MuRF1 activity is present in cardiac mitochondria and regulates reactive oxygen species production in vivo

Erratum: https://link.springer.com/article/10.1007/s10863-014-9597-1MuRF1 is a previously reported ubiquitin-ligase found in striated muscle that targets troponin I and myosin heavy chain for degradation. While MuRF1 has been reported to interact with mitochondrial substrates in yeast two-hybrid studies, no studies have identified MuRF1’s role in regulating mitochondrial function to date. In the present study, we measured cardiac mitochondrial function from isolated permeabilized muscle fibers in previously phenotyped MuRF1 transgenic and MuRF1−/− mouse models to determine the role of MuRF1 in intermediate energy metabolism and ROS production. We identified a significant decrease in reactive oxygen species production in cardiac muscle fibers from MuRF1 transgenic mice with increased α-MHC driven MuRF1 expression. Increased MuRF1 expression in ex vivo and in vitro experiments revealed no alterations in the respiratory chain complex I and II function. Working perfusion experiments on MuRF1 transgenic hearts demonstrated significant changes in glucose oxidation. This is an factual error as written; however, total oxygen consumption was decreased. This data provides evidence for MuRF1 as a novel regulator of cardiac ROS, offering another mechanism by which increased MuRF1 expression may be cardioprotective in ischemia reperfusion injury, in addition to its inhibition of apoptosis via proteasome-mediate degradation of c-Jun. The lack of mitochondrial function phenotype identified in MuRF1−/− hearts may be due to the overlapping interactions of MuRF1 and MuRF2 with energy regulating proteins found by yeast two-hybrid studies reported here, implying a duplicity in MuRF1 and MuRF2’s regulation of mitochondrial function.Funding support from Medical Research Council, United Kingdom; National Institutes of Health, United States; British Heart Foundation, United Kingdo

Intractable Alcoholism in a Patient with a Levine Shunt

Ellen Shaw. M.D., Fellow in Hepatology: Mr. J is a forty-six-year-old white male who was initially seen on the medical service in July 1982. At that time he presented with hepatic encephalopathy, jaundice, and ascites. A liver biopsy was performed, confirming the clinical diagnosis of alcoholic hepatitis superimposed on cirrhosis. Following discharge it was difficult to maintain Mr. J as an outpatient. He did not follow dietary restrictions or take diuretics as prescribed. Additionally he was unable to control his drinking. Finally about a year ago a Levine shunt was implanted in an effort to control his ascites. Subsequently he did well for a period of several months. He was able to abstain from alcohol with a resulting decrease in his ascites and jaundice. Recently he has resumed drinking, with a return of his symptoms. He has missed his last several appointments in the clinic. Control of his medical problems remains problematic unless his alcohol abuse can be better controlled

Expression of MuRF1 or MuRF2 is essential for the induction of skeletal muscle atrophy and dysfunction in a murine pulmonary hypertension model

Background Pulmonary hypertension leads to right ventricular heart failure and ultimately to cardiac cachexia. Cardiac cachexia induces skeletal muscles atrophy and contractile dysfunction. MAFbx and MuRF1 are two key proteins that have been implicated in chronic muscle atrophy of several wasting states. Methods Monocrotaline (MCT) was injected over eight weeks into mice to establish pulmonary hypertension as a murine model for cardiac cachexia. The effects on skeletal muscle atrophy, myofiber force, and selected muscle proteins were evaluated in wild-type (WT), MuRF1, and MuRF2-KO mice by determining muscle weights, in vitro muscle force and enzyme activities in soleus and tibialis anterior (TA) muscle. Results In WT, MCT treatment induced wasting of soleus and TA mass, loss of myofiber force, and depletion of citrate synthase (CS), creatine kinase (CK), and malate dehydrogenase (MDH) (all key metabolic enzymes). This suggests that the murine MCT model is useful to mimic peripheral myopathies as found in human cardiac cachexia. In MuRF1 and MuRF2-KO mice, soleus and TA muscles were protected from atrophy, contractile dysfunction, while metabolic enzymes were not lowered in MuRF1 or MuRF2-KO mice. Furthermore, MuRF2 expression was lower in MuRF1KO mice when compared to C57BL/6 mice. Conclusions In addition to MuRF1, inactivation of MuRF2 also provides a potent protection from peripheral myopathy in cardiac cachexia. The protection of metabolic enzymes in both MuRF1KO and MuRF2KO mice as well as the dependence of MuRF2 expression on MuRF1 suggests intimate relationships between MuRF1 and MuRF2 during muscle atrophy signaling

Healthy Steps for Older Adults (HSOA) - A Falls Prevention Program Outcome Evaluation

Fall prevention is an increasingly important area in the realm of public health and prevention medicine. Falls continue to be the leading cause of fatal injury and the most common cause of non-fatal trauma-related hospital admissions among older adults in the United States, causing over 2.8 million injuries, over 800,000 hospitalizations, and more than 27,000 deaths annually (NCOA, 2018).As the average age of the population increases, the need for programs that inform the public about their risks of falls has begun to increase. The following study is an evaluation of one such program, Healthy Steps for Older Adults (HSOA). Twenty individuals ages 58 and older were recruited to partake in a two-day informational and interactive session designed to teach those participants about falls, to help them evaluate their own risk of falls, and to provide solutions to reduce fall risk. Questionnaires given a at the start of the intervention on day one, at the conclusion of the intervention on day two, and four weeks after completing the program were used to assess changes in knowledge about falls and fall risk and behavior changes to reduce risks of falling. Participants also completed a “Physical Skill screening” on the second day that included three exercises to identify their relative fall risk. Out of the twenty participants, fourteen responded to the follow-up phone interview. Of those fourteen individuals, 85.71% changed at least one behavior to help reduce their risk of falls by the time they were contacted to complete the four-week post-intervention follow-up questionnaire, and the program is therefore an effective falls-prevention program based on our definition (at least 50% of participants changed at least one behavior to reduce their risk of falls). Additional analysis supports the claim that there may be a lower limit age for which the program is effective, and that being placed in a moderate or high risk fall category may be associated with increased likelihood of making a positive behavior change to reduce fall risk. However, more data is needed to establish statistical significance. Areas of concern reflect a suggested need to incorporate family members into the intervention, establish a standardized benchmark for determining program effectiveness, and improve comparability between pre- and post-intervention questionnaires. Overall, the program by our definition was successful, but specific limitations regarding the logistical implementation and evaluation of the program should be addressed if the program were to be run again

Neoliberalisation and 'lad cultures' in higher education

This paper links HE neoliberalisation and ‘lad cultures’, drawing on interviews and focus groups with women students. We argue that retro-sexist ‘laddish’ forms of masculine competitiveness and misogyny have been reshaped by neoliberal rationalities to become modes of consumerist sexualised audit. We also suggest that neoliberal frameworks scaffold an individualistic and adversarial culture among young people that interacts with perceived threats to men’s privilege and intensifies attempts to put women in their place through misogyny and sexual harassment. Furthermore, ‘lad cultures’, sexism and sexual harassment in higher education may be invisibilised by institutions to preserve marketability in a neoliberal context. In response, we ask if we might foster dialogue and partnership between feminist and anti-marketisation politics

Developmental regulation of MURF E3 ubiquitin ligases in skeletal muscle

The striated muscle-specific tripartite motif (TRIM) proteins TRIM63/MURF1, TRIM55/MURF2 and TRIM54/MURF3 can function as E3 ubiquitin ligases in ubiquitin-mediated muscle protein turnover. Despite the well-characterised role of MURF1 in skeletal muscle atrophy, the dynamics of MURF isogene expression in the development and early postnatal adaptation of skeletal muscle is unknown. Here, we show that MURF2 is the isogene most highly expressed in embryonic skeletal muscle at E15.5, with the 50 kDa A isoform predominantly expressed. MURF1 and MURF3 are upregulated only postnatally. Knockdown of MURF2 p50A by isoform-specific siRNA results in delayed myogenic differentiation and myotube formation in vitro, with perturbation of the stable, glutamylated microtubule population. This underscores that MURF2 plays an important role in the earliest stages of skeletal muscle differentiation and myofibrillogenesis. During further development, there is a shift towards the 60 kDa A isoform, which dominates postnatally. Analysis of the fibre-type expression shows that MURF2 A isoforms are predominantly slow-fibre associated, whilst MURF1 is largely excluded from these fibres, and MURF3 is ubiquitously distributed in both type I and II fibres

Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines

The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers

Star Architecture as Socio-Material Assemblage

Taking inspiration from new materialism and assemblage, the chapter deals with star architects and iconic buildings as socio-material network effects that do not pre-exist action, but are enacted in practice, in the materiality of design crafting and city building. Star architects are here conceptualized as part of broader assemblages of actors and practices ‘making star architecture’ a reality, and the buildings they design are considered not just as unique and iconic objects, but dis-articulated as complex crafts mobilizing skills, technologies, materials, and forms of knowledge not necessarily ascribable to architecture. Overcoming narrow criticism focusing on the symbolic order of icons as unique creations and alienated repetitions of capitalist development, the chapter’s main aim is to widen the scope of critique by bridging culture and economy, symbolism and practicality, making star architecture available to a broad, fragmented arena of (potential) critics, unevenly equipped with critical tools and differentiated experiences