Polyunsaturated fatty acids in the pathogenesis and treatment of multiple sclerosis

Epidemiological, biochemical, animal model and clinical trial data described in this overview strongly suggest that polyunsaturated fatty acids, particularly n-6 fatty acids, have a role in the pathogenesis and treatment of multiple sclerosis (MS). Data presented provides further evidence for a disturbance in n-6 fatty acid metabolism in MS. Disturbance of n-6 fatty acid metabolism and dysregulation of cytokines are shown to be linked and a "proof of concept clinical trial" further supports such a hypothesis. In a randomised double-blind, placebo controlled trial of a high dose and low dose selected GLA (18:3n-6)-rich oil and placebo control, the high dose had a marked clinical effect in relapsing-remitting MS, significantly decreasing the relapse rate and the progression of disease. Laboratory findings paralleled clinical changes in the placebo group in that production of mononuclear cell pro-inflammatory cytokines (TNF-alpha, IL-1 beta) was increased and anti-inflammatory TGF-beta markedly decreased with loss of membrane n-6 fatty acids linoleic (18:2n-6) and arachidonic acids (20:4n-6). In contrast there were no such changes in the high dose group. The improvement in disability (Expanded Disability Status Scale) in the high dose suggests there maybe a beneficial effect on neuronal lipids and neural function in MS. Thus disturbed n-6 fatty acid metabolism in MS gives rise to loss of membrane long chain n-6 fatty acids and loss of the anti-inflammatory regulatory cytokine TGF-beta, particularly during the relapse phase, as well as loss of these important neural fatty acids for CNS structure and function and consequent long term neurological deficit in MS

Gravitational Radiation from Pulsating White Dwarfs

Rotating white dwarfs undergoing quasi-radial oscillations can emit gravitational radiation in a frequency range from 0.1 - 0.3 Hz. Assuming that the energy source for the gravitational radiation comes from the oblateness of the white dwarf induced by the rotation, the strain amplitude is found to be \sim 10^{-27} for a white dwarf at \sim 50 pc. The galactic population of these sources is estimated to be \sim 10^7, and may produce a confusion limited foreground for proposed advanced detectors in the frequency band between space-based and ground-based interferometers. Nearby oscillating white dwarfs may provide a clear enough signal to investigate white dwarf interiors through gravitational wave asteroseismology.Comment: Accepted for Astrophysical Journal Letters. Changed value of branching ratio resulting in an order of magnitude drop in gravitational wave amplitude

A practice-inspired mindset for researching the psychophysiological and medical health effects of recreational dance (dance pport)

“Dance” has been associated with many psychophysiological and medical health effects. However, varying definitions of what constitute “dance” have led to a rather heterogenous body of evidence about such potential effects, leaving the picture piecemeal at best. It remains unclear what exact parameters may be driving positive effects. We believe that this heterogeneity of evidence is partly due to a lack of a clear definition of dance for such empirical purposes. A differentiation is needed between (a) the effects on the individual when the activity of “dancing” is enjoyed as a dancer within different dance domains (e.g., professional/”high-art” type of dance, erotic dance, religious dance, club dancing, Dance Movement Therapy (DMT), and what is commonly known as hobby, recreational or social dance), and (b) the effects on the individual within these different domains, as a dancer of the different dance styles (solo dance, partnering dance, group dance; and all the different styles within these). Another separate category of dance engagement is, not as a dancer, but as a spectator of all of the above. “Watching dance” as part of an audience has its own set of psychophysiological and neurocognitive effects on the individual, and depends on the context where dance is witnessed. With the help of dance professionals, we first outline some different dance domains and dance styles, and outline aspects that differentiate them, and that may, therefore, cause differential empirical findings when compared regardless (e.g., amount of interpersonal contact, physical exertion, context, cognitive demand, type of movements, complexity of technique and ratio of choreography/improvisation). Then, we outline commonalities between all dance styles. We identify six basic components that are part of any dance practice, as part of a continuum, and review and discuss available research for each of them concerning the possible health and wellbeing effects of each of these components, and how they may relate to the psychophysiological and health effects that are reported for “dancing”: (1) rhythm and music, (2) sociality, (3) technique and fitness, (4) connection and connectedness (self-intimation), (5) flow and mindfulness, (6) aesthetic emotions and imagination. Future research efforts might take into account the important differences between types of dance activities, as well as the six components, for a more targeted assessment of how “dancing” affects the human body

Coevolved mutations reveal distinct architectures for two core proteins in the bacterial flagellar motor

Switching of bacterial flagellar rotation is caused by large domain movements of the FliG protein triggered by binding of the signal protein CheY to FliM. FliG and FliM form adjacent multi-subunit arrays within the basal body C-ring. The movements alter the interaction of the FliG C-terminal (FliGC) "torque" helix with the stator complexes. Atomic models based on the Salmonella entrovar C-ring electron microscopy reconstruction have implications for switching, but lack consensus on the relative locations of the FliG armadillo (ARM) domains (amino-terminal (FliGN), middle (FliGM) and FliGC) as well as changes during chemotaxis. The generality of the Salmonella model is challenged by the variation in motor morphology and response between species. We studied coevolved residue mutations to determine the unifying elements of switch architecture. Residue interactions, measured by their coevolution, were formalized as a network, guided by structural data. Our measurements reveal a common design with dedicated switch and motor modules. The FliM middle domain (FliMM) has extensive connectivity most simply explained by conserved intra and inter-subunit contacts. In contrast, FliG has patchy, complex architecture. Conserved structural motifs form interacting nodes in the coevolution network that wire FliMM to the FliGC C-terminal, four-helix motor module (C3-6). FliG C3-6 coevolution is organized around the torque helix, differently from other ARM domains. The nodes form separated, surface-proximal patches that are targeted by deleterious mutations as in other allosteric systems. The dominant node is formed by the EHPQ motif at the FliMMFliGM contact interface and adjacent helix residues at a central location within FliGM. The node interacts with nodes in the N-terminal FliGc α-helix triad (ARM-C) and FliGN. ARM-C, separated from C3-6 by the MFVF motif, has poor intra-network connectivity consistent with its variable orientation revealed by structural data. ARM-C could be the convertor element that provides mechanistic and species diversity.JK was supported by Medical Research Council grant U117581331. SK was supported by seed funds from Lahore University of Managment Sciences (LUMS) and the Molecular Biology Consortium

Nna1 Mediates Purkinje Cell Dendritic Development via Lysyl Oxidase Propeptide and NF-κB Signaling

SummaryThe molecular pathways controlling cerebellar Purkinje cell dendrite formation and maturation are poorly understood. The Purkinje cell degeneration (pcd) mutant mouse is characterized by mutations in Nna1, a gene discovered in an axonal regenerative context, but whose actual function in development and disease is unknown. We found abnormal development of Purkinje cell dendrites in postnatal pcdSid mice and linked this deficit to a deletion mutation in exon 7 of Nna1. With single cell gene profiling and virus-based gene transfer, we analyzed a molecular pathway downstream to Nna1 underlying abnormal Purkinje cell dendritogenesis in pcdSid mice. We discovered that mutant Nna1 dramatically increases intranuclear localization of lysyl oxidase propeptide, which interferes with NF-κB RelA signaling and microtubule-associated protein regulation of microtubule stability, leading to underdevelopment of Purkinje cell dendrites. These findings provide insight into Nna1's role in neuronal development and why its absence renders Purkinje cells more vulnerable