Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition.

Mutations of the tricarboxylic acid cycle enzyme fumarate hydratase cause hereditary leiomyomatosis and renal cell cancer. Fumarate hydratase-deficient renal cancers are highly aggressive and metastasize even when small, leading to a very poor clinical outcome. Fumarate, a small molecule metabolite that accumulates in fumarate hydratase-deficient cells, plays a key role in cell transformation, making it a bona fide oncometabolite. Fumarate has been shown to inhibit α-ketoglutarate-dependent dioxygenases that are involved in DNA and histone demethylation. However, the link between fumarate accumulation, epigenetic changes, and tumorigenesis is unclear. Here we show that loss of fumarate hydratase and the subsequent accumulation of fumarate in mouse and human cells elicits an epithelial-to-mesenchymal-transition (EMT), a phenotypic switch associated with cancer initiation, invasion, and metastasis. We demonstrate that fumarate inhibits Tet-mediated demethylation of a regulatory region of the antimetastatic miRNA cluster mir-200ba429, leading to the expression of EMT-related transcription factors and enhanced migratory properties. These epigenetic and phenotypic changes are recapitulated by the incubation of fumarate hydratase-proficient cells with cell-permeable fumarate. Loss of fumarate hydratase is associated with suppression of miR-200 and the EMT signature in renal cancer and is associated with poor clinical outcome. These results imply that loss of fumarate hydratase and fumarate accumulation contribute to the aggressive features of fumarate hydratase-deficient tumours.This work was supported by the Medical Research Council (UK). S.F. was supported by a Herchel Smith Research Studentship and K.F. by an MRC Career Development Award. E.R.M is supported by the ERC Advanced Researcher award 323004–ONCOTREAT. P.H.M. is supported by Senior Investigator Awards from the Wellcome Trust and NIHR. The Cambridge Human Research Tissue Bank and A.W. are supported by the NIHR Cambridge Biomedical Research Centre.This is the author accepted manuscript. The final version is available from Nature Publishing at http://dx.doi.org/10.1038/nature19353

Modification of neuropathic pain sensation through microglial ATP receptors

Neuropathic pain that typically develops when peripheral nerves are damaged through surgery, bone compression in cancer, diabetes, or infection is a major factor causing impaired quality of life in millions of people worldwide. Recently, there has been a rapidly growing body of evidence indicating that spinal glia play a critical role in the pathogenesis of neuropathic pain. Accumulating findings also indicate that nucleotides play an important role in neuron-glia communication through P2 purinoceptors. Damaged neurons release or leak nucleotides including ATP and UTP to stimulate microglia through P2 purinoceptors expressing on microglia. It was shown in an animal model of neuropathic pain that microglial P2X4 and P2X7 receptors are crucial in pain signaling after peripheral nerve lesion. In this review, we describe the modification of neuropathic pain sensation through microglial P2X4 and P2X7, with the possibility of P2Y6 and P2Y12 involvement

Plague and Climate: Scales Matter

Plague is enzootic in wildlife populations of small mammals in central and eastern Asia, Africa, South and North America, and has been recognized recently as a reemerging threat to humans. Its causative agent Yersinia pestis relies on wild rodent hosts and flea vectors for its maintenance in nature. Climate influences all three components (i.e., bacteria, vectors, and hosts) of the plague system and is a likely factor to explain some of plague's variability from small and regional to large scales. Here, we review effects of climate variables on plague hosts and vectors from individual or population scales to studies on the whole plague system at a large scale. Upscaled versions of small-scale processes are often invoked to explain plague variability in time and space at larger scales, presumably because similar scale-independent mechanisms underlie these relationships. This linearity assumption is discussed in the light of recent research that suggests some of its limitations

Roles of Microglial Phagocytosis and Inflammatory Mediators in the Pathophysiology of Sleep Disorders

Sleep serves crucial learning and memory functions in both nervous and immune systems. Microglia are brain immune cells that actively maintain health through their crucial physiological roles exerted across the lifespan, including phagocytosis of cellular debris and orchestration of neuroinflammation. The past decade has witnessed an explosive growth of microglial research. Considering the recent developments in the field of microglia and sleep, we examine their possible impact on various pathological conditions associated with a gain, disruption, or loss of sleep in this focused mini-review. While there are extensive studies of microglial implication in a variety of neuropsychiatric and neurodegenerative diseases, less is known regarding their roles in sleep disorders. It is timely to stimulate new research in this emergent and rapidly growing field of investigation.Peer reviewe

[Fcgamma receptor polymorphisms and systemic lupus erythematosus]

The G Immunoglobulin Fc Receptors (FcgammaR) belong to the TNFR5 receptors family, of the immunoglobulin superfamily and are widely expressed in the immune system; their function follows in importance after the complement receptors for immunocomplexes clearance. On the other hand, the systemic lupus erythematosus (SLE) is the prototype of the autoimmune diseases mediated by immunocomplexes and several studies have shown an impaired handle of these ones in part due to dysfunction of the FcgammaR. Among all types of Fcgamma receptors, the FcgammaRIIA, FcgammaRIIB, FcgammaRIIIA and FcgammaRIIIB have well characterized polymorphisms that produce an alteration in the receptor function. A number of studies have been done worldwide to probe an association between these polymorphism and SLE or some of its clinical features, among these the most important are two meta-analyses in which it is shown that the FcygammaRIIA-R131 polymorphism present a significant association with SLE susceptibility (OR: 1.3, 95% CI: 1.10-1.52), while the FcgammaRIIIA F176 polymorphism showed to be associated with lupic nephritis (OR: 1.47, 95% CI: 1.11-1.93, p = 0.006) but not with SLE susceptibility, the results in the rest of the polymorphisms studied are still contradictories. [References: 30

[Fcgamma receptor polymorphisms and systemic lupus erythematosus]

The G Immunoglobulin Fc Receptors (FcgammaR) belong to the TNFR5 receptors family, of the immunoglobulin superfamily and are widely expressed in the immune system; their function follows in importance after the complement receptors for immunocomplexes clearance. On the other hand, the systemic lupus erythematosus (SLE) is the prototype of the autoimmune diseases mediated by immunocomplexes and several studies have shown an impaired handle of these ones in part due to dysfunction of the FcgammaR. Among all types of Fcgamma receptors, the FcgammaRIIA, FcgammaRIIB, FcgammaRIIIA and FcgammaRIIIB have well characterized polymorphisms that produce an alteration in the receptor function. A number of studies have been done worldwide to probe an association between these polymorphism and SLE or some of its clinical features, among these the most important are two meta-analyses in which it is shown that the FcygammaRIIA-R131 polymorphism present a significant association with SLE susceptibility (OR: 1.3, 95% CI: 1.10-1.52), while the FcgammaRIIIA F176 polymorphism showed to be associated with lupic nephritis (OR: 1.47, 95% CI: 1.11-1.93, p = 0.006) but not with SLE susceptibility, the results in the rest of the polymorphisms studied are still contradictories. [References: 30