Serine 58 of 14-3-3ζ Is a molecular switch regulating ASK1 and oxidant stress-induced cell death

Oxidant stress is a ubiquitous stressor with negative impacts on multiple cell types. ASK1 is a central mediator of oxidant injury, but while mechanisms of its inhibition, such as sequestration by 14-3-3 proteins and thioredoxin, have been identified, mechanisms of activation have remained obscure and the signaling pathways regulating this are not clear. Here, we report that phosphorylation of 14-3-3ζ at serine 58 (S58) is dynamically regulated in the cell and that the phosphorylation status of S58 is a critical factor regulating oxidant stress-induced cell death. Phosphorylation of S58 releases ASK1 from 14-3-3ζ, and ASK1 then activates stress-activated protein kinases, leading to cell death. While several members of the mammalian sterile 20 (Mst) family of kinases can phosphorylate S58 when overexpressed, we identify Ste20/oxidant stress response kinase 1 (SOK-1), an Mst family member known to be activated by oxidant stress, as a central endogenous regulator of S58 phosphorylation and thereby of ASK1-mediated cell death. Our findings identify a novel pathway that regulates ASK1 activation and oxidant stress-induced cell death

High Efficiency Traveling-Wave Tube Power Amplifier for Ka-Band Software Defined Radio on International Space Station-A Platform for Communications Technology Development

The design, fabrication and RF performance of the output traveling-wave tube amplifier (TWTA) for a space based Ka-band software defined radio (SDR) is presented. The TWTA, the SDR and the supporting avionics are integrated to forms a testbed, which is currently located on an exterior truss of the International Space Station (ISS). The SDR in the testbed communicates at Ka-band frequencies through a high-gain antenna directed to NASA s Tracking and Data Relay Satellite System (TDRSS), which communicates to the ground station located at White Sands Complex. The application of the testbed is for demonstrating new waveforms and software designed to enhance data delivery from scientific spacecraft and, the waveforms and software can be upgraded and reconfigured from the ground. The construction and the salient features of the Ka-band SDR are discussed. The testbed is currently undergoing on-orbit checkout and commissioning and is expected to operate for 3 to 5 years in space

Monitoring asthma in childhood : symptoms, exacerbations and quality of life

Acknowledgements The Task Force members and their affiliations are as follows. Paul L.P. Brand: Princess Amalia Children’s Centre, Isala Hospital, Zwolle, and UMCG Postgraduate School of Medicine, University Medical Centre and University of Groningen, Groningen, The Netherlands; Mika J. Mäkelä: Skin and Allergy Hospital, Helsinki University Hospital, Helsinki, Finland; Stanley J. Szefler: Children’s Hospital Colorado and University of Colorado Denver School of Medicine, Denver, CO, USA; Thomas Frischer: Dept of Paediatrics and Paediatric Surgery, Wilhelminenspital, Vienna, Austria; David Price: Dept of Primary Care Respiratory Medicine, Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; Eugenio Baraldi: Women’s and Children’s Health Dept, Unit of Respiratory Medicine and Allergy, University of Padova, Padova, Italy; Kai-Hakon Carlsen: Dept of Paediatrics, Women and Children’s Division, University of Oslo, and Oslo University Hospital, Oslo, Norway; Ernst Eber: Respiratory and Allergic Disease Division, Dept of Paediatrics and Adolescence Medicine, Medical University of Graz, Graz, Austria; Gunilla Hedlin: Dept of Women’s and Children’s Health and Centre for Allergy Research, Karolinska Institutet, and Astrid Lindgren Children’s hospital, Stockholm, Sweden; Neeta Kulkarni: Leicestershire Partnership Trust and Dept of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK; Christiane Lex: Dept of Paediatric Cardiology and Intensive Care Medicine, Division of Paediatric Respiratory Medicine, University Hospital Goettingen, Goettingen, Germany; Karin C. Lødrup Carlsen: Dept of Paediatrics, Women and Children’s Division, Oslo University Hospital, and Dept of Paediatrics, Faculty of Medicine, University of Oslo, Oslo, Norway; Eva Mantzouranis: Dept of Paediatrics, University Hospital of Heraklion, University of Crete, Heraklion, Greece; Alexander Moeller: Division of Respiratory Medicine, University Children’s Hospital Zurich, Zurich, Switzerland; Ian Pavord: Dept of Respiratory Medicine, University of Oxford, Oxford, UK; Giorgio Piacentini: Paediatric Section, Dept of Life and Reproduction Sciences, University of Verona, Verona, Italy; Mariëlle W. Pijnenburg: Dept Paediatrics/Paediatric Respiratory Medicine, Erasmus MC - Sophia Children’s Hospital, Rotterdam, The Netherlands; Bart L. Rottier: Dept of Pediatric Pulmonology and Allergology, GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Sejal Saglani: Leukocyte Biology and Respiratory Paediatrics, National Heart and Lung Institute, Imperial College London, London, UK; Peter D. Sly: Queensland Children’s Medical Research Institute, The University of Queensland, Brisbane, Australia; Steve Turner: Dept of Paediatrics, University of Aberdeen, Aberdeen, UK; Edwina Wooler: Royal Alexandra Children’s Hospital, Brighton, UK.Peer reviewedPublisher PD

IRC+10216's Innermost Envelope -- The eSMA's View

We used the Extended Submillimeter Array (eSMA) in its most extended configuration to investigate the innermost (within a radius of 290 R* from the star) circumstellar envelope (CSE) of IRC+10216. We imaged the CSE using HCN and other molecular lines with a beam size of 0."22 x 0."46, deeply into the very inner edge (15 R*) of the envelope where the expansion velocity is only 3 km/s. The excitation mechanism of hot HCN and KCl maser lines is discussed. HCN maser components are spatially resolved for the first time on an astronomical object. We identified two discrete regions in the envelope: a region with a radius of . 15 R*, where molecular species have just formed and the gas has begun to be accelerated (region I) and a shell region (region II) with a radius of 23 R* and a thickness of 15 R*, whose expansion velocity has reached up to 13 km/s, nearly the terminal velocity of 15 km/s. The Si$^{34}$S line detected in region I shows a large expansion velocity of 16 km/s due to strong wing components, indicating that the emission may arise from a shock region in the innermost envelope. In region II, the P.A. of the most copious mass loss direction was found to be 120 +/- 10 degrees, which may correspond to the equatorial direction of the star. Region II contains a torus-like feature. These two regions may have emerged due to significant differences in the size distributions of the dust particles in the two regions.Comment: 26 pages, 8 figures, accepted for publication in The Astrophysical Journal. Please find the pdf at http://www.submm.caltech.edu/~hs/astroph/0904.0280.pdf and the ps file at http://www.submm.caltech.edu/~hs/astroph/0904.0280.p

Mechanisms of hypertension during and after orthotopic liver transplantation in children

The aim of this study was to assess the hormonal alterations that may mediate the systemic hypertension that develops in patients during the perioperative period of orthotopic liver transplantation. We studied nine pediatric patients without previous hypertension or renal disease during six time points, starting before transplantation and ending at 48 hours after surgery. Hypertension developed in all patients in association with central venous pressures <10 mm Hg. Free water clearance was negative in all nine patients. Vasopressin levels increased intraoperatively but fell as hypertension developed. Atrial natriuretic factor levels increased as systemic blood pressure rose. A high level of plasma renin activity was observed in four patients with renal insufficiency. In six patients, postoperative 24-hour urinary norepinephrine excretion was within the normal age-adjusted range. These findings suggest that the combination of cyclosporine, corticosteroids, and, in some patients, an elevated plasma renin activity prevents the kidney from responding to the acute volume and salt overload with an appropriate diuresis and natriuresis, thus leading to systemic hypertension. The treatment of hypertension after liver transplantation may include salt restriction, diuretics, and, in those patients with a low creatinine excretion index, anglotensin coverting enzyme inhibitors. © 1989 The C. V. Mosby Company

Reclaiming professional identity through postgraduate professional development: Career practitioners reclaiming their professional selves

Careers advisers in the UK have experienced significant change and upheaval within their professional practice. This research explores the role of postgraduate level professional development in contributing to professional identity. The research utilises a case study approach and adopts multiple tools to provide an in-depth examination of practitioners’ perceptions of themselves as professionals within their lived world experience. It presents a group of practitioners struggling to define themselves as professionals due to changing occupational nomenclature resulting from shifting government policy. Postgraduate professional development generated a perceived enhancement in professional identity through exposure to theory, policy and opportunities for reflection, thus contributing to more confident and empowered practitioners. Engagement with study facilitated development of confident, empowered practitioners with a strengthened sense of professional self

Wnt signaling exerts an antiproliferative effect on adult cardiac progenitor cells through IGFBP3.

RATIONALE: Recent work in animal models and humans has demonstrated the presence of organ-specific progenitor cells required for the regenerative capacity of the adult heart. In response to tissue injury, progenitor cells differentiate into specialized cells, while their numbers are maintained through mechanisms of self-renewal. The molecular cues that dictate the self-renewal of adult progenitor cells in the heart, however, remain unclear. OBJECTIVE: We investigate the role of canonical Wnt signaling on adult cardiac side population (CSP) cells under physiological and disease conditions. METHODS AND RESULTS: CSP cells isolated from C57BL/6J mice were used to study the effects of canonical Wnt signaling on their proliferative capacity. The proliferative capacity of CSP cells was also tested after injection of recombinant Wnt3a protein (r-Wnt3a) in the left ventricular free wall. Wnt signaling was found to decrease the proliferation of adult CSP cells, both in vitro and in vivo, through suppression of cell cycle progression. Wnt stimulation exerted its antiproliferative effects through a previously unappreciated activation of insulin-like growth factor binding protein 3 (IGFBP3), which requires intact IGF binding site for its action. Moreover, injection of r-Wnt3a after myocardial infarction in mice showed that Wnt signaling limits CSP cell renewal, blocks endogenous cardiac regeneration and impairs cardiac performance, highlighting the importance of progenitor cells in maintaining tissue function after injury. CONCLUSIONS: Our study identifies canonical Wnt signaling and the novel downstream mediator, IGFBP3, as key regulators of adult cardiac progenitor self-renewal in physiological and pathological states

Autonomic pain responses during sleep: a study of heart rate variability

The autonomic nervous system (ANS) reacts to nociceptive stimulation during sleep, but whether this reaction is contingent to cortical arousal, and whether one of the autonomic arms (sympathetic/parasympathetic) predominates over the other remains unknown. We assessed ANS reactivity to nociceptive stimulation during all sleep stages through heart rate variability, and correlated the results with the presence of cortical arousal measured in concomitant 32-channel EEG. Fourteen healthy volunteers underwent whole-night polysomnography during which nociceptive laser stimuli were applied over the hand. RR intervals (RR) and spectral analysis by wavelet transform were performed to assess parasympathetic (HF(WV)) and sympathetic (LF(WV) and LF(WV)/HF(WV) ratio) reactivity. During all sleep stages, RR significantly decreased in reaction to nociceptive stimulations, reaching a level similar to that of wakefulness, at the 3rd beat post-stimulus and returning to baseline after seven beats. This RR decrease was associated with an increase in sympathetic LF(WV) and LF(WV)/HF(WV) ratio without any parasympathetic HF(WV) change. Albeit RR decrease existed even in the absence of arousals, it was significantly higher when an arousal followed the noxious stimulus. These results suggest that the sympathetic-dependent cardiac activation induced by nociceptive stimuli is modulated by a sleep dependent phenomenon related to cortical activation and not by sleep itself, since it reaches a same intensity whatever the state of vigilance

Learning and development journeys towards effective communications with children

There are continuing concerns about the quality of social workers' communication and engagement with children. This has led to a focus in England on whether qualifying courses prepare students sufficiently for practice. Although research has uncovered the capabilities social workers need to engage and communicate effectively with children, there has continued to be limited evidence in relation to which pedagogical approaches might best enable students to develop capability. This paper attempts to address some of this deficit by reporting in-depth case study findings from a larger longitudinal study into the factors that supported a cohort of students in England in learning to communicate with children. Case analyses are presented in respect of two participants whose learning journeys were emblematic of many in the cohort. Their trajectories draw attention to the significant role that pre-course experience with children can play in the development of students' self-efficacy and in providing a rich source of experiential learning that can be built upon. Suggestions are made for how qualifying courses might provide alternative experiential learning opportunities, including role play, child observation and opportunities for reflection on pre-course experience with adults to help students establish the transferability of their learning

GSK-3alpha directly regulates beta-adrenergic signaling and the response of the heart to hemodynamic stress in mice.

The glycogen synthase kinase-3 (GSK-3) family of serine/threonine kinases consists of 2 highly related isoforms, alpha and beta. Although GSK-3beta has an important role in cardiac development, much remains unknown about the function of either GSK-3 isoform in the postnatal heart. Herein, we present what we believe to be the first studies defining the role of GSK-3alpha in the mouse heart using gene targeting. Gsk3a(-/-) mice over 2 months of age developed progressive cardiomyocyte and cardiac hypertrophy and contractile dysfunction. Following thoracic aortic constriction in young mice, we observed enhanced hypertrophy that rapidly transitioned to ventricular dilatation and contractile dysfunction. Surprisingly, markedly impaired beta-adrenergic responsiveness was found at both the organ and cellular level. This phenotype was reproduced by acute treatment of WT cardiomyocytes with a small molecule GSK-3 inhibitor, confirming that the response was not due to a chronic adaptation to LV dysfunction. Thus, GSK-3alpha appears to be the central regulator of a striking range of essential processes, including acute and direct positive regulation of beta-adrenergic responsiveness. In the absence of GSK-3alpha, the heart cannot respond effectively to hemodynamic stress and rapidly fails. Our findings identify what we believe to be a new paradigm of regulation of beta-adrenergic signaling and raise concerns given the rapid expansion of drug development targeting GSK-3