Ribosome biogenesis during skeletal muscle hypertrophy

Muscle adaptation to chronic resistance exercise (RE) is the result of a cumulative effect on gene expression and protein content. Following a bout of RE, muscle protein synthesis increases and, if followed by consecutive bouts (training), protein accretion and muscle hypertrophy develops. The protein synthetic capacity of the muscle is dictated by ribosome content. Therefore, the general aim of this thesis is to investigate the regulation of ribosome biogenesis during skeletal muscle hypertrophy. To begin addressing this question, we employed a prevalent rodent model of skeletal muscle hypertrophy, synergist ablation (SA) of plantar flexor muscles. SA resulted in muscle hypertrophy with a concomitant increase in total RNA content. We observed a marked re- induction of c-Myc in overloaded skeletal muscle correlating with the expression of Pol I specific factors and 45S pre-rRNA levels. UBF and WSTF were increased at the protein level in myonuclei and enriched at the rDNA promoter following mechanical loading. This was associated with increased Pol I loading and epigenetic marks of active, de-condensed chromatin at the rDNA promoter. Similarly, acute mechanical loading of human skeletal muscle resulted increased mTOR signalling, a re-induction of c-Myc and increased 45s pre- rRNA abundance. Once the hypertrophic phenotype was evident in both mouse and human, rDNA transcription had returned to baseline levels. A conditional, skeletal muscle specific c- Myc knockout model was generated to investigate the mechanistic importance of c-Myc in ribosome biogenesis and hypertrophy. Animals lacking c-Myc in skeletal muscle displayed normal post-natal development with respect to body weight, muscle size, rDNA transcription and RNA content. To further challenge the growth machinery in skeletal muscle lacking c- Myc, animals were subjected to SA-imposed overload. No difference with respect to RNA accumulation or hypertrophic response was detected, indicating that c-Myc is dispensable for cellular hypertrophy in terminally differentiated muscle cells. These results were verified in C2C12 myotubes with compromised c-Myc function (Myra-A). On the contrary, c-Myc inactivation in proliferating C2C12 myoblasts severely compromised rDNA transcription, DNA synthesis as well as cell proliferation. Thus, our data suggests cell stage-specific effects of ablated c-Myc function in cells of the myogenic lineage. Moreover, the importance of the mTOR network for rDNA gene regulation during skeletal muscle hypertrophy was investigated. mTOR inhibition with rapamycin prevented the development of hypertrophy, and decreased mTOR binding to rDNA correlated with decreased 45S pre-rRNA synthesis and perturbed rRNA accumulation. Selective inhibition of RNA Pol I with CX-5461 efficiently prevented skeletal muscle hypertrophy in a similar fashion. Collectively, the data presented in this thesis proposes an important role for ribosome biogenesis at the onset of skeletal muscle hypertrophy, which, if blocked, prevents the development of the hypertrophic phenotype. During the time in which measurable hypertrophy is evident, rRNA synthesis rates have normalized. In addition, our results indicate that mTOR regulates this process via numerous different mechanisms, including direct binding to the rDNA promoter but likely not via p70S6K1-dependent functions. c-Myc proved dispensable for Pol I transcription and skeletal muscle hypertrophy in the differentiated state both in vivo and in vitro, instead controlling cell proliferation in myoblasts, likely via a Pol I-dependent mechanism

Modulation of neural cell membrane conductance by the herbal anxiolytic and antiepileptic drug aswal

To evaluate the effects of aswal on ionic fluxes and neuronal excitation, we performed extracellular and whole cell patch clamp recordings on CA1 pyramidal neurons of guinea pigs and Long-Evans rats. Aswal (100-250 mg/l) was administered systemically, and its effects on the rate of synchronized extracellular field potentials (EFP), membrane parameters, action potentials and postsynaptic potentials were recorded. The extracellular results obtained are consistent with calcium antagonistic properties. Intracellular recordings suggest that a direct sodium antagonistic effect as seen in many antiepileptic drugs plays no significant role. Further effects on ligand gated ion channels are discussed controversially. In summary, the cellular action of aswal appears heterogeneous with calcium antagonism playing a prominent role in counteracting excitation which may be a common feature in epilepsy and different psychiatric conditions as mood and anxiety disorder. Copyright (C) 2000 S. Karger AG, Basel

Modulation of calcium and potassium currents by lamotrigine

Actions of the new antiepileptic drug lamotrigine (LTG) were characterized using extracellular and whole cell patch clamp recordings from rat CAI and CA3 pyramidal cells in vitro. The results suggest that LTG, beside its previously described effect on the fast sodium inward current, also modulates - presumably voltage-gated - calcium currents and the transient potassium outward current ID. These may be effective mechanisms to inhibit pathological excitation in epilepsy and may be of potential benefit in treating: underlying cellular disturbances in bipolar disorder

A responsitivity-based criterion for accurate calibration of FTIR spectra: theoretical development and bandwidth estimation

An analytical expression for the variance of the radiance measured by Fourier-transform infrared (FTIR) emission spectrometers exists only in the limit of low noise. Outside this limit, the variance needs to be calculated numerically. In addition, a criterion for low noise is needed to identify properly calibrated radiances and optimize the instrument bandwidth. In this work, the variance and the magnitude of a noise-dependent spectral bias are calculated as a function of the system responsivity (r) and the noise level in its estimate (? r ). The criterion ? r /

Responsivity-based Criterion For Accurate Calibration Of Ftir Emission Spectra: Theoretical Development And Bandwidth Estimation

An analytical expression for the variance of the radiance measured by Fourier-transform infrared (FTIR) emission spectrometers exists only in the limit of low noise. Outside this limit, the variance needs to be calculated numerically. In addition, a criterion for low noise is needed to identify properly calibrated radiances and optimize the instrument bandwidth. In this work, the variance and the magnitude of a noise-dependent spectral bias are calculated as a function of the system responsivity (r) and the noise level in its estimate (sigma(r)). The criterion sigma(r)/r \u3c 0.3, applied to downwelling and upwelling FTIR emission spectra, shows that the instrument bandwidth is specified properly for one instrument but needs to be restricted for another

Evaluation of Temperature-Dependent Complex Refractive Indices of Supercooled Liquid Water Using Downwelling Radiance and In-Situ Cloud Measurements at South Pole

Clouds have a large effect on the radiation budget and represent a major source of uncertainty in climate models. Supercooled liquid clouds can exist at temperatures as low as 235 K, and the radiative effect of these clouds depends on the complex refractive index (CRI) of liquid water. Laboratory measurements have demonstrated that the liquid-water CRI is temperature-dependent, but corroboration with field measurements is difficult. Here we present measurements of the downwelling infrared radiance and in-situ measurements of supercooled liquid water in a cloud at temperatures as low as 240 K, made at South Pole Station in 2001. These results demonstrate that including the temperature dependence of the liquid-water CRI is essential for accurate calculations of radiative transfer through supercooled liquid clouds. Furthermore, we show that when cloud properties are retrieved from infrared radiances (using the spectral range 500–1,200 cm−1) spurious ice may be retrieved if the 300 K CRI is used for cold liquid clouds (∼240 K). These results have implications for radiative transfer in climate models as well as for retrievals of cloud properties from infrared radiance spectra.publishedVersio

Evaluation of Six Atmospheric Reanalyses over Arctic Sea Ice from Winter to Early Summer

© Copyright 19 June 2019 American Meteorological Society (AMS). Permission to use figures, tables, and brief excerpts from this work in scientific and educational works is hereby granted provided that the source is acknowledged. Any use of material in this work that is determined to be “fair use” under Section 107 of the U.S. Copyright Act or that satisfies the conditions specified in Section 108 of the U.S. Copyright Act (17 USC §108) does not require the AMS’s permission. Republication, systematic reproduction, posting in electronic form, such as on a website or in a searchable database, or other uses of this material, except as exempted by the above statement, requires written permission or a license from the AMS. All AMS journals and monograph publications are registered with the Copyright Clearance Center (http://www.copyright.com). Questions about permission to use materials for which AMS holds the copyright can also be directed to [email protected]. Additional details are provided in the AMS Copyright Policy statement, available on the AMS website (http://www.ametsoc.org/CopyrightInformation).This study evaluates the performance of six atmospheric reanalyses (ERA-Interim, ERA5, JRA-55, CFSv2, MERRA-2, and ASRv2) over Arctic sea ice from winter to early summer. The reanalyses are evaluated using observations from the Norwegian Young Sea Ice campaign (N-ICE2015), a 5-month ice drift in pack ice north of Svalbard. N-ICE2015 observations include surface meteorology, vertical profiles from radiosondes, as well as radiative and turbulent heat fluxes. The reanalyses simulate surface analysis variables well throughout the campaign, but have difficulties with most forecast variables. Wintertime (January–March) correlation coefficients between the reanalyses and observations are above 0.90 for the surface pressure, 2-m temperature, total column water vapor, and downward longwave flux. However, all reanalyses have a positive wintertime 2-m temperature bias, ranging from 1° to 4°C, and negative (i.e., upward) net longwave bias of 3–19 W m−2. These biases are associated with poorly represented surface inversions and are largest during cold-stable periods. Notably, the recent ERA5 and ASRv2 datasets have some of the largest temperature and net longwave biases, respectively. During spring (April–May), reanalyses fail to simulate observed persistent cloud layers. Therefore they overestimate the net shortwave flux (5–79 W m−2) and underestimate the net longwave flux (8–38 W m−2). Promisingly, ERA5 provides the best estimates of downward radiative fluxes in spring and summer, suggesting improved forecasting of Arctic cloud cover. All reanalyses exhibit large negative (upward) residual heat flux biases during winter, and positive (downward) biases during summer. Turbulent heat fluxes over sea ice are simulated poorly in all seasons

BioFACTS : biomarkers of rhabdomyolysis in the diagnosis of acute compartment syndrome - protocol for a prospective multinational, multicentre study involving patients with tibial fractures

Introduction The ischaemic pain of acute compartment syndrome (ACS) can be difficult to discriminate from the pain linked to an associated fracture. Lacking objective measures, the decision to perform fasciotomy is based on clinical findings and performed at a low level of suspicion. Biomarkers of muscle cell damage may help to identify and monitor patients at risk, similar to current routines for patients with acute myocardial infarction. This study will test the hypothesis that biomarkers of muscle cell damage can predict ACS in patients with tibial fractures. Methods and analysis Patients aged 15-65 years who have suffered a tibial fracture will be included. Plasma (P)-myoglobin and P-creatine phosphokinase will be analysed at 6-hourly intervals after admission to the hospital (for 48 hours) and-if applicable-after surgical fixation or fasciotomy (for 24 hours). In addition, if ACS is suspected at any other point in time, blood samples will be collected at 6-hourly intervals. An independent expert panel will assess the study data and will classify those patients who had undergone fasciotomy into those with ACS and those without ACS. All primary comparisons will be perforated between fracture patients with and without ACS. The area under the receiver operator characteristics curves will be used to identify the success of the biomarkers in discriminating between fracture patients who develop ACS and those who do not. Logistic regression analyses will be used to assess the discriminative abilities of the biomarkers to predict ACS corrected for prespecified covariates. Ethics and dissemination The study has been approved by the Regional Ethical Review Boards in Linkoping (2017/514-31) and Helsinki/Uusimaa (HUS/2500/2000). The BioFACTS study will be reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology recommendations.Peer reviewe