Mitochondrion to endoplasmic reticulum apposition length in zebrafish embryo spinal progenitors is unchanged in response to perturbations associated with Alzheimer’s disease

Published: June 21, 2017Mutations in the human genes PRESENILIN1 (PSEN1), PRESENILIN2 (PSEN2) and AMYLOID BETA A4 PRECURSOR PROTEIN (APP) have been identified in familial Alzheimer's disease (AD). The length of mitochondrion-endoplasmic reticulum (M-ER) appositions is increased in Psen1-/-/Psen2-/- double knockout murine embryonic fibroblasts and in fibroblasts from AD-affected individuals. Development of an easily accessible, genetically manipulable, in vivo system for studying M-ER appositions would be valuable so we attempted to manipulate M-ER apposition length in zebrafish (Danio rerio) embryos. We injected fertilized zebrafish eggs with antisense morpholino oligonucleotides (MOs) that inhibit expression of zebrafish familial AD gene orthologues psen1 and psen2. Furthermore, we treated zebrafish embryos with DAPT (a highly specific γ-secretase inhibitor) or with sodium azide (to mimic partially hypoxic conditions). We then analyzed M-ER apposition in an identified, presumably proliferative neural cell type using electron microscopy. Our analysis showed no significant differences in M-ER apposition lengths at 48 hours post fertilization (hpf) between psen1 & psen2 MO co-injected embryos, embryos treated with DAPT, or sodium azide, and control embryos. Instead, the distribution of M-ER apposition lengths into different length classes was close to identical. However, this indicates that it is feasible to reproducibly measure M-ER size distributions in zebrafish embryos. While our observations differ from those of murine and human studies, this may be due to differences in cellular differentiation and metabolic state, cell age, or species-specific responses. In particular, by focusing on a presumably proliferative embryonic cell type, we may have selected a cell heavily already reliant on anaerobic glycolysis and less responsive to factors affecting M-ER apposition. Future examination of more differentiated, more secretory cell types may reveal measurable responses of M-ER apposition to environmental and genetic manipulation.Morgan Newman, Lena Halter, Anne Lim, Michael Lardell

Design and implementation of an electro-optical backplane with pluggable in-plane connectors

The design, implementation and characterisation of an electro-optical backplane and an active pluggable in-plane optical connector technology is presented. The connection architecture adopted allows line cards to be mated to and unmated from a passive electro-optical backplane with embedded polymeric waveguides. The active connectors incorporate a photonics interface operating at 850 nm and a mechanism to passively align the interface to the optical waveguides embedded in the backplane. A demonstration platform has been constructed to assess the viability of embedded electro-optical backplane technology in dense data storage systems. The demonstration platform includes four switch cards, which connect both optically and electronically to the electro-optical backplane in a chassis. These switch cards are controlled by a single board computer across a Compact PCI bus on the backplane. The electrooptical backplane is comprised of copper layers for power and low speed bus communication and one polymeric optical layer, wherein waveguides have been patterned by a direct laser writing scheme. The optical waveguide design includes densely arrayed multimode waveguides with a centre to centre pitch of 250μm between adjacent channels, multiple cascaded waveguide bends, non-orthogonal crossovers and in-plane connector interfaces. In addition, a novel passive alignment method has been employed to simplify high precision assembly of the optical receptacles on the backplane. The in-plane connector interface is based on a two lens free space coupling solution, which reduces susceptibility to contamination. Successful transfer of 10.3 Gb/s data along multiple waveguides in the electro-optical backplane has been demonstrated and characterised

Uptake of advanced clinical practice roles in the health service in England: perspectives at the micro level

Health care organisations in many countries are developing advanced clinical practitioner roles to address workforce shortages and growing demand for services. Even in countries where advanced practice roles are more established there are low numbers, clustered in a limited range of professions, mostly nursing specialities. Successful implementation of national policies encouraging increased advanced practice roles and from a broader range of professions, requires attention to all levels of the health system. There is a lack of evidence as to the motivation to take-up these roles at the micro, individual actor level. This study explored the motivations important at the micro level in influencing a range of health professionals to undertake advanced practice roles. The study used an interpretive methodology with thematic analysis and was framed by theories of motivational domains in the work environment. Semi-structured interviews were undertaken with eighteen advanced clinical practitioners working in health care organisations in England. The motivators for role take-up were found to be predominantly intrinsic reflecting participants’ desires for advancement, both personal and for their profession, and improved efficiency of patient care. Participants described experiencing limited organisational support and sometimes discouragement from other professionals. There is potential for health organisations at the meso level of health care systems to support national growth of advanced practice roles by giving attention to the motivations of diverse health professionals. We propose a new theoretical framework of motivators for advanced clinical practice role uptake at the micro level

Retaining nurses in metropolitan areas: insights from senior nurse and human resource managers.

AIM: To investigate the views of senior nurse and human resource managers of strategies to retain hospital nurses in a metropolitan area. BACKGROUND: Against a global shortage, retaining nurses is a management imperative for the quality of hospital services. METHOD: Semi-structured interviews, thematically analysed. RESULTS: Metropolitan areas have many health organisations in geographical proximity, offering nurses choices in employer and employment. Senior nurse and human resource managers recognised the complexity of factors influencing nurse turnover, including those that 'pulled' nurses out of their jobs to other posts and factors that 'pushed' nurses to leave. Four themes emerged in retaining nurses: strategy and leadership, including analysis of workforce and leavers' data, remuneration, the type of nursing work and career development and the immediate work environment. CONCLUSIONS: In contexts where multiple organisations compete for nurses, addressing retention through strategic leadership is likely to be important in paying due attention and apportioning resources to effective strategies. IMPLICATIONS FOR NURSING MANAGEMENT: Aside from good human resource management practices for all, strategies tailored to different segments of the nursing workforce are likely to be important. This metropolitan study suggests attention should be paid to strategies that address remuneration, progressing nursing careers and the immediate work environment

A simple computer program for calculating stress and strain rate in 2D viscous inclusion-matrix systems

Computer-based numerical solutions of geomechanical problems are important to understand the processes forming rock structures as well as to quantify the associated pressure, stresses and strain rates. However, the development of such computer programs and the underlying mathematical methods are commonly not taught in a standard structural geology curriculum. Here, we present a simple computer program to calculate the stress, pressure, velocity and strain rate fields for two-dimensional (2D) viscous inclusion-matrix systems under pure shear and simple shear. The main aim of our contribution is to explain this computer program in a simple and transparent way, so that it can be used for introductory courses on geomechanical numerical modelling in structural geology. We present the governing equations of 2D viscous deformation and program the equations in the same order and style, so that the equations are still recognizable in the computer program. The computer program can treat stiff and weak inclusions of any shape and considers both linear and power-law viscous flow laws. We present numerical calculations for various inclusion-matrix scenarios. The program is written with the software MATLAB, is provided as supplementary material, and can also be run with the freely available software GNU Octave

Optimal Experiment Design and Leveraging Competition for Shared Resources in Cell-Free Extracts

The fact that genes compete for shared cellular resources poses a fundamental challenge when identifying parameters of genetic parts. A recently developed model of gene expression tackles this problem by explicitly accounting for resource competition. In addition to accurately describing experimental data, this model only depends on a small number of easily identifiable parameters with clear physical interpretation. Based on this model, we outline a procedure to select the optimal set of experiments to characterize biomolecular parts in synthetic biology. Additionally, we reveal the role competition for shared resources plays, provide guidelines how to minimize its detrimental effects, and how to leverage this phenomenon to extract the most information about unknown parameters. To illustrate the results, we consider the case of part characterization in cell-free extracts, treat plasmid DNA concentrations as decision variables, and demonstrate the significant performance difference between naive and optimal experiment design

A simple method for the determination of refractive indices of (rough) transparent solids

Simple methods for the determination of refractive indices of transparent polymers and inorganic and organic solids of irregular geometry or with scratched or corrugated surfaces are rare. A classical procedure is based on the invisibility of a body immersed in a liquid with the same refractive index as that of the body. In order to avoid the laborious procedure connected with the search for a liquid with matching refractive index and to find an approach which is independent of the observation by eye, we describe here a modified immersion method which allows the ready determination of the refractive index of solids. The present method is based on the interpolation of the maximum transmission (nTmax) of a solid immersed in liquids with different, typically non-matching, refractive indices. Illustrations with quartz glass, crown glass and poly(vinylidene fluoride) (PVDF) films showed that nTmax can be determined with a reproducibility of ± 0.003. By comparison with refractive indices determined by ellipsometry, it was concluded that the refractive index of a solid can be determined with the modified immersion method within an accuracy better than ± 0.01 when systematic errors resulting from the fit method are also taken into consideratio

Bodin and Althusius on the nature of sovereignty

Shows how Bodin's theory of absolute sovereignty and Althusius' doctrine of popular sovereignty both lead to the notion of constitutional law which is binding on the sovereign

Are advanced clinical practice roles in England’s National Health Service a remedy for workforce problems? A qualitative study of senior staff perspectives

Objective: A major issue facing all health systems is improving population health while at the same time responding to both growing patient numbers and needs and developing and retaining the health care workforce. One policy response to workforce shortages has been the development of advanced clinical practice roles. In the context of an English national policy promoting such roles in the health service, we explored senior managers’ and senior clinicians’ perceptions of factors at the organization level that support or inhibit the introduction of advanced clinical practice roles. The investigation was framed by theories of the diffusion of innovation and the system of professions. Methods: We conducted a qualitative interview study of 39 senior manager and clinicians in 19 National Health Service acute, community, mental health and ambulance organizations across a metropolitan area in 2019. Results: Small numbers of advanced clinical practice roles were reported, often in single services. Four main influences were identified in the development of advanced clinical practice roles: staff shortages (particularly of doctors in training grades) combined with rising patient demand, the desire to retain individual experienced staff, external commissioners or purchasers of services looking to shape services in line with national policy, and commissioner-funded new roles in new ambulatory care services and primary care. Three factors were reported as enabling the roles: finance for substantive posts, evidence of value of the posts, and structural support within the organization. Three factors were perceived as inhibiting developing the roles: confusion and lack of knowledge amongst clinicians and managers, the availability of finance for the roles, and a nervousness (sometimes resistance) to introducing the new roles. Conclusions: While the national policy was to promote advanced clinical practice roles, the evidence suggested there was and would continue to be limited implementation at the operational level. Development scenarios that introduced new monies for such roles reduced some of the inhibiting factors. However, where the introduction of roles required funding to move from one part of a service to another, and potentially from one staff group to another, the growth of these roles was and is likely to be contested. In such scenarios, research and business evidence of relative advantage will be important, as too will be supporters in powerful positions. The paucity of publicly available evidence on the effectiveness of advanced clinical practice roles across the specialties and professions in the context requires urgent attention

Atypisches Erythema induratum Bazin bei tuberkulöser Osteomyelitis

Zusammenfassung: Hauttuberkulosen können sich mit sehr unterschiedlichen klinischen Bildern manifestieren und damit die Diagnosestellung erschweren. Wir stellen den Fall einer 79-jährigen Patientin vor, mit einer atypischen Präsentation eines Erythema induratum Bazin (EIB) am Oberkörper und einer tuberkulösen Osteomyelitis des Olekranon links. Aus den Biopsien der EIB-Knoten konnte M.tuberculosis kulturell nachgewiesen werden. Das widerspricht der klassischen Vorstellung, dass das EIB als Folge einer Hypersensitivitätsreaktion auf Mykobakterien entsteht, und unterstützt die Hypothese, dass das EIB auch durch eine hämatogene oder lymphogene Streuung von lebenden M.tuberculosis entstehen kan