The determinants of transverse tubular volume in resting skeletal muscle.

The transverse tubular (t)-system of skeletal muscle couples sarcolemmal electrical excitation with contraction deep within the fibre. Exercise, pathology and the composition of the extracellular fluid (ECF) can alter t-system volume (t-volume). T-volume changes are thought to contribute to fatigue, rhabdomyolysis and disruption of excitation-contraction coupling. However, mechanisms that underlie t-volume changes are poorly understood. A multicompartment, history-independent computer model of rat skeletal muscle was developed to define the minimum conditions for t-volume stability. It was found that the t-system tends to swell due to net ionic fluxes from the ECF across the access resistance. However, a stable t-volume is possible when this is offset by a net efflux from the t-system to the cell and thence to the ECF, forming a net ion cycle ECF→t-system→sarcoplasm→ECF that ultimately depends on Na(+)/K(+)-ATPase activity. Membrane properties that maximize this circuit flux decrease t-volume, including PNa(t) > PNa(s), PK(t) < PK(s) and N(t) < N(s) [P, permeability; N, Na(+)/K(+)-ATPase density; (t), t-system membrane; (s), sarcolemma]. Hydrostatic pressures, fixed charges and/or osmoles in the t-system can influence the magnitude of t-volume changes that result from alterations in this circuit flux. Using a parameter set derived from literature values where possible, this novel theory of t-volume was tested against data from previous experiments where t-volume was measured during manipulations of ECF composition. Predicted t-volume changes correlated satisfactorily. The present work provides a robust, unifying theoretical framework for understanding the determinants of t-volume.JAF was supported by a David Phillips Fellowship (BB/FO23863/1) awarded by the Biotechnology and Biological Sciences Research Council (UK). JS was supported by the Agency for Science, Technology and Research (Singapore) and a Caius Medical Association summer studentship from Gonville and Caius College, University of Cambridge.This is the final version. It was first published by Wiley at http://onlinelibrary.wiley.com/doi/10.1113/jphysiol.2014.281170/abstract

Loss of NFIX transcription factor biases postnatal stem/progenitor cells towards oligodendrogenesis

Murine postnatal neural stem cells (NSCs) give rise to neurons, astrocytes, or oligodendrocytes (OLs); however, our knowledge of the genes that control this lineage specification is incomplete. In this study, we show that nuclear factor I X (NFIX), a transcription factor known to regulate NSC quiescence, also suppresses oligodendrogenesis (ODG) from NSCs. Immunostaining reveals little or no expression of NFIX in OL lineage cells both in vivo and in vitro. Loss of NFIX from subventricular zone (SVZ) NSCs results in enhanced ODG both in vivo and in vitro, while forced expression of NFIX blocks NSC differentiation into OLs in vitro. RNA-seq analysis shows that genes previously shown to be differentially expressed in OL progenitors are significantly enriched in RNA from Nfix(-/-) versus wild-type NSCs. These data indicate that NFIX influences the lineage specification of postnatal SVZ NSCs, specifically suppressing ODG

A progenitor candidate for the type II-P supernova SN 2018aoq in NGC 4151

We present our findings based on pre-and post-explosion data of the type II-Plateau SN 2018aoq that exploded in NGC 4151. As distance estimates to NGC 4151 vary by an order of magnitude, we utilised the well-known correlation between ejecta velocity and plateau brightness, i.e. the standard candle method, to obtain a distance of 18.2 ± 1.2 Mpc, which is in very good agreement with measurements based on geometric methods. The above distance implies a mid-plateau absolute magnitude of MV 50 = 15.76 ± 0.14 suggesting that it is of intermediate brightness when compared to IIP SNe such as SN 2005cs at the faint end, and more typical events such as SN 1999em. This is further supported by relatively low expansion velocities (Fe IIλ5169 ∼ 3000 km s-1 at +42 d). Using archival HST/WFC3 imaging data, we find a point source coincident with the supernova position in the F350LP, F555W, F814W, and F160W filters. This source shows no significant variability over the ∼2 month time span of the data. From fits to the spectral energy distribution of the candidate progenitor, we find log L/L4.7 and T3.5 kK, implying an M-type red supergiant progenitor. From comparisons to single and binary star models, we find that both favour the explosion of a star with a zero-age main sequence mass of ∼10M.</p

A progenitor candidate for the type II-P supernova SN 2018aoq in NGC 4151

We present our findings based on pre- and post-explosion data of the type II-Plateau SN 2018aoq that exploded in NGC 4151. As distance estimates to NGC 4151 vary by an order of magnitude, we utilised the well-known correlation between ejecta velocity and plateau brightness, i.e. the standard candle method, to obtain a distance of 18.2 ± 1.2 Mpc, which is in very good agreement with measurements based on geometric methods. The above distance implies a mid-plateau absolute magnitude of MV50 = - 15.76 ± 0.14 suggesting that it is of intermediate brightness when compared to IIP SNe such as SN 2005cs at the faint end, and more typical events such as SN 1999em. This is further supported by relatively low expansion velocities (Fe IIλ5169 ˜ 3000 km s-1 at +42 d). Using archival HST/WFC3 imaging data, we find a point source coincident with the supernova position in the F350LP, F555W, F814W, and F160W filters. This source shows no significant variability over the ˜2 month time span of the data. From fits to the spectral energy distribution of the candidate progenitor, we find log(L/L⊙) ˜ 4.7 and Teff ˜ 3.5 kK, implying an M-type red supergiant progenitor. From comparisons to single and binary star models, we find that both favour the explosion of a star with a zero-age main sequence mass of ˜10 M⊙.</p

p38γ MAPK delays myelination and remyelination and is abundant in multiple sclerosis lesions

Multiple sclerosis is a chronic inflammatory disease in which disability results from the disruption of myelin and axons. During the initial stages of the disease, injured myelin is replaced by mature myelinating oligodendrocytes that differentiate from oligodendrocyte precursor cells. However, myelin repair fails in secondary and chronic progressive stages of the disease and with ageing, as the environment becomes progressively more hostile. This may be attributable to inhibitory molecules in the multiple sclerosis environment including activation of the p38MAPK family of kinases. We explored oligodendrocyte precursor cell differentiation and myelin repair using animals with conditional ablation of p38MAPKγ from oligodendrocyte precursors. We found that p38γMAPK ablation accelerated oligodendrocyte precursor cell differentiation and myelination. This resulted in an increase in both the total number of oligodendrocytes and the migration of progenitors ex vivo and faster remyelination in the cuprizone model of demyelination/remyelination. Consistent with its role as an inhibitor of myelination, p38γMAPK was significantly downregulated as oligodendrocyte precursor cells matured into oligodendrocytes. Notably, p38γMAPK was enriched in multiple sclerosis lesions from patients. Oligodendrocyte progenitors expressed high levels of p38γMAPK in areas of failed remyelination but did not express detectable levels of p38γMAPK in areas where remyelination was apparent. Our data suggest that p38γ could be targeted to improve myelin repair in multiple sclerosis.Peer reviewe

Documentation of breakthrough pain in narrative clinical records of children with life-limiting conditions : feasibility of a retrospective review

This study explored the feasibility of generating reliable information on the frequency, nature and management of breakthrough pain (BTP) in children with life-limiting conditions (LLCs) and life threatening illnesses (LTIs) from narrative clinical records. In the absence of standardised ways for documenting BTP, we conducted a consensus exercise, to develop a glossary of terms that could denote BTP in the records. Thirteen clinicians who contributed to the records reached consensus on 45 terms which could denote BTP, whilst emphasising the importance of contextual information. The results of this approach together with guidance for improving the reliability of retrospective reviews informed a data extraction instrument. A pilot test of this instrument showed poor agreement between raters. Given the challenges encountered, we do not recommend a retrospective review of BTP using narrative records. This study highlighted challenges of data extraction for complex symptoms such as BTP from narrative clinical records. For both clinical and research purposes, the recording of complex symptoms such as BTP would benefit from clear criteria for applying definitions, a more structured format and the inclusion of validated assessment tools. This study also showed the value of consensus exercises in improving understanding and interpretation of clinical notes within a service

OGLE-2013-SN-079: A LONELY SUPERNOVA CONSISTENT WITH A HELIUM SHELL DETONATION

We present observational data for a peculiar supernova discovered by the OGLE-IV survey and followed by the Public ESO Spectroscopic Survey for Transient Objects. The inferred redshift of z = 0.07 implies an absolute magnitude in the rest-frame I-band of MI ~ –17.6 mag. This places it in the luminosity range between normal Type Ia SNe and novae. Optical and near infrared spectroscopy reveal mostly Ti and Ca lines, and an unusually red color arising from strong depression of flux at rest wavelengths <5000 Å. To date, this is the only reported SN showing Ti-dominated spectra. The data are broadly consistent with existing models for the pure detonation of a helium shell around a low-mass CO white dwarf and "double-detonation" models that include a secondary detonation of a CO core following a primary detonation in an overlying helium shell

Defining the Conformational Features of Anchorless, Poorly Neuroinvasive Prions

Infectious prions cause diverse clinical signs and form an extraordinary range of structures, from amorphous aggregates to fibrils. How the conformation of a prion dictates the disease phenotype remains unclear. Mice expressing GPI-anchorless or GPI-anchored prion protein exposed to the same infectious prion develop fibrillar or nonfibrillar aggregates, respectively, and show a striking divergence in the disease pathogenesis. To better understand how a prion's physical properties govern the pathogenesis, infectious anchorless prions were passaged in mice expressing anchorless prion protein and the resulting prions were biochemically characterized. Serial passage of anchorless prions led to a significant decrease in the incubation period to terminal disease and altered the biochemical properties, consistent with a transmission barrier effect. After an intraperitoneal exposure, anchorless prions were only weakly neuroinvasive, as prion plaques rarely occurred in the brain yet were abundant in extracerebral sites such as heart and adipose tissue. Anchorless prions consistently showed very high stability in chaotropes or when heated in SDS, and were highly resistant to enzyme digestion. Consistent with the results in mice, anchorless prions from a human patient were also highly stable in chaotropes. These findings reveal that anchorless prions consist of fibrillar and highly stable conformers. The additional finding from our group and others that both anchorless and anchored prion fibrils are poorly neuroinvasive strengthens the hypothesis that a fibrillar prion structure impedes efficient CNS invasion

On the diversity of superluminous supernovae: ejected mass as the dominant factor

We assemble a sample of 24 hydrogen-poor super-luminous supernovae (SLSNe). Parameterizing the light curve shape through rise and decline timescales shows that the two are highly correlated. Magnetar-powered models can reproduce the correlation, with the diversity in rise and decline rates driven by the diffusion timescale. Circumstellar interaction models can exhibit a similar rise-decline relation, but only for a narrow range of densities, which may be problematic for these models. We find that SLSNe are approximately 3.5 magnitudes brighter and have light curves 3 times broader than SNe Ibc, but that the intrinsic shapes are similar. There are a number of SLSNe with particularly broad light curves, possibly indicating two progenitor channels, but statistical tests do not cleanly separate two populations. The general spectral evolution is also presented. Velocities measured from Fe II are similar for SLSNe and SNe Ibc, suggesting that diffusion time differences are dominated by mass or opacity. Flat velocity evolution in most SLSNe suggests a dense shell of ejecta. If opacities in SLSNe are similar to other SNe Ibc, the average ejected mass is higher by a factor 2-3. Assuming $\kappa=0.1\,$cm$^2\,$g$^{-1}$, we estimate a mean (median) SLSN ejecta mass of 10$\,$M$_\odot$ (6$\,$M$_\odot$), with a range of 3-30$\,$M$_\odot$. Doubling the assumed opacity brings the masses closer to normal SNe Ibc, but with a high-mass tail. The most probable mechanism for generating SLSNe seems to be the core-collapse of a very massive hydrogen-poor star, forming a millisecond magnetar.Comment: 28 pages, 22 figs, 4 tables -- Updated on 2016-01-13 to fix typo in Table