Molecular aging and rejuvenation of human muscle stem cells

Very little remains known about the regulation of human organ stem cells (in general, and during the aging process), and most previous data were collected in short-lived rodents. We examined whether stem cell aging in rodents could be extrapolated to genetically and environmentally variable humans. Our findings establish key evolutionarily conserved mechanisms of human stem cell aging. We find that satellite cells are maintained in aged human skeletal muscle, but fail to activate in response to muscle attrition, due to diminished activation of Notch compounded by elevated transforming growth factor beta (TGF-β)/phospho Smad3 (pSmad3). Furthermore, this work reveals that mitogen-activated protein kinase (MAPK)/phosphate extracellular signal-regulated kinase (pERK) signalling declines in human muscle with age, and is important for activating Notch in human muscle stem cells. This molecular understanding, combined with data that human satellite cells remain intrinsically young, introduced novel therapeutic targets. Indeed, activation of MAPK/Notch restored ‘youthful’ myogenic responses to satellite cells from 70-year-old humans, rendering them similar to cells from 20-year-old humans. These findings strongly suggest that aging of human muscle maintenance and repair can be reversed by ‘youthful’ calibration of specific molecular pathways

“Maybe I Made Up the Whole Thing”: Placebos and Patients’ Experiences in a Randomized Controlled Trial

Patients in the placebo arms of randomized controlled trials (RCT) often experience positive changes from baseline. While multiple theories concerning such “placebo effects” exist, peculiarly, none has been informed by actual interviews of patients undergoing placebo treatment. Here, we report on a qualitative study (n = 27) embedded within a RCT (n = 262) in patients with irritable bowel syndrome. Besides identical placebo acupuncture treatment in the RCT, the qualitative study patients also received an additional set of interviews at the beginning, midpoint, and end of the trial. Interviews of the 12 qualitative subjects who underwent and completed placebo treatment were transcribed. We found that patients (1) were persistently concerned with whether they were receiving placebo or genuine treatment; (2) almost never endorsed “expectation” of improvement but spoke of “hope” instead and frequently reported despair; (3) almost all reported improvement ranging from dramatic psychosocial changes to unambiguous, progressive symptom improvement to tentative impressions of benefit; and (4) often worried whether their improvement was due to normal fluctuations or placebo effects. The placebo treatment was a problematic perturbation that provided an opportunity to reconstruct the experiences of the fluctuations of their illness and how it disrupted their everyday life. Immersion in this RCT was a co-mingling of enactment, embodiment and interpretation involving ritual performance and evocative symbols, shifts in bodily sensations, symptoms, mood, daily life behaviors, and social interactions, all accompanied by self-scrutiny and re-appraisal. The placebo effect involved a spectrum of factors and any single theory of placebo—e.g. expectancy, hope, conditioning, anxiety reduction, report bias, symbolic work, narrative and embodiment—provides an inadequate model to explain its salubrious benefits

Just enough structure at the edge of chaos: Agile information system development in practice

Agile information systems development is not well understood and suffers from a lack of sustainable theories, which are based on empirical research of practice. We use a framework that focuses on the ‘edge of chaos’ as the area, where agile information systems development takes place to fill in this gap. Our study identifies for a concrete project under investigation, where the beneficial balance between stability and instability lies. It discusses the circumstances, which influence this balance and the relationships of the elements, which constitute it

Incommensurable worldviews? Is public use of complementary and alternative medicines incompatible with support for science and conventional medicine?

Proponents of controversial Complementary and Alternative Medicines, such as homeopathy, argue that these treatments can be used with great effect in addition to, and sometimes instead of, ?conventional? medicine. In doing so, they accept the idea that the scientific approach to the evaluation of treatment does not undermine use of and support for some of the more controversial CAM treatments. For those adhering to the scientific canon, however, such efficacy claims lack the requisite evidential basis from randomised controlled trials. It is not clear, however, whether such opposition characterises the views of the general public. In this paper we use data from the 2009 Wellcome Monitor survey to investigate public use of and beliefs about the efficacy of a prominent and controversial CAM within the United Kingdom, homeopathy. We proceed by using Latent Class Analysis to assess whether it is possible to identify a sub-group of the population who are at ease in combining support for science and conventional medicine with use of CAM treatments, and belief in the efficacy of homeopathy. Our results suggest that over 40% of the British public maintain positive evaluations of both homeopathy and conventional medicine simultaneously. Explanatory analyses reveal that simultaneous support for a controversial CAM treatment and conventional medicine is, in part, explained by a lack of scientific knowledge as well as concerns about the regulation of medical research

Transport of Proteins into Mitochondria

The mitochondrial ADP/ATP carrier is an integral transmembrane protein of the inner membrane. It is synthesized on cytoplasmic ribosomes. Kinetic data suggested that this protein is transferred into mitochondria in a posttranslational manner. The following results provide further evidence for such a mechanism and provide information on its details. 1. In homologous and heterologous translation systems the newly synthesized ADP/ATP carrier protein is present in the postribosomal supernatant. 2. Analysis by density gradient centrifugation and gel filtration shows, that the ADP/ATP carrier molecules in the postribosomal fraction are present as soluble complexes with apparent molecular weights of about 120000 and 500000 or larger. The carrier binds detergents such as Triton X-100 and deoxycholate forming mixed micelles with molecular weights of about 200000–400000. 3. Incubation of a postribosomal supernatant of a reticulocyte lysate containing newly synthesized ADP/ATP carrier with mitochondria isolated from Neurospora spheroplasts results in efficient transfer of the carrier into mitochondria. About 20–30% of the transferred carrier are resistant to proteinase in whole mitochondria. The authentic mature protein is also largely resistant to proteinase in whole mitochondria and sensitive after lysis of mitochondria with detergent. Integrity of mitochondria is a prerequisite for translocation into proteinase resistant position. 4. The transfer in vitro into a proteinase-resistant form is inhibited by the uncoupler carbonyl-cyanide m-chlorophenylhydrazone but not the proteinase-sensitive binding. These observations suggest that the posttranslational transfer of ADP/ATP carrier occurs via the cytosolic space through a soluble oligomeric precursor form. This precursor is taken up by intact mitochondria into an integral position in the membrane. These findings are considered to be of general importance for the intracellular transfer of insoluble membrane proteins. They support the view that such proteins can exist in a water-soluble form its precursors and upon integration into the membrane undergo a conformational change. Uptake into the membrane may involve the cleavage of an additional sequence in some proteins, but this appears not to be a prerequisite as demonstrated by the ADP/ATP carrier protein

Different Transport Pathways of Individual Precursor Proteins in Mitochondria

Transport of mitochondrial precursor proteins into mitochondria of Neurospora crassa was studied in a cellfree reconstituted system. Precursors were synthesized in a reticulocyte lysate programmed with Neurospora mRNA and transported into isolated mitochondria in the absence of protein synthesis. Uptake of the following precursors was investigated: apocytochrome c, ADP/ATP carrier and subunit 9 of the oligomycin-sensitive ATPase. Addition of high concentrations of unlabelled chemically prepared apocytochrome c (1–10 μM) inhibited the appearance in the mitochondrial of labelled cytochrome c synthesized in vitro because the unlabelled protein dilutes the labelled one and because the translocation system has a limited capacity [apparent V is 1–3 pmol × min−1× (mg mitochondrial protein)−1]. Concentrations of added apocytochrome c exceeding the concentrations of precursor proteins synthesized in vitro by a factor of about 104 did not inhibit the transfer of ADP/ATP carrier or ATPase subunit 9 into mitochondria. Carbonylcyanide m-chlorophenylhydrazone, an uncoupler of oxidative phosphorylation, inhibited transfer in vitro of ADP/ATP carrier and of ATPase subunit 9, but not of cytochrome c. These findings suggest that cytochrome c and the other two proteins have different import pathways into mitochondria. It can be inferred from the data presented that different 'receptors' on the mitochondrial surface mediate the specific recognition of precursor proteins by mitochondria as a first step in the transport process

Enterprise agility: A Balancing Act - a local government case study

Austerity and financial constraints have been threatening the public sector in the UK for a number of years. Foreseeing the threat of continued budget cuts, and addressing the situation many local councils face, requires internal transformations for financial stability without losing the key focus on public service. Agile transformations have been undertaken by organisations wanting to learn from the software development community and bringing agile principles into the wider organisation. This paper describes and analyses an ongoing behaviour-led transformation in a district council in the UK. It presents the results of the analysis of 19 interviews with internal stakeholders at the council, of observations of meetings among senior and middle management in a five-month period. The paper explores the successes and the challenges encountered towards the end of the transformation process and reflects on balancing acts to address the challenges, be-tween: disruption and business as usual, empowerment and goal setting, autonomy and processes and procedures, and behaviours and skills. Based on our findings, we suggest that behaviours on their own cannot guarantee a sustained agile culture, and that this is equally important for enterprise agility and for large-scale agile software development transformations

Escala de perceção dos alunos sobre o feedback dos professores: construção e validação

O presente estudo procura testar as propriedades psicométricas de um questionário que avalia (a) perceção do aluno sobre o feedback do professor; a identificação escolar do aluno; as trajetórias escolares (factos e expectativas) e; a perceção do aluno sobre o seu envolvimento escolar. O questionário foi aplicado a 1089 alunos dos 6º, 7º, 9º e 10º anos de escolaridade (M=13.4, DP=1.7), sendo que 52% são do sexo feminino. A amostra é composta por alunos essencialmente de nacionalidade portuguesa (95.9%). A partir dos resultados da análise factorial e seguindo o racional teórico, chegou-se a uma estrutura composta por oito dimensões principais. O QFITE apresenta bons índices de consistência interna, com sete das oito principais dimensões a obterem valores entre .77 e .89. Assim, as análises psicométricas realizadas revelam valores satisfatórios, concluindo-se que o QFITE é um instrumento útil e adequado para avaliar a identificação escolar dos alunos, o envolvimento comportamental escolar, e as perceções dos alunos sobre o feedback do professor

Biosynthesis of Mitochondrial Porin and Insertion into the Outer Mitochondrial Membrane of Neuruspora crassa

Mitochondrial porin, the major protein of the outer mitochondrial membrane is synthesized by free cytoplasmic polysomes. The apparent molecular weight of the porin synthesized in homologous or heterologous cell-free systems is the same as that of the mature porin. Transfer in vitro of mitochondrial porin from the cytosolic fraction into the outer membrane of mitochondria could be demonstrated. Before membrane insertion, mitochondrial porin is highly sensitive to added proteinase; afterwards it is strongly protected. Binding of the precursor form to mitochondria occurs at 4°C and appears to precede insertion into the membrane. Unlike transfer of many precursor proteins into or across the inner mitochondrial membrane, assembly of the porin is not dependent on an electrical potential across the inner membrane

How Malthusian Ideology crept into the Newsroom: British tabloids and the coverage of the ‘underclass’

This article argues that Malthusianism as a series of discursive regimes, developed in the Victorian-era, serves in times of austerity to reproduce an elite understanding of social exclusion in which those in a state of poverty are to blame for their own situation. It highlights that Malthusianism is present in the public discourse, becoming an underlining feature in news coverage of the so-called ‘underclass’. Our findings broadly contradict the normative claim that journalism ‘speaks truth to power’, and suggest instead that overall as a political practice, journalism tends to reproduce and reinforce hegemonic discourses of power. The piece is based on critical discourse analysis (CDA), which has been applied to a significant sample of news articles published by tabloid newspapers in Britain which focussed on the concept of the ‘underclass’. By looking at the evidence, the authors argue that the ‘underclass’ is a concept used by some journalists to cast people living in poverty as ‘undeserving’ of public and state support. In so doing, these journalists help create a narrative which supports cuts in welfare provisions and additional punitive measures against some of the most vulnerable members of society