Beekeeping adoption : A case study of three smallholder farming communities in Baringo County, Kenya

Peer reviewedPublisher PD

Naked mole-rat cortical neurons are resistant to acid-induced cell death.

Regulation of brain pH is a critical homeostatic process and changes in brain pH modulate various ion channels and receptors and thus neuronal excitability. Tissue acidosis, resulting from hypoxia or hypercapnia, can activate various proteins and ion channels, among which acid-sensing ion channels (ASICs) a family of primarily Na+ permeable ion channels, which alongside classical excitotoxicity causes neuronal death. Naked mole-rats (NMRs, Heterocephalus glaber) are long-lived, fossorial, eusocial rodents that display remarkable behavioral/cellular hypoxia and hypercapnia resistance. In the central nervous system, ASIC subunit expression is similar between mouse and NMR with the exception of much lower expression of ASIC4 throughout the NMR brain. However, ASIC function and neuronal sensitivity to sustained acidosis has not been examined in the NMR brain. Here, we show with whole-cell patch-clamp electrophysiology of cultured NMR and mouse cortical and hippocampal neurons that NMR neurons have smaller voltage-gated Na+ channel currents and more hyperpolarized resting membrane potentials. We further demonstrate that acid-mediated currents in NMR neurons are of smaller magnitude than in mouse, and that all currents in both species are reversibly blocked by the ASIC antagonist benzamil. We further demonstrate that NMR neurons show greater resistance to acid-induced cell death than mouse neurons. In summary, NMR neurons show significant cellular resistance to acidotoxicity compared to mouse neurons, contributing factors likely to be smaller ASIC-mediated currents and reduced NaV activity

Epigenome-wide Association Studies and the Interpretation of Disease -Omics

Epigenome-wide association studies represent one means of applying genome-wide assays to identify molecular events that could be associated with human phenotypes. The epigenome is especially intriguing as a target for study, as epigenetic regulatory processes are, by definition, heritable from parent to daughter cells and are found to have transcriptional regulatory properties. As such, the epigenome is an attractive candidate for mediating long-term responses to cellular stimuli, such as environmental effects modifying disease risk. Such epigenomic studies represent a broader category of disease -omics, which suffer from multiple problems in design and execution that severely limit their interpretability. Here we define many of the problems with current epigenomic studies and propose solutions that can be applied to allow this and other disease -omics studies to achieve their potential for generating valuable insights

Storageless and caching Tier-2 models in the UK context

Operational and other pressures have lead to WLCG experiments moving increasingly to a stratified model for Tier-2 resources, where ``fat" Tier-2s (``T2Ds") and ``thin" Tier-2s (``T2Cs") provide different levels of service. In the UK, this distinction is also encouraged by the terms of the current GridPP5 funding model. In anticipation of this, testing has been performed on the implications, and potential implementation, of such a distinction in our resources. In particular, this presentation presents the results of testing of storage T2Cs, where the ``thin" nature is expressed by the site having either no local data storage, or only a thin caching layer; data is streamed or copied from a ``nearby" T2D when needed by jobs. In OSG, this model has been adopted successfully for CMS AAA sites; but the network topology and capacity in the USA is significantly different to that in the UK (and much of Europe). We present the result of several operational tests: the in-production University College London (UCL) site, which runs ATLAS workloads using storage at the Queen Mary University of London (QMUL) site; the Oxford site, which has had scaling tests performed against T2Ds in various locations in the UK (to test network effects); and the Durham site, which has been testing the specific ATLAS caching solution of ``Rucio Cache" integration with ARC's caching layer

The overthrow of Pedro II of Brazil: An explanation as provided by an examination of some contemporary novels

Traditional explanations for the overthrow of the monarchy in Brazil, and its replacement by a Republic, have never seemed entirely satisfactory. Some, indeed, have seemed contradicted by both the expectation and the experience of the Republic. I have, therefore, attempted to find additional evidence from non-traditional historical sources, namely, the novels of the 20-year span preceding the toppling of Pedro II. To begin, I considered the legitimacy of using fiction as a source for explaining political fact, and was convinced that this principle behind the thesis was sound. I next examined the "traditional" explanations with two purposes in mind; firstly, to see if individually or in concert they provided grounds for what was outwardly a radical change in political direction, and, secondly, to illustrate the historical context in which authors were writing, to highlight the "burning issues" of their societies. Then I made a more particular review of the literary context in which they operated. Subsequently, I examined six authors and fifteen of their novels; the authors were selected on the basis of their contemporary literary popularity and critical acclaim, and were equally divided between the early 1870s and the late 1880s; the novels were selected with regard to their date of publication. My objective was to consider the themes to which each novel addressed itself, with a view to identifying which themes were common to which authors, how the themes differed between authors and over time, and to determine what conclusions could be drawn from this evidence. In the broadest terms what this examination revealed was that far from being radical, the establishment of a Republican system of government was made possible by a widespread desire within the elite group to forestall and limit social change. Authors represented this desire in an increasingly critical account of the values they perceived in their contemporary society, and the existing order was held implicitly, and often explicitly, to blame for the deterioration. But although the 1880s group differed from their predecessors, they struck no accord amongst themselves either; so while they wished change, it was couched in terms of opposition to the existing order without a coherent alternative being expounded. Further, the later group tend to display anti-social behaviour as fundamental to human-kind whereas the 1870s group saw it more as aberrant and peculiar to individuals. In short, the desire for political change stemmed from a wish to halt the deterioration in society's values (in the authors' perception) and the form that change was to take was determined by the perceived need for control of people rather than exhortations to individuals. A new and firmer order was required than Pedro II seemed able or willing to dictate

Acid-sensing ion channel 3: An analgesic target.

Acid-sensing ion channel 3 (ASIC3) belongs to the epithelial sodium channel/degenerin (ENaC/DEG) superfamily. There are 7 different ASIC subunits encoded by 5 different genes. Most ASIC subunits form trimeric ion channels that upon activation by extracellular protons mediate a transient inward current inducing cellular excitability. ASIC subunits exhibit differential tissue expression and biophysical properties, and the ability of subunits to form homo- and heteromeric trimers further increases the complexity of currents measured and their pharmacological properties. ASIC3 is of particular interest, not only because it exhibits high expression in sensory neurones, but also because upon activation it does not fully inactivate: a transient current is followed by a sustained current that persists during a period of extracellular acidity, i.e. ASIC3 can encode prolonged acidosis as a nociceptive signal. Furthermore, certain mediators sensitize ASIC3 enabling smaller proton concentrations to activate it and other mediators can directly activate the channel at neutral pH. Moreover, there is a plethora of evidence using transgenic mouse models and pharmacology, which supports ASIC3 as being a potential target for development of analgesics. This review will focus on current understanding of ASIC3 function to provide an overview of how ASIC3 contributes to physiology and pathophysiology, examining the mechanisms by which it can be modulated, and highlighting gaps in current understanding and future research directions.Work in the Smith Lab is supported by Versus Arthritis Research Grant (RG21973) and Biotechnology and Biological Sciences Research Council grant (BB/R006210/1)

Evolution of acid nociception: ion channels and receptors for detecting acid.

Nociceptors, i.e. sensory neurons tuned to detect noxious stimuli, are found in numerous phyla of the Animalia kingdom and are often polymodal, responding to a variety of stimuli, e.g. heat, cold, pressure and chemicals, such as acid. Owing to the ability of protons to have a profound effect on ionic homeostasis and damage macromolecular structures, it is no wonder that the ability to detect acid is conserved across many species. To detect changes in pH, nociceptors are equipped with an assortment of different acid sensors, some of which can detect mild changes in pH, such as the acid-sensing ion channels, proton-sensing G protein-coupled receptors and several two-pore potassium channels, whereas others, such as the transient receptor potential vanilloid 1 ion channel, require larger shifts in pH. This review will discuss the evolution of acid sensation and the different mechanisms by which nociceptors can detect acid. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.Versus Arthritis (RG21973) University of Cambridge BBSRC Doctoral Training Programme (BB/M011194/1

Human visceral nociception: findings from translational studies in human tissue.

Peripheral sensitization of nociceptors during disease has long been recognized as a leading cause of inflammatory pain. However, a growing body of data generated over the last decade has led to the increased understanding that peripheral sensitization is also an important mechanism driving abdominal pain in highly prevalent functional bowel disorders, in particular, irritable bowel syndrome (IBS). As such, the development of drugs that target pain-sensing nerves innervating the bowel has the potential to be a successful analgesic strategy for the treatment of abdominal pain in both organic and functional gastrointestinal diseases. Despite the success of recent peripherally restricted approaches for the treatment of IBS, not all drugs that have shown efficacy in animal models of visceral pain have reduced pain end points in clinical trials of IBS patients, suggesting innate differences in the mechanisms of pain processing between rodents and humans and, in particular, how we model disease states. To address this gap in our understanding of peripheral nociception from the viscera and the body in general, several groups have developed experimental systems to study nociception in isolated human tissue and neurons, the findings of which we discuss in this review. Studies of human tissue identify a repertoire of human primary afferent subtypes comparable to rodent models including a nociceptor population, the targeting of which will shape future analgesic development efforts. Detailed mechanistic studies in human sensory neurons combined with unbiased RNA-sequencing approaches have revealed fundamental differences in not only receptor/channel expression but also peripheral pain pathways.Non

Characterization of cutaneous and articular sensory neurons

Background: A wide range of stimuli can activate sensory neurons and neurons innervating specific tissues often have distinct properties. Here we used retrograde tracing to identify sensory neurons innervating the hind paw skin (cutaneous) and ankle/knee joints (articular), and combined immunohistochemistry and electrophysiology analysis to determine the neurochemical phenotype of cutaneous and articular neurons, as well as their electrical and chemical excitability. Results: Immunohistochemistry analysis using RetroBeads as a retrograde tracer confirmed previous data that cutaneous and articular neurons are a mixture of myelinated and unmyelinated neurons, and the majority of both populations are peptidergic. In whole-cell patch-clamp recordings from cultured dorsal root ganglion neurons, voltage-gated inward currents and action potential parameters were largely similar between articular and cutaneous neurons, although cutaneous neuron action potentials had a longer half-peak duration. An assessment of chemical sensitivity showed that all neurons responded to a pH 5.0 solution, but that acid-sensing ion channel (ASIC) currents, determined by inhibition with the non-selective ASIC antagonist benzamil, were of a greater magnitude in cutaneous compared to articular neurons. 40 – 50% of cutaneous and articular neurons responded to capsaicin, cinnamaldehyde and menthol, indicating similar expression levels of TRPV1, TRPA1 and TRPM8 respectively. By contrast, significantly more articular neurons responded to ATP than cutaneous neurons. Conclusion: This work makes a detailed characterization of cutaneous and articular sensory neurons, and highlights the importance of making recordings from identified neuronal populations: sensory neurons innervating different tissues have subtly different properties, possibly reflecting different functions.ISS was funded by an Erasmus for Graduate Students grant from the University of Coimbra. ZMAH and experiments were funded by an Arthritis Research Project Grant (Grant Reference 20930) to ESS. JDB was funded by a Corpus Christi College Study and Travel Grant. EStJS was funded by an Early Career Research Grant from the International Association for the Study of Pain. Thanks to Christoforos Tsantoulas for assistance with immunohistochemistry and members of the Smith lab for their technical assistance and help in preparing the manuscript.This is the final version of the article. It first appeared from SAGE via http://dx.doi.org/10.1177/174480691663638