Magnetic signatures of plasma-depleted flux tubes in the Saturnian inner magnetosphere

Initial Cassini observations have revealed evidence for interchanging magnetic flux tubes in the inner Saturnian magnetosphere. Some of the reported flux tubes differ remarkably by their magnetic signatures, having a depressed or enhanced magnetic pressure relative to their surroundings. The ones with stronger fields have been interpreted previously as either outward moving mass-loaded or inward moving plasma-depleted flux tubes based on magnetometer observations only. We use detailed multi-instrumental observations of small and large density depletions in the inner Saturnian magnetosphere from Cassini Rev. A orbit that enable us to discriminate amongst the two previous and opposite interpretations. Our analysis undoubtedly confirms the similar nature of both types of reported interchanging magnetic flux tubes, which are plasma-depleted, whatever their magnetic signatures are. Their different magnetic signature is clearly an effect associated with latitude. These Saturnian plasma-depleted flux tubes ultimately may play a similar role as the Jovian ones

TGF-β stimulates biglycan core protein synthesis but not glycosaminoglycan chain elongation via Akt phosphorylation in vascular smooth muscle

Transforming growth factor-b (TGF-b) can mediate proteoglycan synthesis via Smad and non-Smad signalling pathways in vascular smooth muscle (VSM). We investigated whether TGF-b-mediated proteoglycan synthesis is via PI3K/Akt. TGF-b induced a rapid phosphorylation of Akt that continued upto 4 h. Akt phosphorylation was blocked by Akt1/2 inhibitor SN30978; however, it did not block Smad2 phosphorylation at either the carboxy or linker regions indicating that TGF-bmediated Akt phosphorylation is independent of Smad2 signalling. The role of Akt in TGF-b-mediated proteoglycan synthesis was investigated. Treatment with SN30978 showed a concentration-dependent decrease in TGF-b-mediated [35S]- sulphate and [35S]-Met/Cys incorporation into secreted proteoglycans; however, SDS-PAGE showed no change in biglycan size. In TGF-b-treated cells, biglycan mRNA levels increased by 40-100% in 24 h and was significantly blocked by SN30978. Our findings demonstrate that Akt is a downstream signalling component of TGF-b-mediated biglycan core protein synthesis but not glycosaminoglycan chain hyper-elongation in VSM

Functional Analysis of a Unique Troponin C Mutation, GLY159ASP, that Causes Familial Dilated Cardiomyopathy, Studied in Explanted Heart Muscle

Background-Familial dilated cardiomyopathy can be caused by mutations in the proteins of the muscle thin filament. In vitro, these mutations decrease Ca2+ sensitivity and cross-bridge turnover rate, but the mutations have not been investigated in human tissue. We studied the Ca2+-regulatory properties of myocytes and troponin extracted from the explanted heart of a patient with inherited dilated cardiomyopathy due to the cTnC G159D mutation.Methods and Results-Mass spectroscopy showed that the mutant cTnC was expressed approximately equimolar with wild-type cTnC. Contraction was compared in skinned ventricular myocytes from the cTnC G159D patient and nonfailing donor heart. Maximal Ca2+-activated force was similar in cTnC G159D and donor myocytes, but the Ca2+ sensitivity of cTnC G159D myocytes was higher (EC50 G159D/donor=0.60). Thin filaments reconstituted with skeletal muscle actin and human cardiac tropomyosin and troponin were studied by in vitro motility assay. Thin filaments containing the mutation had a higher Ca2+ sensitivity (EC(50)G159D/donor=0.55 +/- 0.13), whereas the maximally activated sliding speed was unaltered. In addition, the cTnC G159D mutation blunted the change in Ca2+ sensitivity when TnI was dephosphorylated. With wild-type troponin, Ca2+ sensitivity was increased (EC50 P/unP=4.7 +/- 1.9) but not with cTnC G159D troponin (EC50 P/unP=1.2 +/- 0.1).Conclusions-We propose that uncoupling of the relationship between phosphorylation and Ca2+ sensitivity could be the cause of the dilated cardiomyopathy phenotype. The differences between these data and previous in vitro results show that native phosphorylation of troponin I and troponin T and other posttranslational modifications of sarcomeric proteins strongly influence the functional effects of a mutation. (Circ Heart Fail. 2009;2:456-464.

The continuum limit of the static-light meson spectrum

We investigate the continuum limit of the low lying static-light meson spectrum using Wilson twisted mass lattice QCD with N_f = 2 dynamical quark flavours. We consider three values of the lattice spacing a ~ 0.051 fm, 0.064 fm, 0.080 fm and various values of the pion mass in the range 280 MeV < m_PS < 640 MeV. We present results in the continuum limit for light cloud angular momentum j = 1/2, 3/2, 5/2 and for parity P = +, -. We extrapolate our results to physical quark masses, make predictions regarding the spectrum of B and B_s mesons and compare with available experimental results.Comment: 18 pages, 3 figure

Diagnostic performance and reference values of novel biomarkers of paediatric heart failure

Objective: Biomarkers play a pivotal role in heart failure (HF) management. Reference values and insights from studies in adults cannot be extrapolated to the paediatric population due to important differences in pathophysiology and compensatory reserve. We assessed the diagnostic utility of four novel biomarkers in paediatric HF. Methods: Midregional (MR) pro-atrial natriuretic peptide (proANP), soluble ST2 (sST2), growth differentiation factor-15 (GDF-15), MR-pro-adrenomedullin (proADM) and N-terminal pro-B natriuretic peptide (NT-proBNP) were measured in 114 patients and 89 controls. HF was defined as the presence of HF symptoms and/or abnormal systolic ventricular function. Receiver-operating characteristics were plotted, and the area under the curve (AUC) was measured. This was repeated for subgroups with cardiomyopathy and congenital heart disease (CHD). Ventricular systolic function was measured by magnetic resonance or echocardiography. Reference values were calculated according to the current guidelines. Results: The AUC for diagnosing HF was 0.76 for MR-proANP (CI 0.70 to 0.84) and 0.82 for NT-proBNP (CI 0.75 to 0.88). These parameters performed similarly in the subgroups with CHD and cardiomyopathy. By contrast, MR-proADM, GDF-15 and sST2 performed poorly. When used in conjunction with NT-proBNP, no parameter added significantly to its diagnostic accuracy. NT-proBNP, MR-proANP, GDF-15 and sST2 could accurately discriminate between patients with preserved and patients with poor functional status. In a subset of patients with dilated cardiomyopathy, NT-proBNP, MR-proANP, MR-proADM and GDF-15 were associated with poor LV function. Conclusions: MR-proANP could accurately detect HF in children and adolescents. Its diagnostic performance was comparable with that of NT-proBNP, regardless of the underlying condition. Reference values are presented

Perceptions of graduating students from eight medical schools in Vietnam on acquisition of key skills identified by teachers

<p>Abstract</p> <p>Background</p> <p>The eight main Vietnamese medical schools recently cooperated to produce a book listing the knowledge, attitudes and skills expected of a graduate, including specification of the required level for each skill. The teaching program should ensure that students can reach that level. The objective of this study was to determine the perception of graduating students on whether they had achieved the level set for a selection of clinical and public health skills as a guide for the schools to adjust either the levels or the teaching.</p> <p>Methods</p> <p>From all eight schools, 1136 of the 1528 final year students completed questionnaires just before completed all the requirements for graduation, a response rate of 87% overall (ranging from 74–99% per school). They rated their own competence on a scale of 0–5 for 129 skills selected from the 557 skills listed in the book, and reported where they thought they had learned them. The scores that the students gave themselves were then compared to the levels proposed by the teachers for each skill. The proportions of the self-assessed achievement to the levels expected by the teachers, means self-assessed scores and the coefficients of variation were calculated to make comparisons among disciplines, among schools and among learning sites.</p> <p>Results</p> <p>Most students felt they had learned most of the skills for key clinical departments to the required level; this varied little among the schools. Self-assessed skill acquisition in public health and minor clinical disciplines was lower and varied more. Sites outside the classroom were especially important for learning skills. The results revealed key similarities and differences between the teachers and the students in their perception about what could be learned and where</p> <p>Conclusion</p> <p>Revising a curriculum for medical schools demands inputs from all stakeholders. Graduating class students can provide valuable feedback on what they have learned in the existing system. Learning objectives should always be checked with students who have followed their study under existing teaching conditions. The information from the graduates helped to identify potential problem areas where either the objectives or the teaching need adjustment.</p

MAGE-A cancer/testis antigens inhibit MDM2 ubiquitylation function and promote increased levels of MDM4

Melanoma antigen A (MAGE-A) proteins comprise a structurally and biochemically similar sub-family of Cancer/Testis antigens that are expressed in many cancer types and are thought to contribute actively to malignancy. MAGE-A proteins are established regulators of certain cancer-associated transcription factors, including p53, and are activators of several RING finger-dependent ubiquitin E3 ligases. Here, we show that MAGE-A2 associates with MDM2, a ubiquitin E3 ligase that mediates ubiquitylation of more than 20 substrates including mainly p53, MDM2 itself, and MDM4, a potent p53 inhibitor and MDM2 partner that is structurally related to MDM2. We find that MAGE-A2 interacts with MDM2 via the N-terminal p53-binding pocket and the RING finger domain of MDM2 that is required for homo/hetero-dimerization and for E2 ligase interaction. Consistent with these data, we show that MAGE-A2 is a potent inhibitor of the E3 ubiquitin ligase activity of MDM2, yet it does not have any significant effect on p53 turnover mediated by MDM2. Strikingly, however, increased MAGE-A2 expression leads to reduced ubiquitylation and increased levels of MDM4. Similarly, silencing of endogenous MAGE-A expression diminishes MDM4 levels in a manner that can be rescued by the proteasomal inhibitor, bortezomid, and permits increased MDM2/MDM4 association. These data suggest that MAGE-A proteins can: (i) uncouple the ubiquitin ligase and degradation functions of MDM2; (ii) act as potent inhibitors of E3 ligase function; and (iii) regulate the turnover of MDM4. We also find an association between the presence of MAGE-A and increased MDM4 levels in primary breast cancer, suggesting that MAGE-A-dependent control of MDM4 levels has relevance to cancer clinically

Distributions of epistasis in microbes fit predictions from a fitness landscape model.

How do the fitness effects of several mutations combine? Despite its simplicity, this question is central to the understanding of multilocus evolution. Epistasis (the interaction between alleles at different loci), especially epistasis for fitness traits such as reproduction and survival, influences evolutionary predictions "almost whenever multilocus genetics matters". Yet very few models have sought to predict epistasis, and none has been empirically tested. Here we show that the distribution of epistasis can be predicted from the distribution of single mutation effects, based on a simple fitness landscape model. We show that this prediction closely matches the empirical measures of epistasis that have been obtained for Escherichia coli and the RNA virus vesicular stomatitis virus. Our results suggest that a simple fitness landscape model may be sufficient to quantitatively capture the complex nature of gene interactions. This model may offer a simple and widely applicable alternative to complex metabolic network models, in particular for making evolutionary predictions

Hsc70 Focus Formation at the Periphery of HSV-1 Transcription Sites Requires ICP27

The cellular chaperone protein Hsc70, along with components of the 26S proteasome and ubiquitin-conjugated proteins have been shown to be sequestered in discrete foci in the nuclei of herpes simplex virus 1 (HSV-1) infected cells. We recently reported that cellular RNA polymerase II (RNAP II) undergoes proteasomal degradation during robust HSV-1 transcription, and that the immediate early protein ICP27 interacts with the C-terminal domain and is involved in the recruitment of RNAP II to viral transcription/replication compartments.Here we show that ICP27 also interacts with Hsc70, and is required for the formation of Hsc70 nuclear foci. During infection with ICP27 mutants that are unable to recruit RNAP II to viral replication sites, viral transcript levels were greatly reduced, viral replication compartments were poorly formed and Hsc70 focus formation was curtailed. Further, a dominant negative Hsc70 mutant that cannot hydrolyze ATP, interfered with RNAP II degradation during HSV-1 infection, and an increase in ubiquitinated forms of RNAP II was observed. There was also a decrease in virus yields, indicating that proteasomal degradation of stalled RNAP II complexes during robust HSV-1 transcription and replication benefits viral gene expression.We propose that one function of the Hsc70 nuclear foci may be to serve to facilitate the process of clearing stalled RNAP II complexes from viral genomes during times of highly active transcription

The AQUA-FONTIS study: protocol of a multidisciplinary, cross-sectional and prospective longitudinal study for developing standardized diagnostics and classification of non-thyroidal illness syndrome

<p>Abstract</p> <p>Background</p> <p>Non-thyroidal illness syndrome (NTIS) is a characteristic functional constellation of thyrotropic feedback control that frequently occurs in critically ill patients. Although this condition is associated with significantly increased morbidity and mortality, there is still controversy on whether NTIS is caused by artefacts, is a form of beneficial adaptation, or is a disorder requiring treatment. Trials investigating substitution therapy of NTIS revealed contradictory results. The comparison of heterogeneous patient cohorts may be the cause for those inconsistencies.</p> <p>Objectives</p> <p>Primary objective of this study is the identification and differentiation of different functional states of thyrotropic feedback control in order to define relevant evaluation criteria for the prognosis of affected patients. Furthermore, we intend to assess the significance of an innovative physiological index approach (SPINA) in differential diagnosis between NTIS and latent (so-called "sub-clinical") thyrotoxicosis.</p> <p>Secondary objective is observation of variables that quantify distinct components of NTIS in the context of independent predictors of evolution, survival or pathophysiological condition and influencing or disturbing factors like medication.</p> <p>Design</p> <p>The <b>a</b>pproach to a <b>qua</b>ntitative <b>f</b>ollow-up <b>o</b>f <b>n</b>on-<b>t</b>hyroidal <b>i</b>llness <b>s</b>yndrome (AQUA FONTIS study) is designed as both a cross-sectional and prospective longitudinal observation trial in critically ill patients. Patients are observed in at least two evaluation points with consecutive assessments of thyroid status, physiological and clinical data in additional weekly observations up to discharge. A second part of the study investigates the neuropsychological impact of NTIS and medium-term outcomes.</p> <p>The study design incorporates a two-module structure that covers a reduced protocol in form of an observation trial before patients give informed consent. Additional investigations are performed if and after patients agree in participation.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov NCT00591032</p