interacting co-regulated genes distinguish the inner cell mass (ICM) from the
differentiated trophectoderm (TE) in the preimplantation blastocyst, in a species specific manner. In mouse the ground state pluripotency of the ICM appears to be maintained in murine embryonic stem cells (ESCs) derived from the ICM. This is not the case for human ESCs. In order to gain insight into this phenomenon, we have used quantitative network analysis to identify how similar human (h)ESCs are to the human ICM. Using the hESC lines MAN1, HUES3 and HUES7 we have shown that all have only a limited overlap with ICM specific gene expression, but that this overlap is enriched for network
properties that correspond to key aspects of function including transcription factor activity and the hierarchy of network modules. These analyses provide an important framework which highlights the developmental origins of hESCs
Tinker, tailor, policy-maker: can the UK government’s teaching excellence framework deliver its objectives?
The Teaching Excellence Framework (TEF), originally proposed in the UK government’s Higher Education White Paper, now the Higher Education and Research Act 2017, is a national mechanism to assess teaching quality in universities. This article provides a critical account of the TEF, underpinned by an overview of the policy context and marketisation and employability agendas exploring the rationale for implementing TEF within universities. We argue, first, that the White Paper’s narrative, the rhetoric of the TEF, seems positive but its implementation appears to be conceptually flawed. Second, its complex quality metrics system demands yet another layer of bureaucracy in an already micro-managed system of higher education. Third, claims made by the White Paper must be supported by evidence-based research to ensure that the objectives are clear. We conclude by questioning whether the quality of the student experience can be improved by the TEF reforms
Origin of ferroelectricity in the multiferroic barium fluorides BaMF4
We present a first principles study of the series of multiferroic barium
fluorides with the composition BaMF4, where M is Mn, Fe, Co, or Ni. We discuss
trends in the structural, electronic, and magnetic properties, and we show that
the ferroelectricity in these systems results from the "freezing in" of a
single unstable polar phonon mode. In contrast to the case of the standard
perovskite ferroelectrics, this structural distortion is not accompanied by
charge transfer between cations and anions. Thus, the ferroelectric instability
in the multiferroic barium fluorides arises solely due to size effects and the
special geometrical constraints of the underlying crystal structure.Comment: 8 pages, 6 figures, 3 table
Hydrogen bonding and coordination in normal and supercritical water from X-ray inelastic scattering
A direct measure of hydrogen bonding in water under conditions ranging from
the normal state to the supercritical regime is derived from the Compton
scattering of inelastically-scattered X-rays. First, we show that a measure of
the number of electrons involved in hydrogen bonding at varying
thermodynamic conditions can be directly obtained from Compton profile
differences. Then, we use first-principles simulations to provide a connection
between and the number of hydrogen bonds . Our study shows that
over the broad range studied the relationship between and is
linear, allowing for a direct experimental measure of bonding and coordination
in water. In particular, the transition to supercritical state is characterized
by a sharp increase in the number of water monomers, but also displays a
significant number of residual dimers and trimers.Comment: 14 pages, 5 figures, 1 tabl
IL-21 receptor expression in human tendinopathy
The pathogenetic mechanisms underlying tendinopathy remain unclear,
with much debate as to whether inflammation or degradation has the prominent
role. Increasing evidence points toward and early inflammatory infiltrate and
associated inflammatory cytokine production in human and animal models of
tendon disease.
The IL-21/IL-21R axis is a proinflammatory cytokine complex that has
been associated with chronic inflammatory diseases including rheumatoid
arthritis and inflammatory bowel disease. This project aimed to investigate the
role and expression of the cytokine/receptor pair IL-21/IL-21R in human
tendinopathy.
We found significantly elevated expression of IL-21 receptor message and
protein in human tendon samples but found no convincing evidence of the
presence of IL-21 at message or protein level. The level of expression of IL-21R
message/protein in human tenocytes was significantly up regulated by
proinflammatory cytokines (TNFα/IL-1β) in vitro.
These findings demonstrate that IL-21R is present in early human
tendinopathy mainly expressed by tenocytes and macrophages. Despite a lack of
IL-21 expression these data again suggest that early tendinopathy has an
inflammatory/cytokine phenotype, which may provide novel translational targets
in the treatment of tendinopathy
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