Persistence of the mitochondrial permeability transition in the absence of subunit c of human ATP synthase.

The permeability transition in human mitochondria refers to the opening of a nonspecific channel, known as the permeability transition pore (PTP), in the inner membrane. Opening can be triggered by calcium ions, leading to swelling of the organelle, disruption of the inner membrane, and ATP synthesis, followed by cell death. Recent proposals suggest that the pore is associated with the ATP synthase complex and specifically with the ring of c-subunits that constitute the membrane domain of the enzyme's rotor. The c-subunit is produced from three nuclear genes, ATP5G1, ATP5G2, and ATP5G3, encoding identical copies of the mature protein with different mitochondrial-targeting sequences that are removed during their import into the organelle. To investigate the involvement of the c-subunit in the PTP, we generated a clonal cell, HAP1-A12, from near-haploid human cells, in which ATP5G1, ATP5G2, and ATP5G3 were disrupted. The HAP1-A12 cells are incapable of producing the c-subunit, but they preserve the characteristic properties of the PTP. Therefore, the c-subunit does not provide the PTP. The mitochondria in HAP1-A12 cells assemble a vestigial ATP synthase, with intact F1-catalytic and peripheral stalk domains and the supernumerary subunits e, f, and g, but lacking membrane subunits ATP6 and ATP8. The same vestigial complex plus associated c-subunits was characterized from human 143B ρ(0) cells, which cannot make the subunits ATP6 and ATP8, but retain the PTP. Therefore, none of the membrane subunits of the ATP synthase that are involved directly in transmembrane proton translocation is involved in forming the PTP.This work was supported by the Medical Research Council (MRC) of the United Kingdom by Grant MC_U1065663150 and by Programme Grant MR/M009858/1 (to J.E.W.). H.C.F. received an MRC PhD studentship

Hubble Frontier Field Free-form Mass Mapping of the Massive Multiple-merging Cluster MACSJ0717.5+3745

published_or_final_versio

Hubble Frontier Field Free-form Mass Mapping of the Massive Multiple-merging Cluster MACSJ0717.5+3745

published_or_final_versio

Current research into brain barriers and the delivery of therapeutics for neurological diseases: a report on CNS barrier congress London, UK, 2017.

This is a report on the CNS barrier congress held in London, UK, March 22-23rd 2017 and sponsored by Kisaco Research Ltd. The two 1-day sessions were chaired by John Greenwood and Margareta Hammarlund-Udenaes, respectively, and each session ended with a discussion led by the chair. Speakers consisted of invited academic researchers studying the brain barriers in relation to neurological diseases and industry researchers studying new methods to deliver therapeutics to treat neurological diseases. We include here brief reports from the speakers

The Evolutionary Status of Clusters of Galaxies at z ~ 1

Combined HST, X-ray, and ground-based optical studies show that clusters of galaxies are largely "in place" by $z \sim 1$, an epoch when the Universe was less than half its present age. High resolution images show that elliptical, S0, and spiral galaxies are present in clusters at redshifts up to $z \sim 1.3$. Analysis of the CMDs suggest that the cluster ellipticals formed their stars several Gyr earlier, near redshift 3. The morphology--density relation is well established at $z\sim1$, with star-forming spirals and irregulars residing mostly in the outer parts of the clusters and E/S0s concentrated in dense clumps. The intracluster medium has already reached the metallicity of present-day clusters. The distributions of the hot gas and early-type galaxies are similar in $z\sim1$ clusters, indicating both have largely virialized in the deepest potentials wells. In spite of the many similarities between $z\sim1$ and present-day clusters, there are significant differences. The morphologies revealed by the hot gas, and particularly the early-type galaxies, are elongated rather than spherical. We appear to be observing the clusters at an epoch when the sub-clusters and groups are still assembling into a single regular cluster. Support for this picture comes from CL0152 where the gas appears to be lagging behind the luminous and dark mass in two merging sub-components. Moreover, the luminosity difference between the first and second brightest cluster galaxies at $z\sim1$ is smaller than in 93% of present-day Abell clusters, which suggests that considerable luminosity evolution through merging has occurred since that epoch. Evolution is also seen in the bolometric X-ray luminosity function.Comment: 18 pages, 12 figures, to appear in Penetrating Bars through Masks of Cosmic Dust: the Hubble Tuing Fork Strikes a New Note, eds. D.L. Block, K.C. Freeman, I. Puerari & R. Groess. Figures degraded to meet astroph size limit; a version with higher resolution figures may be downloaded from: http://acs.pha.jhu.edu/~jpb/z1clusters/ford_clusters.pd

Chaos and Elliptical Galaxies

Recent results on chaos in triaxial galaxy models are reviewed. Central mass concentrations like those observed in early-type galaxies -- either stellar cusps, or massive black holes -- render most of the box orbits in a triaxial potential stochastic. Typical Liapunov times are 3-5 crossing times, and ensembles of stochastic orbits undergo mixing on time scales that are roughly an order of magnitude longer. The replacement of the regular orbits by stochastic orbits reduces the freedom to construct self-consistent equilibria, and strong triaxiality can be ruled out for galaxies with sufficiently high central mass concentrations.Comment: uuencoded gziped PostScript, 12 pages including figure

Does the revised cardiac risk index predict cardiac complications following elective lung resection?

Background: Revised Cardiac Risk Index (RCRI) score and Thoracic Revised Cardiac Risk Index (ThRCRI) score were developed to predict the risks of postoperative major cardiac complications in generic surgical population and thoracic surgery respectively. This study aims to determine the accuracy of these scores in predicting the risk of developing cardiac complications including atrial arrhythmias after lung resection surgery in adults. Methods: We studied 703 patients undergoing lung resection surgery in a tertiary thoracic surgery centre. Observed outcome measures of postoperative cardiac morbidity and mortality were compared against those predicted by risk. Results: Postoperative major cardiac complications and supraventricular arrhythmias occurred in 4.8% of patients. Both index scores had poor discriminative ability for predicting postoperative cardiac complications with an area under receiver operating characteristic (ROC) curve of 0.59 (95% CI 0.51-0.67) for the RCRI score and 0.57 (95% CI 0.49-0.66) for the ThRCRI score. Conclusions: In our cohort, RCRI and ThRCRI scores failed to accurately predict the risk of cardiac complications in patients undergoing elective resection of lung cancer. The British Thoracic Society (BTS) recommendation to seek a cardiology referral for all asymptomatic pre-operative lung resection patients with > 3 RCRI risk factors is thus unlikely to be of clinical benefit

Young Galaxy Candidates in the Hubble Frontier Fields. IV. MACS J1149.5+2223

We search for high-redshift dropout galaxies behind the Hubble Frontier Fields (HFF) galaxy cluster MACS J1149.5+2223, a powerful cosmic lens that has revealed a number of unique objects in its field. Using the deep images from the Hubble and Spitzer space telescopes, we find 11 galaxies at z > 7 in the MACS J1149.5+2223 cluster field, and 11 in its parallel field. The high-redshift nature of the bright z sime 9.6 galaxy MACS1149-JD, previously reported by Zheng et al., is further supported by non-detection in the extremely deep optical images from the HFF campaign. With the new photometry, the best photometric redshift solution for MACS1149-JD reduces slightly to z = 9.44 ± 0.12. The young galaxy has an estimated stellar mass of (7\pm 2)\times {10}^{8}\,{M}_{\odot }, and was formed at $z={13.2}_{-1.6}^{+1.9} when the universe was ≈300 Myr old. Data available for the first four HFF clusters have already enabled us to find faint galaxies to an intrinsic magnitude of {M}_{{UV}}\simeq -15.5, approximately a factor of 10 deeper than the parallel fields

Agreement between an online dietary assessment tool (myfood24) and an interviewer-administered 24-h dietary recall in British adolescents aged 11–18 years

myfood24 Is an online 24-h dietary assessment tool developed for use among British adolescents and adults. Limited information is available regarding the validity of using new technology in assessing nutritional intake among adolescents. Thus, a relative validation of myfood24 against a face-to-face interviewer-administered 24-h multiple-pass recall (MPR) was conducted among seventy-five British adolescents aged 11–18 years. Participants were asked to complete myfood24 and an interviewer-administered MPR on the same day for 2 non-consecutive days at school. Total energy intake (EI) and nutrients recorded by the two methods were compared using intraclass correlation coefficients (ICC), Bland–Altman plots (using between and within-individual information) and weighted κ to assess the agreement. Energy, macronutrients and other reported nutrients from myfood24 demonstrated strong agreement with the interview MPR data, and ICC ranged from 0·46 for Na to 0·88 for EI. There was no significant bias between the two methods for EI, macronutrients and most reported nutrients. The mean difference between myfood24 and the interviewer-administered MPR for EI was −230 kJ (−55 kcal) (95 % CI −490, 30 kJ (−117, 7 kcal); P=0·4) with limits of agreement ranging between 39 % (3336 kJ (−797 kcal)) lower and 34 % (2874 kJ (687 kcal)) higher than the interviewer-administered MPR. There was good agreement in terms of classifying adolescents into tertiles of EI (κ w =0·64). The agreement between day 1 and day 2 was as good for myfood24 as for the interviewer-administered MPR, reflecting the reliability of myfood24. myfood24 Has the potential to collect dietary data of comparable quality with that of an interviewer-administered MPR

Kilohertz quasi-periodic oscillations in low-mass X-ray binaries

In early 1996 a series of discoveries begun with NASA's Rossi X-ray Timing Explorer of a new, up to then unknown astrophysical phenomenon. It turned out that accreting low magnetic-field neutron stars show quasi-periodic oscillations in their X-ray flux at rates of up to more than a kilohertz. These kHz QPO, now reported from eleven different systems, are among the fastest phenomena in the sky and can provide us with new information about the fundamental properties of neutron stars and help testing general relativity in the strong-field regime. If, for example, their frequencies can be identified with the Keplerian frequencies of matter in orbit around a 1.4 Solar-mass neutron star, then the radius of the star would have to be less than 15 km, which directly constrains the equation of state of bulk nuclear-density matter, and for an only slightly tighter orbit or slightly more massive neutron star the orbital radius would equal the Schwarzschild-geometry general-relativistic marginally stable orbit (12.5 km for a 1.4 Solar mass object). So far all models that have been put forward for explaining the new phenomenon have encountered problems. In this paper I review the relatively simple and highly suggestive phenomenology as it has emerged from the data up to now, and discuss some of the proposed models.Comment: To be published in the Proceedings of the Wise Observatory 25th Anniversary Symposium "Astronomical Time Series", Tel Aviv, January 199