The neuro-immune pathophysiology of central and peripheral fatigue in systemic immune-inflammatory and neuro-immune diseases

Many patients with systemic immune-inflammatory and neuro-inflammatory disorders, including depression, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's disease, cancer, cardiovascular disorder, Parkinson's disease, multiple sclerosis, stroke, and chronic fatigue syndrome/myalgic encephalomyelitis, endure pathological levels of fatigue. The aim of this narrative review is to delineate the wide array of pathways that may underpin the incapacitating fatigue occurring in systemic and neuro-inflammatory disorders. A wide array of immune, inflammatory, oxidative and nitrosative stress (O&NS), bioenergetic, and neurophysiological abnormalities are involved in the etiopathology of these disease states and may underpin the incapacitating fatigue that accompanies these disorders. This range of abnormalities comprises: increased levels of pro-inflammatory cytokines, e.g., interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF) α and interferon (IFN) α; O&NS-induced muscle fatigue; activation of the Toll-Like Receptor Cycle through pathogen-associated (PAMPs) and damage-associated (DAMPs) molecular patterns, including heat shock proteins; altered glutaminergic and dopaminergic neurotransmission; mitochondrial dysfunctions; and O&NS-induced defects in the sodium-potassium pump. Fatigue is also associated with altered activities in specific brain regions and muscle pathology, such as reductions in maximum voluntary muscle force, downregulation of the mitochondrial biogenesis master gene peroxisome proliferator-activated receptor gamma coactivator 1-alpha, a shift to glycolysis and buildup of toxic metabolites within myocytes. As such, both mental and physical fatigue, which frequently accompany immune-inflammatory and neuro-inflammatory disorders, are the consequence of interactions between multiple systemic and central pathways.

Evolution of optogenetic microdevices

Implementation of optogenetic techniques is a recent addition to the neuroscientists' preclinical research arsenal, helping to expose the intricate connectivity of the brain and allowing for on-demand direct modulation of specific neural pathways. Developing an optogenetic system requires thorough investigation of the optogenetic technique and of previously fabricated devices, which this review accommodates. Many experiments utilize bench-top systems that are bulky, expensive, and necessitate tethering to the animal. However, these bench-top systems can make use of power-demanding technologies, such as concurrent electrical recording. Newer portable microdevices and implantable systems carried by freely moving animals are being fabricated that take advantage of wireless energy harvesting to power a system and allow for natural movements that are vital for behavioral testing and analysis. An investigation of the evolution of tethered, portable, and implantable optogenetic microdevices is presented, and an analysis of benefits and detriments of each system, including optical power output, device dimensions, electrode width, and weight is given. Opsins, light sources, and optical fiber coupling are also discussed to optimize device parameters and maximize efficiency from the light source to the fiber, respectively. These attributes are important considerations when designing and developing improved optogenetic microdevices.

The putative role of viruses, bacteria, and chronic fungal biotoxin exposure in the genesis of intractable fatigue accompanied by cognitive and physical disability

Patients who present with severe intractable apparently idiopathic fatigue accompanied by profound physical and or cognitive disability present a significant therapeutic challenge. The effect of psychological counseling is limited, with significant but very slight improvements in psychometric measures of fatigue and disability but no improvement on scientific measures of physical impairment compared to controls. Similarly, exercise regimes either produce significant, but practically unimportant, benefit or provoke symptom exacerbation. Many such patients are afforded the exclusionary, non-specific diagnosis of chronic fatigue syndrome if rudimentary testing fails to discover the cause of their symptoms. More sophisticated investigations often reveal the presence of a range of pathogens capable of establishing life-long infections with sophisticated immune evasion strategies, including Parvoviruses, HHV6, variants of Epstein-Barr, Cytomegalovirus, Mycoplasma, and Borrelia burgdorferi. Other patients have a history of chronic fungal or other biotoxin exposure. Herein, we explain the epigenetic factors that may render such individuals susceptible to the chronic pathology induced by such agents, how such agents induce pathology, and, indeed, how such pathology can persist and even amplify even when infections have cleared or when biotoxin exposure has ceased. The presence of active, reactivated, or even latent Herpes virus could be a potential source of intractable fatigue accompanied by profound physical and or cognitive disability in some patients, and the same may be true of persistent Parvovirus B12 and mycoplasma infection. A history of chronic mold exposure is a feasible explanation for such symptoms, as is the presence of B. burgdorferi. The complex tropism, life cycles, genetic variability, and low titer of many of these pathogens makes their detection in blood a challenge. Examination of lymphoid tissue or CSF in such circumstances may be warranted.

Lipid abundance in zebrafish embryos is regulated by complementary actions of the endocannabinoid system and retinoic acid pathway

The endocannabinoid system (ECS) and retinoic acid (RA) signaling have been associated with influencing lipid metabolism. We hypothesized that modulation of these pathways could modify lipid abundance in developing vertebrates and that these pathways could have a combinatorial effect on lipid levels. Zebrafish embryos were exposed to chemical treatments altering the activity of the ECS and RA pathway. Embryos were stained with the neutral lipid dye Oil-Red-O (ORO) and underwent whole-mount in situ hybridization. Mouse 3T3-L1 fibroblasts were differentiated under exposure to RA modulating chemicals and subsequently stained with ORO and analyzed for gene expression by qRT-PCR. ECS activation and RA exposure increased lipid abundance and the expression of lipoprotein lipase. Additionally, RA treatment increased expression of CCAAT/enhancer binding protein alpha. Both ECS receptors and RA receptor subtypes were separately involved in modulating lipid abundance. Finally, increased ECS or RA activity ameliorated the reduced lipid abundance caused by peroxisome proliferator-activated receptor gamma (PPARγ) inhibition. Therefore, the ECS and RA pathway influence lipid abundance in zebrafish embryos and have an additive effect when treated simultaneously. Furthermore, we demonstrated that these pathways act downstream or independently of PPARγ to influence lipid levels. Our study shows for the first time that the RA and ECS pathways have additive function in lipid abundance during vertebrate development.

CXCR4 Antagonism attenuates the development of diabetic cardiac fibrosis

Heart failure (HF) is an increasingly recognized complication of diabetes. Cardiac fibrosis is an important causative mechanism of HF associated with diabetes. Recent data indicate that inflammation may be particularly important in the pathogenesis of cardiovascular fibrosis. We sought to determine the mechanism by which cardiac fibrosis develops and to specifically investigate the role of the CXCR4 axis in this process. Animals with type I diabetes (streptozotocin treated mice) or type II diabetes (Israeli Sand-rats) and controls were randomized to treatment with a CXCR4 antagonist, candesartan or vehicle control. Additional groups of mice also underwent bone marrow transplantation (GFP+ donor marrow) to investigate the potential role of bone marrow derived cell mobilization in the pathogenesis of cardiac fibrosis. Both type I and II models of diabetes were accompanied by the development of significant cardiac fibrosis. CXCR4 antagonism markedly reduced cardiac fibrosis in both models of diabetes, similar in magnitude to that seen with candesartan. In contrast to candesartan, the anti-fibrotic actions of CXCR4 antagonism occurred in a blood pressure independent manner. Whilst the induction of diabetes did not increase the overall myocardial burden of GFP+ cells, it was accompanied by an increase in GFP+ cells expressing the fibroblast marker alpha-smooth muscle actin and this was attenuated by CXCR4 antagonism. CXCR4 antagonism was also accompanied by increased levels of circulating regulatory T cells. Taken together the current data indicate that pharmacological inhibition of CXCR4 significantly reduces diabetes induced cardiac fibrosis, providing a potentially important therapeutic approach.

Digital shimmer: popular music and the intimate nexus between fan and star

Conception of ‘star performance’ through popular music is stratified which generates diverse and often contradictory forms of thought. For example, stars and celebrities plausibly act as a ‘culture medium’ in which, through imagination, one’s identity is assembled, realised or constructed. What to become and how to be are questions we individually and collectively contend with throughout our lives to varying degrees (Maslow, 1954; 1968). Predominant use of digital technologies has seen the delivery of sound much altered. Music, be it Giuseppe Verdi’s La Traviata or Iron Maiden’s The Number of the Beast, once sourced via analogue legacy devices such as ‘old-school’ tape cassette or vinyl record is now a series of zero and one digits. Advocates argue that the key benefit of digitalisation is the ability to compress data because sound generates large files of information. The discourse of digitalisation begs the question of how a series of ones and zeros, albeit in a plethora of configurations, registers with listening bodies and affects ‘the sublime’. It is without doubt that some musical experiences afford indescribable, unlocatable sensation—even enchantment (as defined by Bennett, 2001: 5 and called forth by Redmond: 2014: 126). Such musical experiences might be in the presence of the performer or in their absence such as in the case of recorded music. In this context, any sense of ’real’ space and place is less definitive allowing for ‘special encounters’ to be imagined and felt. For these reasons, music and all that the use of the word might convey, the proposed notion of phaino-ken here, acts as the lens through which to examine the meaning and value of celebrity and star embodiment.

New insights from geolocators deployed on waders in Australia

Geolocators were deployed on waders in Australia for a third successive year, in Feb/Apr 2011 including on Eastern Curlew and Sanderling for the first time. Retrieval rates, in the 2011/12 austral summer, varied markedly between species. Technical performance of the geolocators was better than in previous years. However units on Greater Sand Plovers, migrating to breeding grounds in the Gobi Desert, China/Mongolia, again behaved erratically, and exhibited symptoms suggesting extraneous electromagnetic interference. Generally, for each species studied, the results confirm earlier indications that the first step of northward migration from Australia is a long non-stop flight. Subsequent movements to breeding areas are usually shorter with up to three stopovers in SE Asia or Siberia. Similarly southward migration strategies include at least one long nonstop flight, though this is usually the second (or later) leg of the journey. The timing of migration appears to be particularly related to breeding latitude. Eastern Curlews, which breed at relatively southern latitudes, depart from SE Australia from early March, reach the breeding grounds and lay eggs in April, set off on return migration in early June and, after a long stopover in the Yellow Sea, arrive back in SE Australia in early August. In contrast arctic-breeding Ruddy Turnstones do not depart from SE Australia until mid/late April and do not arrive back at their non-breeding locations until October, with the last individuals (which have taken a trans-Pacific route) not returning until late November/early December. Recorded migration speeds (assuming the birds take a great circle route) were quite variable, ranging from 32 to 84 km/h, presumably due to wind conditions. They generally averaged nearer to 50 km/h rather than the 60–70 km/h which waders are known to be capable of achieving and which has been the basis of some past flight range calculations.

A very short fairly interesting and reasonably cheap book about studying leadership

In teaching you how to critically appraise and work with leadership theories rather than faithfully accept them, this book will not merely make you a better student of leadership; it could make you a better leader too.

AHS classics: Australia and the First World War: the First World War in Australian history

This article introduces the first volume of AHS Classics: Australia and the First World War. It surveys the critical scholarship on the Australian experience of war, taking its cue from Ken Inglis' seminal article, ‘The Anzac Tradition’ (1965), and tracing the development of his challenge to Australian historians over the following five decades. It argues that the adaptability of the Anzac legend, and its assimilation of varied experiences of the First World War, requires both investigation and caution in the production of new histories of events almost a century distant.

The deleterious effects of oxidative and nitrosative stress on palmitoylation, membrane lipid rafts and lipid-based cellular signalling : new drug targets in neuroimmune disorders

Oxidative and nitrosative stress (O&NS) is causatively implicated in the pathogenesis of Alzheimer’s and Parkinson’s disease, multiple sclerosis, chronic fatigue syndrome, schizophrenia and depression. Many of the consequences stemming from O&NS, including damage to proteins, lipids and DNA, are well known, whereas the effects of O&NS on lipoprotein-based cellular signalling involving palmitoylation and plasma membrane lipid rafts are less well documented. The aim of this narrative review is to discuss the mechanisms involved in lipid-based signalling, including palmitoylation, membrane/lipid raft (MLR) and n-3 polyunsaturated fatty acid (PUFA) functions, the effects of O&NS processes on these processes and their role in the abovementioned diseases. S-palmitoylation is a post-translational modification, which regulates protein trafficking and association with the plasma membrane, protein subcellular location and functions. Palmitoylation and MRLs play a key role in neuronal functions, including glutamatergic neurotransmission, and immune-inflammatory responses. Palmitoylation, MLRs and n-3 PUFAs are vulnerable to the corruptive effects of O&NS. Chronic O&NS inhibits palmitoylation and causes profound changes in lipid membrane composition, e.g. n-3 PUFA depletion, increased membrane permeability and reduced fluidity, which together lead to disorders in intracellular signal transduction, receptor dysfunction and increased neurotoxicity. Disruption of lipid-based signalling is a source of the neuroimmune disorders involved in the pathophysiology of the abovementioned diseases. n-3 PUFA supplementation is a rational therapeutic approach targeting disruptions in lipid-based signalling.

Zinc doped ferrite magnetic resonance imaging contrast agent for atherosclerosis

 This project focuses on the development of zinc doped ferrite nanoparticle based MRI contrast agents with enhanced contrast and site-specific targeting for atherosclerosis diagnosis. The engineered nanocomplexes developed were validated through MRI scans using rat models with potential for multimodal imaging and effective therapy.

"Cancer 2015": a prospective, population-based cancer cohort-phase 1: feasibility of genomics-guided precision medicine in the clinic

"Cancer 2015" is a longitudinal and prospective cohort. It is a phased study whose aim was to pilot recruiting 1000 patients during phase 1 to establish the feasibility of providing a population-based genomics cohort. Newly diagnosed adult patients with solid cancers, with residual tumour material for molecular genomics testing, were recruited into the cohort for the collection of a dataset containing clinical, molecular pathology, health resource use and outcomes data. 1685 patients have been recruited over almost 3 years from five hospitals. Thirty-two percent are aged between 61-70 years old, with a median age of 63 years. Diagnostic tumour samples were obtained for 90% of these patients for multiple parallel sequencing. Patients identified with somatic mutations of potentially "actionable" variants represented almost 10% of those tumours sequenced, while 42% of the cohort had no mutations identified. These genomic data were annotated with information such as cancer site, stage, morphology, treatment and patient outcomes and health resource use and cost. This cohort has delivered its main objective of establishing an upscalable genomics cohort within a clinical setting and in phase 2 aims to develop a protocol for how genomics testing can be used in real-time clinical decision-making, providing evidence on the value of precision medicine to clinical practice.