Osmotic Properties of the Sealed Tubular System of Toad and Rat Skeletal Muscle

A method was developed that allows conversion of changes in maximum Ca2+-dependent fluorescence of a fixed amount of fluo-3 into volume changes of the fluo-3–containing solution. This method was then applied to investigate by confocal microscopy the osmotic properties of the sealed tubular (t-) system of toad and rat mechanically skinned fibers in which a certain amount of fluo-3 was trapped. When the osmolality of the myoplasmic environment was altered by simple dilution or addition of sucrose within the range 190–638 mosmol kg−1, the sealed t-system of toad fibers behaved almost like an ideal osmometer, changing its volume inverse proportionally to osmolality. However, increasing the osmolality above 638 to 2,550 mosmol kg−1 caused hardly any change in t-system volume. In myoplasmic solutions made hypotonic to 128 mosmol kg−1, a loss of Ca2+ from the sealed t-system of toad fibers occurred, presumably through either stretch-activated cationic channels or store-operated Ca2+ channels. In contrast to the behavior of the t-system in toad fibers, the volume of the sealed t-system of rat fibers changed little (by <20%) when the osmolality of the myoplasmic environment changed between 210 and 2,800 mosmol kg−1. Results were also validated with calcein. Clear differences between rat and toad fibers were also found with respect to the t-system permeability for glycerol. Thus, glycerol equilibrated across the rat t-system within seconds to minutes, but was not equilibrated across the t-system of toad fibers even after 20 min. These results have broad implications for understanding osmotic properties of the t-system and reversible vacuolation in muscle fibers. Furthermore, we observed for the first time in mammalian fibers an orderly lateral shift of the t-system networks whereby t-tubule networks to the left of the Z-line crossover to become t-tubule networks to the right of the Z-line in the adjacent sarcomere (and vice versa). This orderly rearrangement can provide a pathway for longitudinal continuity of the t-system along the fiber axis

Hans-Christoph Lüttgau 20 July 1926-5 November 2017

No abstract available

Identification of Candidate Driver Genes in Common Focal Chromosomal Aberrations of Microsatellite Stable Colorectal Cancer

Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. Chromosomal instability (CIN) is a major driving force of microsatellite stable (MSS) sporadic CRC. CIN tumours are characterised by a large number of somatic chromosomal copy number aberrations (SCNA) that frequently affect oncogenes and tumour suppressor genes. The main aim of this work was to identify novel candidate CRC driver genes affected by recurrent and focal SCNA. High resolution genome-wide comparative genome hybridisation (CGH) arrays were used to compare tumour and normal DNA for 53 sporadic CRC cases. Context corrected common aberration (COCA) analysis and custom algorithms identified 64 deletions and 32 gains of focal minimal common regions (FMCR) at high frequency (>10%). Comparison of these FMCR with published genomic profiles from CRC revealed common overlap (42.2% of deletions and 34.4% of copy gains). Pathway analysis showed that apoptosis and p53 signalling pathways were commonly affected by deleted FMCR, and MAPK and potassium channel pathways by gains of FMCR. Candidate tumour suppressor genes in deleted FMCR included RASSF3, IFNAR1, IFNAR2 and NFKBIA and candidate oncogenes in gained FMCR included PRDM16, TNS1, RPA3 and KCNMA1. In conclusion, this study confirms some previously identified aberrations in MSS CRC and provides in silico evidence for some novel candidate driver gene

How much do delayed health care seeking, delayed care provision and diversion from primary care contribute to the transmission of STIs

Objectives: To explore the changing pattern of condom use from 1990 to 2000; to identify sociodemographic and behavioural factors associated with condom use; and reasons for condom use in 2000. Methods: Large probability sample surveys administered among those resident in Britain aged 16–44 (n = 13 765 in 1990, n = 11 161 in 2000). Face to face interviews with self completion components collected sociodemographic, behavioural, and attitudinal data. Results: Condom use in the past year among sexually active 16–24 year old men increased from 61.0% in 1990 to 82.1% in 2000 (p<0.0001), and from 42.0% to 63.2% (p<0.0001) among women of the same age, with smaller increases among older age groups. Among individuals reporting at least two partners in the previous 4 week period, approximately two thirds reported inconsistent or no condom use (63.1% (95% CI 55.9% to 69.8%) of the men and 68.5% (95% CI 57.6% to 77.7%) of the women). Conclusions: Rates of condom use increased substantially between 1990 and 2000, particularly among young people. However, inconsistent condom use by individuals with high rates of partner acquisition may contribute significantly to the recent resurgence in STIs. This group is an important target for intensive and specific sexual health interventions

The Extrasolar Planet epsilon Eridani b - Orbit and Mass

Hubble Space Telescope observations of the nearby (3.22 pc), K2 V star epsilon Eridani have been combined with ground-based astrometric and radial velocity data to determine the mass of its known companion. We model the astrometric and radial velocity measurements simultaneously to obtain the parallax, proper motion, perturbation period, perturbation inclination, and perturbation size. Because of the long period of the companion, \eps b, we extend our astrometric coverage to a total of 14.94 years (including the three year span of the \HST data) by including lower-precision ground-based astrometry from the Allegheny Multichannel Astrometric Photometer. Radial velocities now span 1980.8 -- 2006.3. We obtain a perturbation period, P = 6.85 +/- 0.03 yr, semi-major axis, alpha =1.88 +/- 0.20 mas, and inclination i = 30.1 +/- 3.8 degrees. This inclination is consistent with a previously measured dust disk inclination, suggesting coplanarity. Assuming a primary mass M_* = 0.83 M_{\sun}, we obtain a companion mass M = 1.55 +/- 0.24 M_{Jup}. Given the relatively young age of epsilon Eri (~800 Myr), this accurate exoplanet mass and orbit can usefully inform future direct imaging attempts. We predict the next periastron at 2007.3 with a total separation, rho = 0.3 arcsec at position angle, p.a. = -27 degrees. Orbit orientation and geometry dictate that epsilon Eri b will appear brightest in reflected light very nearly at periastron. Radial velocities spanning over 25 years indicate an acceleration consistent with a Jupiter-mass object with a period in excess of 50 years, possibly responsible for one feature of the dust morphology, the inner cavity

NHE- and diffusion-dependent proton fluxes across the tubular system membranes of fast-twitch muscle fibers of the rat

The complex membrane structure of the tubular system (t-system) in skeletal muscle fibers is open to the extracellular environment, which prevents measurements of H+ movement across its interface with the cytoplasm by conventional methods. Consequently, little is known about the t-system's role in the regulation of cytoplasmic pH, which is different from extracellular pH. Here we describe a novel approach to measure H+-flux measurements across the t-system of fast-twitch fibers under different conditions. The approach involves loading the t-system of intact rat fast-twitch fibers with a strong pH buffer (20 mM HEPES) and pH-sensitive fluorescent probe (10 mM HPTS) before the t-system is sealed off. The pH changes in the t-system are then tracked by confocal microscopy after rapid changes in cytoplasmic ionic conditions. T-system sealing is achieved by removing the sarcolemma by microdissection (mechanical skinning), which causes the tubules to pinch off and seal tight. After this procedure, the t-system repolarizes to physiological levels and can be electrically stimulated when placed in K+-based solutions of cytosolic-like ionic composition. Using this approach, we show that the t-system of fast-twitch skeletal fibers displays amiloride-sensitive Na+/H+ exchange (NHE), which decreases markedly at alkaline cytosolic pH and has properties similar to that in mammalian cardiac myocytes. We observed mean values for NHE density and proton permeability coefficient of 339 pmol/m2 of t-system membrane and 158 µm/s, respectively. We conclude that the cytosolic pH in intact resting muscle can be quantitatively explained with respect to extracellular pH by assuming that these values apply to the t-system membrane and the sarcolemma

The Association of Coloproctology of Great Britain and Ireland consensus guidelines in emergency colorectal surgery

ACKNOWLEDGEMENTS Review and editing: S.R. Brown, Professor of Surgery, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. Email [email protected]. Patient summary: R.G. Arnott, Retired Professor, Patient Liaison Group, Association of Coloproctology of Great Britain and Ireland, Royal College of Surgeons of England, London, UK. Email [email protected]. Delphi review: C.P. Macklin. BMedSci BM BS FRCS DM, Consultant Colorectal Surgeon, Mid Yorkshire Hospitals, UK. Email [email protected] reviewedPublisher PD

“Hot” and “Cold” Cognition in Users of Club Drugs/Novel Psychoactive Substances

Novel psychoactive substances (NPS) are popular “club/party” drugs that first attracted attention in the UK in 2009 and remained legal until the 2016 Psychoactive Substances Act criminalized their distribution. Unlike “traditional” illicit drugs, very little is known about the influence of their analogs on neuropsychological functioning. We characterized the cognitive and emotional profile of NPS/polydrug users using the Cambridge Neuropsychological Test Automated Battery (CANTAB) and EMOTICOM test battery in adult male (aged 20–49 years) recreational users without psychiatric comorbidities (n = 27; “psychonauts”), service users attending a UK specialist “Club Drug” Clinic for problematic use (n = 20) and healthy control volunteers without significant drug-taking histories (n = 35). Tasks were selected to distinguish “hot” cognitive processes that are highly influenced by emotion from “cold” cognitive processes that are largely independent of emotional influence. Both user groups reported significantly higher sensation-seeking traits compared with non-users. Recreational NPS users demonstrated more risk-taking behavior compared with controls and treatment-seeking NPS users showed poorer learning, episodic memory and response inhibition compared with the other two groups. These effects persisted, when controlling for age, intelligence, alcohol and cannabis use severity, nicotine dependence, trait anxiety, depression, childhood adversity, impulsivity, and sensation seeking. Overall, recreational NPS users showed elevated “hot” (emotion-laden) cognition in the absence of “cold” (non-emotional) cognitive deficits, whereas “cold” cognitive dysfunction was pronounced in individuals seeking treatment for problematic NPS use. High trait impulsivity and poor self-control may confer additional risk to NPS/polydrug use severity and separate those seeking treatment from those using NPS recreationally

Thermochronology of the modern Indus River bedload: New insight into the controls on the marine stratigraphic record

The Indus River is the only major drainage in the western Himalaya and delivers a long geological record of continental erosion to the Arabian Sea, which may be deciphered and used to reconstruct orogenic growth if the modern bedload can be related to the mountains. In this study we collected thermochronologic data from river sediment collected near the modern delta. U-Pb ages of zircons spanning 3 Gyr show that only ∼5% of the eroding crust has been generated since India-Asia collision. The Greater Himalaya are the major source of zircons, with additional contributions from the Karakoram and Lesser Himalaya. The 39Ar/40Ar dating of muscovites gives ages that cluster between 10 and 25 Ma, differing from those recorded in the Bengal Fan. Biotite ages are generally younger, ranging 0–15 Ma. Modern average exhumation rates are estimated at ∼0.6 km/m.y. or less, and have slowed progressively since the early Miocene (∼20 Ma), although fission track (FT) dating of apatites may indicate a recent moderate acceleration in rates since the Pliocene (∼1.0 km/m.y.) driven by climate change. The 39Ar/40Ar and FT techniques emphasize the dominance of high topography in controlling the erosional flux to the ocean. Localized regions of tectonically driven, very rapid exhumation (e.g., Nanga Parbat, S. Karakoram metamorphic domes) do not dominate the erosional record