MEF2 impairment underlies skeletal muscle atrophy in polyglutamine disease

Polyglutamine (polyQ) tract expansion leads to proteotoxic misfolding and drives a family of nine diseases. We study spinal and bulbar muscular atrophy (SBMA), a progressive degenerative disorder of the neuromuscular system caused by the polyQ androgen receptor (AR). Using a knock-in mouse model of SBMA, AR113Q mice, we show that E3 ubiquitin ligases which are a hallmark of the canonical muscle atrophy machinery are not induced in AR113Q muscle. Similarly, we find no evidence to suggest dysfunction of signaling pathways that trigger muscle hypertrophy or impairment of the muscle stem cell niche. Instead, we find that skeletal muscle atrophy is characterized by diminished function of the transcriptional regulator Myocyte Enhancer Factor 2 (MEF2), a regulator of myofiber homeostasis. Decreased expression of MEF2 target genes is age- and glutamine tract length-dependent, occurs due to polyQ AR proteotoxicity, and is associated with sequestration of MEF2 into intranuclear inclusions in muscle. Skeletal muscle from R6/2 mice, a model of Huntington disease which develops progressive atrophy, also sequesters MEF2 into inclusions and displays age-dependent loss of MEF2 target genes. Similarly, SBMA patient muscle shows loss of MEF2 target gene expression, and restoring MEF2 activity in AR113Q muscle rescues fiber size and MEF2-regulated gene expression. This work establishes MEF2 impairment as a novel mechanism of skeletal muscle atrophy downstream of toxic polyglutamine proteins and as a therapeutic target for muscle atrophy in these disorders

CMV infection of liver transplant recipients: comparison of antigenemia and molecular biology assays

BACKGROUND: CMV is a major clinical problem in transplant recipients. Thus, it is important to use sensitive and specific diagnostic techniques to rapidly and accurately detect CMV infection and identify patients at risk of developing CMV disease. In the present study, CMV infection after liver transplantation was monitored retrospectively by two molecular biology assays - a quantitative PCR assay and a qualitative NASBA assay. The results were compared with those obtained by prospective pp65 antigenemia determinations. MATERIALS AND METHODS: 87 consecutive samples from 10 liver transplanted patients were tested for CMV by pp65 antigenemia, and CMV monitor and NASBA pp67 mRNA assay. RESULTS: CMV infection was detected in all patients by antigenemia and CMV monitor, whereas NASBA assay identified only 8/10 patients with viremia. Furthermore, CMV infection was never detected earlier by molecular biology assays than by antigenemia. Only 5/10 patients with CMV infection developed CMV disease. Using a cut off value of 8 cells/50,000, antigenemia was found to be the assay that better identified patients at risk of developing CMV disease. However, the kinetics of the onset of infection detected by NASBA and CMV monitor seemed to have better identified patients at risk of developing CMV disease. Furthermore, before onset of disease, CMV pp67 mRNA was found to have similar or better negative and positive predictive values for the development of CMV disease. CONCLUSIONS: The present data, suggests that the concomitant use of antigenemia and pp67 mRNA assay gives the best identification of patients at risk of developing CMV disease

Chiral plasmonics of self-assembled nanorod dimers

Chiral nanoscale photonic systems typically follow either tetrahedral or helical geometries that require four or more different constituent nanoparticles. Smaller number of particles and different chiral geometries taking advantage of the self-organization capabilities of nanomaterials will advance understanding of chiral plasmonic effects, facilitate development of their theory, and stimulate practical applications of chiroplasmonics. Here we show that gold nanorods self-assemble into side-by-side orientated pairs and ‘‘ladders’’ in which chiral properties originate from the small dihedral angle between them. Spontaneous twisting of one nanorod versus the other one breaks the centrosymmetric nature of the parallel assemblies. Two possible enantiomeric conformations with positive and negative dihedral angles were obtained with different assembly triggers. The chiral nature of the angled nanorod pairs was confirmed by 4p full space simulations and the first example of single-particle CD spectroscopy. Self-assembled nanorod pairs and ‘‘ladders’’ enable the development of chiral metamaterials, (bio)sensors, and new catalytic processes

Wikipedia Information Flow Analysis Reveals the Scale-Free Architecture of the Semantic Space

In this paper we extract the topology of the semantic space in its encyclopedic acception, measuring the semantic flow between the different entries of the largest modern encyclopedia, Wikipedia, and thus creating a directed complex network of semantic flows. Notably at the percolation threshold the semantic space is characterised by scale-free behaviour at different levels of complexity and this relates the semantic space to a wide range of biological, social and linguistics phenomena. In particular we find that the cluster size distribution, representing the size of different semantic areas, is scale-free. Moreover the topology of the resulting semantic space is scale-free in the connectivity distribution and displays small-world properties. However its statistical properties do not allow a classical interpretation via a generative model based on a simple multiplicative process. After giving a detailed description and interpretation of the topological properties of the semantic space, we introduce a stochastic model of content-based network, based on a copy and mutation algorithm and on the Heaps' law, that is able to capture the main statistical properties of the analysed semantic space, including the Zipf's law for the word frequency distribution

Integrating transposable elements in the 3D genome

Chromosome organisation is increasingly recognised as an essential component of genome regulation, cell fate and cell health. Within the realm of transposable elements (TEs) however, the spatial information of how genomes are folded is still only rarely integrated in experimental studies or accounted for in modelling. Whilst polymer physics is recognised as an important tool to understand the mechanisms of genome folding, in this commentary we discuss its potential applicability to aspects of TE biology. Based on recent works on the relationship between genome organisation and TE integration, we argue that existing polymer models may be extended to create a predictive framework for the study of TE integration patterns. We suggest that these models may offer orthogonal and generic insights into the integration profiles (or "topography") of TEs across organisms. In addition, we provide simple polymer physics arguments and preliminary molecular dynamics simulations of TEs inserting into heterogeneously flexible polymers. By considering this simple model, we show how polymer folding and local flexibility may generically affect TE integration patterns. The preliminary discussion reported in this commentary is aimed to lay the foundations for a large-scale analysis of TE integration dynamics and topography as a function of the three-dimensional host genome

Morphological changes of injected calcium phosphate cement in osteoporotic compressed vertebral bodies

SUMMARY: This study was undertaken to investigate the radiologic and clinical outcomes of vertebroplasty with calcium phosphate (CaP) cement in patients with osteoporotic vertebral compression fractures. The morphological changes of injected CaP cement in osteoporotic compressed vertebral bodies were variable and unpredictable. We suggest that the practice of vertebroplasty using CaP should be reconsidered. INTRODUCTION: Recently, CaP, an osteoconductive filler material, has been used in the treatment of osteoporotic compression fractures. However, the clinical results of CaP-cement-augmented vertebrae are still not well established. The purpose of this study is to assess the clinical results of vertebroplasty with CaP by evaluating the morphological changes of CaP cement in compressed vertebral bodies. METHODS: Fourteen patients have been followed for more than 2 years after vertebroplasty. The following parameters were reviewed: age, sex, T score, compliance with osteoporosis medications, visual analog scale score, compression ratio, subsequent compression fractures, and any morphological changes in the filler material. RESULTS: The morphological changes of injected CaP included reabsorption, condensation, bone formation (osteogenesis), fracture of the CaP solid hump, and heterotopic ossification. Out of 14 patients, 11 (78.6%) developed progression of the compression of the CaP-augmented vertebral bodies after vertebroplasty. CONCLUSIONS: The morphological changes of the injected CaP cement in the vertebral bodies were variable and unpredictable. The compression of the CaP-augmented vertebrae progressed continuously for 2 years or more. The findings of this study suggest that vertebroplasty using CaP cement should be reconsidered.ope

Classifications for Cesarean Section: A Systematic Review

Background: Rising cesarean section (CS) rates are a major public health concern and cause worldwide debates. To propose and implement effective measures to reduce or increase CS rates where necessary requires an appropriate classification. Despite several existing CS classifications, there has not yet been a systematic review of these. This study aimed to 1) identify the main CS classifications used worldwide, 2) analyze advantages and deficiencies of each system.Methods and Findings: Three electronic databases were searched for classifications published 1968-2008. Two reviewers independently assessed classifications using a form created based on items rated as important by international experts. Seven domains (ease, clarity, mutually exclusive categories, totally inclusive classification, prospective identification of categories, reproducibility, implementability) were assessed and graded. Classifications were tested in 12 hypothetical clinical case-scenarios. From a total of 2948 citations, 60 were selected for full-text evaluation and 27 classifications identified. Indications classifications present important limitations and their overall score ranged from 2-9 (maximum grade = 14). Degree of urgency classifications also had several drawbacks (overall scores 6-9). Woman-based classifications performed best (scores 5-14). Other types of classifications require data not routinely collected and may not be relevant in all settings (scores 3-8).Conclusions: This review and critical appraisal of CS classifications is a methodologically sound contribution to establish the basis for the appropriate monitoring and rational use of CS. Results suggest that women-based classifications in general, and Robson's classification, in particular, would be in the best position to fulfill current international and local needs and that efforts to develop an internationally applicable CS classification would be most appropriately placed in building upon this classification. the use of a single CS classification will facilitate auditing, analyzing and comparing CS rates across different settings and help to create and implement effective strategies specifically targeted to optimize CS rates where necessary.Universidade Federal de São Paulo, Dept Obstet, São Paulo, BrazilBrazilian Cochrane Ctr, São Paulo, BrazilWorld Hlth Org, Dept Reprod Hlth & Res, Geneva, SwitzerlandWorld Hlth Org, Dept Knowledge Management & Sharing, Geneva, SwitzerlandUniversidade Federal de São Paulo, Dept Obstet, São Paulo, BrazilWeb of Scienc

Implementation of Anaphylaxis Management Guidelines: A Register-Based Study

BACKGROUND: Anaphylaxis management guidelines recommend the use of intramuscular adrenaline in severe reactions, complemented by antihistamines and corticoids; secondary prevention includes allergen avoidance and provision of self-applicable first aid drugs. Gaps between recommendations and their implementation have been reported, but only in confined settings. Hence, we analysed nation-wide data on the management of anaphylaxis, evaluating the implementation of guidelines. METHODS: Within the anaphylaxis registry, allergy referral centres across Germany, Austria and Switzerland provided data on severe anaphylaxis cases. Based on patient records, details on reaction circumstances, diagnostic workup and treatment were collected via online questionnaire. Report of anaphylaxis through emergency physicians allowed for validation of registry data. RESULTS: 2114 severe anaphylaxis patients from 58 centres were included. 8% received adrenaline intravenously, 4% intramuscularly; 50% antihistamines, and 51% corticoids. Validation data indicated moderate underreporting of first aid drugs in the Registry. 20% received specific instructions at the time of the reaction; 81% were provided with prophylactic first aid drugs at any time. CONCLUSION: There is a distinct discrepancy between current anaphylaxis management guidelines and their implementation. To improve patient care, a revised approach for medical education and training on the management of severe anaphylaxis is warranted

Transverse electric field dragging of DNA in a nanochannel

Nanopore analysis is an emerging single-molecule strategy for non-optical and high-throughput DNA sequencing, the principle of which is based on identification of each constituent nucleobase by measuring trans-membrane ionic current blockade or transverse tunnelling current as it moves through the pore. A crucial issue for nanopore sequencing is the fact that DNA translocates a nanopore too fast for addressing sequence with a single base resolution. Here we report that a transverse electric field can be used to slow down the translocation. We find 400-fold decrease in the DNA translocation speed by adding a transverse field of 10 mV/nm in a gold-electrode-embedded silicon dioxide channel. The retarded flow allowed us to map the local folding pattern in individual DNA from trans-pore ionic current profiles. This field dragging approach may provide a new way to control the polynucleotide translocation kinetics