Героическое в произведениях А.А. Фета о Крымской войне в контексте эстетической полемики ХIХ века

Проблемы героического в военной прозе и поэзии А.А Фета рассматриваются в контексте эстетической полемики второй половины Х1Х века. В ходе исследования литературно-критических материалов и произведений поэта делается попытка пересмотреть существование традиционных стереотипов относительно творчества и личной жизни художника-эстета и прийти к выводу: военная тематика поэта "чистого искусства" не была обособленной от всего его литературного наследия, она органически вписывалась в его эстетическую программу. Героическое в эстетике и творчестве А. Фета представлено наравне с категорией красоты как составляющей категории прекрасного.Проблеми героiчного в военiй прозi та поезii А.А.Фета разглядаються в контекстi літературної полемікі другоїї половини Х1Х сторіччя. В ході дослiдництва лiтературно-крiтичних матерiалiв та творiв поета робиться спроба переглянути iснування традицiйних стереотипiв вiдносно творчостi та особистого життя художника- естета та прийти до висновка: вiйськова тематика поета "чистого мистецтва" не була вiдокремленою вiд всii його спадщини, вона органiчно вписувалась в його естетичну програму. Героiчне в естетицi та творчостi А.Фета надано нарiвнi з категорiєю красоти, як складовоi категорii прекрасного.Heroic problems in war prose and poetry of A.A.Fet are examined in the context of literal controversy of the second part of the 19thcenturi. In the way of research of literal and critical materials and works of the poet the attempt is making to reexamine existence of formed stereotypes which are related to creative work and personal life of artist-design and go up to the conclusion that poet?s war subject-matter of "pure art" was not isolated from all his legacy. It enters organically into his aesthetic program

The effect of watchful waiting compared to immediate test ordering instructions on general practitioners' blood test ordering behaviour for patients with unexplained complaints; a randomized clinical trial (ISRCTN55755886)

<p>Abstract</p> <p>Background</p> <p>Immediate blood testing for patients presenting with unexplained complaints in family practice is superfluous from a diagnostic point of view. However, many general pracitioners (GPs) order tests immediately. Watchful waiting reduces the number of patients to be tested and the number of false-positive results. The objectives of this study are: to determine the feasibility of watchful waiting compared to immediate test ordering; to determine if a special quality improvement strategy can improve this feasibility; and to determine if watchful waiting leads to testing at a later time.</p> <p>Methods</p> <p>The study is a cluster-randomized clinical trial with three groups, on blood test ordering strategies in patients with unexplained complaints. GPs in group one were instructed to order tests immediately and GPs in group two to apply a watchful waiting approach. GPs in group three received the same instruction as group two, but they were supported by a systematically designed quality improvement strategy. A total of 498 patients with unexplained complaints from 63 practices of Dutch GPs participated. We measured: the percentage of patients for whom tests were ordered and number of tests ordered at the first consultation; performance on the strategy's performance objectives (i.e., ordering fewer tests and specific communication skills); the number of tests ordered after four weeks; and GP and patient characteristics.</p> <p>Results</p> <p>Immediate test ordering proved feasible in 92% of the patients; watchful waiting in 86% and 84%, respectively, for groups two and three. The two watchful waiting groups did not differ significantly in the achievement of any of the performance objectives. Of the patients who returned after four weeks, none from group one and six from the two watchful waiting groups had tests ordered for them.</p> <p>Conclusions</p> <p>Watchful waiting is a feasible approach. It does not lead to testing immediately afterwards. Furthermore, watchful waiting was not improved by the quality improvement strategy.</p> <p>Trial registration</p> <p>Clinical trial registration: <a href="http://www.controlled-trials.com/ISRCTN55755886">ISRCTN55755886</a></p

The interplay between helicity and rotation in turbulence: implications for scaling laws and small-scale dynamics

Invariance properties of physical systems govern their behavior: energy conservation in turbulence drives a wide distribution of energy among modes, observed in geophysical or astrophysical flows. In ideal hydrodynamics, the role of helicity conservation (correlation between velocity and its curl, measuring departures from mirror symmetry) remains unclear since it does not alter the energy spectrum. However, with solid body rotation, significant differences emerge between helical and non-helical flows. We first outline several results, like the energy and helicity spectral distribution and the breaking of strict universality for the individual spectra. Using massive numerical simulations, we then show that small-scale structures and their intermittency properties differ according to whether helicity is present or not, in particular with respect to the emergence of Beltrami-core vortices (BCV) that are laminar helical vertical updrafts. These results point to the discovery of a small parameter besides the Rossby number; this could relate the problem of rotating helical turbulence to that of critical phenomena, through renormalization group and weak turbulence theory. This parameter can be associated with the adimensionalized ratio of the energy to helicity flux to small scales, the three-dimensional energy cascade being weak and self-similar

Blood test ordering for unexplained complaints in general practice: the VAMPIRE randomised clinical trial protocol. [ISRCTN55755886]

BACKGROUND: General practitioners (GPs) frequently order blood tests when they see patients presenting with unexplained complaints. Due to the low prevalence of serious pathology in general practice, the risk of false-positive test results is relatively high. This may result in unnecessary further testing, leading to unfavourable effects such as patient anxiety, high costs, somatisation and morbidity. A policy of watchful waiting is expected to lower both the number of patients to be tested and the risk of false-positive test results, without missing serious pathology. However, many general practitioners experience barriers when trying to postpone blood testing by watchful waiting. The objectives of this study are (1) to determine the accuracy of blood tests in patients presenting with unexplained complaints in terms of detecting pathology, (2) to determine the accuracy of a watchful waiting strategy and (3) to determine the effects of a quality improvement strategy to promote the postponement of blood test ordering by GPs for patients with unexplained complaints. DESIGN: General practices are randomised over three groups. Group 1 is instructed to order blood tests immediately, group 2 to apply a watchful waiting policy and group 3 also to postpone testing, but supported by our quality improvement strategy. The trial consists of two sub-studies: a diagnostic study at patient level (group 1 versus groups 2 and 3) and a quality improvement study at GP level (group 2 versus group 3). The diagnostic strategy to be used involves of both customary and innovative tests. The quality improvement strategy consists of two small-group meetings and a practice outreach visit. Patient follow-up ends at 12 months after the initial consultation. Primary outcome measures are the accuracy and added value of blood tests for detecting pathology, the effect of a 4-week postponement of test ordering on the blood test characteristics and the quantity of tests ordered. Secondary outcome measures are the course of complaints, quality of life, satisfaction with care, anxiety of patients and practitioners, determinants of physicians' behaviour, health care utilisation and costs. DISCUSSION: The innovative aspect of this trial is that it combines a clinical-epidemiological study and a quality of care study

The deleted in brachydactyly B domain of ROR2 is required for receptor activation by recruitment of Src

The transmembrane receptor 'ROR2' resembles members of the receptor tyrosine kinase family of signalling receptors in sequence but its' signal transduction mechanisms remain enigmatic. This problem has particular importance because mutations in ROR2 are associated with two human skeletal dysmorphology syndromes, recessive Robinow Syndrome (RS) and dominant acting Brachydactyly type B (BDB). Here we show, using a constitutive dimerisation approach, that ROR2 exhibits dimerisation-induced tyrosine kinase activity and the ROR2 C-terminal domain, which is deleted in BDB, is required for recruitment and activation of the non-receptor tyrosine kinase Src. Native ROR2 phosphorylation is induced by the ligand Wnt5a and is blocked by pharmacological inhibition of Src kinase activity. Eight sites of Src-mediated ROR2 phosphorylation have been identified by mass spectrometry. Activation via tyrosine phosphorylation of ROR2 receptor leads to its internalisation into Rab5 positive endosomes. These findings show that BDB mutant receptors are defective in kinase activation as a result of failure to recruit Src

SCN1A-deficient excitatory neuronal networks display mutation-specific phenotypes

Dravet syndrome is a severe epileptic encephalopathy, characterized by (febrile) seizures, behavioural problems and developmental delay. Eighty per cent of patients with Dravet syndrome have a mutation in SCN1A, encoding Nav1.1. Milder clinical phenotypes, such as GEFS+ (generalized epilepsy with febrile seizures plus), can also arise from SCN1A mutations. Predicting the clinical phenotypic outcome based on the type of mutation remains challenging, even when the same mutation is inherited within one family. This clinical and genetic heterogeneity adds to the difficulties of predicting disease progression and tailoring the prescription of anti-seizure medication. Understanding the neuropathology of different SCN1A mutations may help to predict the expected clinical phenotypes and inform the selection of best-fit treatments. Initially, the loss of Na+-current in inhibitory neurons was recognized specifically to result in disinhibition and consequently seizure generation. However, the extent to which excitatory neurons contribute to the pathophysiology is currently debated and might depend on the patient clinical phenotype or the specific SCN1A mutation. To examine the genotype-phenotype correlations of SCN1A mutations in relation to excitatory neurons, we investigated a panel of patient-derived excitatory neuronal networks differentiated on multi-electrode arrays. We included patients with different clinical phenotypes, harbouring various SCN1A mutations, along with a family in which the same mutation led to febrile seizures, GEFS+ or Dravet syndrome. We hitherto describe a previously unidentified functional excitatory neuronal network phenotype in the context of epilepsy, which corresponds to seizurogenic network prediction patterns elicited by proconvulsive compounds. We found that excitatory neuronal networks were affected differently, depending on the type of SCN1A mutation, but did not segregate according to clinical severity. Specifically, loss-of-function mutations could be distinguished from missense mutations, and mutations in the pore domain could be distinguished from mutations in the voltage sensing domain. Furthermore, all patients showed aggravated neuronal network responses at febrile temperatures compared with controls. Finally, retrospective drug screening revealed that anti-seizure medication affected GEFS+ patient- but not Dravet patient-derived neuronal networks in a patient-specific and clinically relevant manner. In conclusion, our results indicate a mutation-specific excitatory neuronal network phenotype, which recapitulates the foremost clinically relevant features, providing future opportunities for precision therapies.</p

Neuronal network dysfunction in a model for Kleefstra syndrome mediated by enhanced NMDAR signaling

Kleefstra syndrome (KS) is a neurodevelopmental disorder caused by mutations in the histone methyltransferase EHMT1. To study the impact of decreased EHMT1 function in human cells, we generated excitatory cortical neurons from induced pluripotent stem (iPS) cells derived from KS patients. Neuronal networks of patient-derived cells exhibit network bursting with a reduced rate, longer duration, and increased temporal irregularity compared to control networks. We show that these changes are mediated by upregulation of NMDA receptor (NMDAR) subunit 1 correlating with reduced deposition of the repressive H3K9me2 mark, the catalytic product of EHMT1, at the GRIN1 promoter. In mice EHMT1 deficiency leads to similar neuronal network impairments with increased NMDAR function. Finally, we rescue the KS patient-derived neuronal network phenotypes by pharmacological inhibition of NMDARs. Summarized, we demonstrate a direct link between EHMT1 deficiency and NMDAR hyperfunction in human neurons, providing a potential basis for more targeted therapeutic approaches for KS

Regulation of MYCN expression in human neuroblastoma cells

Contains fulltext : 81722.pdf (publisher's version ) (Open Access)BACKGROUND: Amplification of the MYCN gene in neuroblastoma (NB) is associated with a poor prognosis. However, MYCN-amplification does not automatically result in higher expression of MYCN in children with NB. We hypothesized that the discrepancy between MYCN gene expression and prognosis in these children might be explained by the expression of either MYCN-opposite strand (MYCNOS) or the shortened MYCN-isoform (DeltaMYCN) that was recently identified in fetal tissues. Both MYCNOS and DeltaMYCN are potential inhibitors of MYCN either at the mRNA or at the protein level. METHODS: Expression of MYCN, MYCNOS and DeltaMYCN was measured in human NB tissues of different stages. Transcript levels were quantified using a real-time reverse transcriptase polymerase chain reaction assay (QPCR). In addition, relative expression of these three transcripts was compared to the number of MYCN copies, which was determined by genomic real-time PCR (gQPCR). RESULTS: Both DeltaMYCN and MYCNOS are expressed in all NBs examined. In NBs with MYCN-amplification, these transcripts are significantly higher expressed. The ratio of MYCN:DeltaMYCN expression was identical in all tested NBs. This indicates that DeltaMYCN and MYCN are co-regulated, which suggests that DeltaMYCN is not a regulator of MYCN in NB. However, the ratio of MYCNOS:MYCN expression is directly correlated with NB disease stage (p = 0.007). In the more advanced NB stages and NBs with MYCN-amplification, relatively more MYCNOS is present as compared to MYCN. Expression of the antisense gene MYCNOS might be relevant to the progression of NB, potentially by directly inhibiting MYCN transcription by transcriptional interference at the DNA level. CONCLUSION: The MYCNOS:MYCN-ratio in NBs is significantly correlated with both MYCN-amplification and NB-stage. Our data indicate that in NB, MYCN expression levels might be influenced by MYCNOS but not by DeltaMYCN

Analysis of Large Phenotypic Variability of EEC and SHFM4 Syndromes Caused by K193E Mutation of the TP63 Gene

EEC (ectrodactyly, ectodermal dysplasia, clefting; OMIM 604292) is an autosomal dominant developmental disorder resulting mainly from pathogenic mutations of the DNA-binding domain (DBD) of the TP63 gene. In this study, we showed that K193E mutation in nine affected individuals of a four-generation kindred with a large degree of phenotypic variability causes four different syndromes or TP63-related disorders: EEC, Ectrodactyly-ectodermal dysplasia (EE), isolated ectodermal dysplasia, and isolated Split Hand/Foot Malformation type 4 (SHFM4). Genotype-phenotype and DBD structural modeling analysis showed that the K193-located loop L2-A is associated with R280 through hydrogen bonding interactions, while R280 mutations also often cause large phenotypic variability of EEC and SHFM4. Thus, we speculate that K193 and several other DBD mutation-associated syndromes may share similar pathogenic mechanisms, particularly in the case of the same mutation with different phenotypes. Our study and others also suggest that the phenotypic variability of EEC is attributed, at least partially, to genetic and/or epigenetic modifiers

The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress

The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex might be connected on a unique pathway essential for the safe expansion of neuronal cells. Here, we show that MYCN transcriptionally controls the expression of each component of the MRN complex. By genetic and pharmacological inhibition of the MRN complex in a MYCN overexpression model and in the more physiological context of the Hedgehog-dependent expansion of primary cerebellar granule progenitor cells, we also show that the MRN complex is required for MYCN-dependent proliferation. Indeed, its inhibition resulted in DNA damage, activation of a DNA damage response, and cell death in a MYCN- and replication-dependent manner. Our data indicate the MRN complex is essential to restrain MYCN-induced replication stress during neural cell proliferation and support the hypothesis that replication-born DNA damage is responsible for the neuronal defects associated with MRN dysfunctions.Cell Death and Differentiation advance online publication, 12 June 2015; doi:10.1038/cdd.2015.81