If it’s not one thing, HIF’s another : immunoregulation by hypoxia inducible factors in disease

Hypoxia‐inducible factors (HIFs) have emerged in recent years as critical regulators of immunity. Localised, low oxygen tension is a hallmark of inflamed and infected tissues. Subsequent myeloid cell HIF stabilisation plays key roles in the innate immune response, alongside emerging oxygen‐independent roles. Manipulation of regulatory proteins of the HIF transcription factor family can profoundly influence inflammatory profiles, innate immune cell function and pathogen clearance and, as such, has been proposed as a therapeutic strategy against inflammatory diseases. The direction and mode of HIF manipulation as a therapy are dictated by the inflammatory properties of the disease in question, with innate immune cell HIF reduction being, in general, advantageous during chronic inflammatory conditions, while upregulation of HIF is beneficial during infections. The therapeutic potential of targeting myeloid HIFs, both genetically and pharmacologically, has been recently illuminated in vitro and in vivo , with an emerging range of inhibitory and activating strategies becoming available. This review focuses on cutting edge findings that uncover the roles of myeloid cell HIF signalling on immunoregulation in the contexts of inflammation and infection and explores future directions of potential therapeutic strategies

Tribbles1 is host protective during in vivo mycobacterial infection

Tuberculosis is a major global health problem and is one of the top 10 causes of death worldwide. There is a pressing need for new treatments that circumvent emerging antibiotic resistance. Mycobacterium tuberculosis parasitises macrophages, reprogramming them to establish a niche in which to proliferate, therefore macrophage manipulation is a potential host-directed therapy if druggable molecular targets could be identified. The pseudokinase Tribbles1 (Trib1) regulates multiple innate immune processes and inflammatory profiles making it a potential drug target in infections. Trib1 controls macrophage function, cytokine production, and macrophage polarisation. Despite wide-ranging effects on leukocyte biology, data exploring the roles of Tribbles in infection in vivo are limited. Here, we identify that human Tribbles1 is expressed in monocytes and is upregulated at the transcript level after stimulation with mycobacterial antigen. To investigate the mechanistic roles of Tribbles in the host response to mycobacteria in vivo, we used a zebrafish Mycobacterium marinum (Mm) infection tuberculosis model. Zebrafish Tribbles family members were characterised and shown to have substantial mRNA and protein sequence homology to their human orthologues. trib1 overexpression was host-protective against Mm infection, reducing burden by approximately 50%. Conversely, trib1 knockdown/knockout exhibited increased infection. Mechanistically, trib1 overexpression significantly increased the levels of proinflammatory factors il-1β and nitric oxide. The host-protective effect of trib1 was found to be dependent on the E3 ubiquitin kinase Cop1. These findings highlight the importance of Trib1 and Cop1 as immune regulators during infection in vivo and suggest that enhancing macrophage TRIB1 levels may provide a tractable therapeutic intervention to improve bacterial infection outcomes in tuberculosis

Human Disease/Clinical Medical Sciences in Dentistry: Current state and future development of undergraduate assessments in the UK and Ireland

Introduction The United Kingdom and Ireland teachers of Human Disease/Clinical Medical Science for Dentistry (HD/CMSD) group continues to work together, and most recently collaborated to review current and future assessments. Materials and methods The first part of the review of assessments in HD/CMSD took place at a face‐to‐face meeting with presentations from delegates on assessments in their home institutions. The second, and larger part, comprised an online survey where all eighteen schools in the UK and Ireland participated. Results All schools had some element of formative assessment, and the majority had a stand‐alone summative assessment at the end of the HD/CMSD teaching block. Most schools had a written paper and practical elements to their assessments, most commonly a combination of a multiple‐choice type question combined with an objective structured clinical examination (OSCE). There was a trend towards the use of single best answer (SBA) questions and a willingness among participants to share a question bank. All schools incorporated elements of HD/CMSD in their final examinations. Discussion & Conclusion This collaboration promoted the sharing of developments in assessment for HD/CMSD and demonstrated a willingness to co‐operate between institutions. Assessment in HD/CMSD in the UK and Ireland continues to be refined by those responsible for its content and delivery and assessment methods are progressing following evidence‐based best practice

The antagonist and synergist potential of cholinium-based deep eutectic solvents

The design of environmentally friendlier solvents has gained increasing relevance in the last decade. Deep eutectic solvents (DES) have recently emerged, with advantages like low-cost and putative lower environmental impact. However, information about DES toxicity is still scarce. This work aims to contribute to profiling the ecotoxicity of DES based on cholinium chloride ([Chol]Cl). Six DES were addressed, combining [Chol]Cl (as hydrogen bond acceptor - HBA) with ethylene glycol, glycerol, 1,2-propanediol, propionic acid, 1-propanol, and urea as hydrogen bond donors (HBD), in different molar ratios. The Microtox® Acute Toxicity Test, was used for assessing their toxicity towards the marine bacteria Allivibrio fischeri . Because the dissociation of DES in water is expected, analysis appraising the mixtures toxicity theory should be considered, which is a step forward in this field. This analysis suggested that [Chol]Cl and all HBD with the exception of propionic acid:[Chol]Cl 1:2 and 4:1 behave antagonistically, which is contrary to what has been suggested previously. The most extreme cases are Urea:[Chol]Cl and 1-Propanol:[Chol]Cl, with EC50 values higher than their starting materials dosed singly, configuring very promising and biocompatible alternative solvents. Toxicity was found to be dependent on DES composition, as well as on molar proportions of the starting materials.publishe

Managing to lead in private enterprise in China: Work values, demography and the development of trust

Previous work on trust has focused on employee trust in management. However, issues of how leaders develop trust in their followers in leader-member exchange (LMX) are under-explored. Based on theories of leader-member exchange, attribution and industrial convergence, this study investigates how the work values of leaders influence the development of their trust in followers and how this is moderated by demographic factors. A survey of 219 leaders was conducted in privately owned enterprises in China. The findings suggest that the work value of centralization is negatively related to leader trust in follower predictability. Group orientation and formalization are positively related to the development of trust in follower good faith. Moreover, age and level of formal education are found to moderate significantly the relationships between leader work values and development of their trust in followers within the context of China. Copyright © 2007 SAGE Publications

Sustratos de cobertura y suplementación del compost en cultivo de champiñón

El objetivo de este trabajo fue describir el comportamiento de la corteza de pino, de la fibra de coco y del sustrato postcultivo, como capas de cobertura, en el cultivo del champiñón (Agaricus bisporus). Tras la caracterización física, química y biológica de las capas de cobertura, se evaluaron los parámetros de producción cualitativos y cuantitativos, en un ciclo de cultivo de champiñón con cuatro floradas. La menor porosidad y capacidad de retención de agua del suelo mineral, sin aditivos, y la alta conductividad eléctrica del sustrato postcultivo del champiñón utilizado, asociado a la suplementación nutritiva, son los factores determinantes en el diferente comportamiento agronómico observado. Las mezclas de cobertura influenciaron el rendimiento y el número de champiñones, la eficiencia biológica, la tasa de producción y la precocidad. El mejor rendimiento total se obtuvo con la mezcla de suelo mineral y fibra de coco suplementado. Las capas de coberturas evaluadas pueden ser utilizadas comercialmente para la producción de champiñón

Gendering the careers of young professionals: some early findings from a longitudinal study. in Organizing/theorizing: developments in organization theory and practice

Wonders whether companies actually have employees best interests at heart across physical, mental and spiritual spheres. Posits that most organizations ignore their workforce – not even, in many cases, describing workers as assets! Describes many studies to back up this claim in theis work based on the 2002 Employment Research Unit Annual Conference, in Cardiff, Wales

Search for Tensor, Vector, and Scalar Polarizations in the Stochastic Gravitational-Wave Background

The detection of gravitational waves with Advanced LIGO and Advanced Virgo has enabled novel tests of general relativity, including direct study of the polarization of gravitational waves. While general relativity allows for only two tensor gravitational-wave polarizations, general metric theories can additionally predict two vector and two scalar polarizations. The polarization of gravitational waves is encoded in the spectral shape of the stochastic gravitational-wave background, formed by the superposition of cosmological and individually unresolved astrophysical sources. Using data recorded by Advanced LIGO during its first observing run, we search for a stochastic background of generically polarized gravitational waves. We find no evidence for a background of any polarization, and place the first direct bounds on the contributions of vector and scalar polarizations to the stochastic background. Under log-uniform priors for the energy in each polarization, we limit the energy densities of tensor, vector, and scalar modes at 95% credibility to Ω0T<5.58×10-8, Ω0V<6.35×10-8, and Ω0S<1.08×10-7 at a reference frequency f0=25 Hz. © 2018 American Physical Society