Vitamin D for the management of asthma

Background Several clinical trials of vitamin D to prevent asthma exacerbation and improve asthma control have been conducted in children and adults, but a meta-analysis restricted to double-blind, randomised, placebo-controlled trials of this intervention is lacking. Objectives To evaluate the efficacy of administration of vitamin D and its hydroxylated metabolites in reducing the risk of severe asthma exacerbations (defined as those requiring treatment with systemic corticosteroids) and improving asthma symptom control. Search methods We searched the Cochrane Airways Group Trial Register and reference lists of articles. We contacted the authors of studies in order to identify additional trials. Date of last search: January 2016. Selection criteria Double-blind, randomised, placebo-controlled trials of vitamin D in children and adults with asthma evaluating exacerbation risk or asthma symptom control or both. Data collection and analysis Two review authors independently applied study inclusion criteria, extracted the data, and assessed risk of bias. We obtained missing data from the authors where possible. We reported results with 95% confidence intervals (CIs). Main results We included seven trials involving a total of 435 children and two trials involving a total of 658 adults in the primary analysis. Of these, one trial involving 22 children and two trials involving 658 adults contributed to the analysis of the rate of exacerbations requiring systemic corticosteroids. Duration of trials ranged from four to 12 months, and the majority of participants had mild to moderate asthma. Administration of vitamin D reduced the rate of exacerbations requiring systemic corticosteroids (rate ratio 0.63, 95% CI 0.45 to 0.88; 680 participants; 3 studies; high-quality evidence), and decreased the risk of having at least one exacerbation requiring an emergency department visit or hospitalisation or both (odds ratio (OR) 0.39, 95% CI 0.19 to 0.78; number needed to treat for an additional beneficial outcome, 27; 963 participants; 7 studies; high-quality evidence). There was no effect of vitamin D on % predicted forced expiratory volume in one second (mean difference (MD) 0.48, 95% CI -0.93 to 1.89; 387 participants; 4 studies; high-quality evidence) or Asthma Control Test scores (MD -0.08, 95% CI -0.70 to 0.54; 713 participants; 3 studies; high-quality evidence). Administration of vitamin D did not influence the risk of serious adverse events (OR 1.01, 95% CI 0.54 to 1.89; 879 participants; 5 studies; moderate-quality evidence). One trial comparing low-dose versus high-dose vitamin D reported two episodes of hypercalciuria, one in each study arm. No other study reported any adverse event potentially attributable to administration of vitamin D. No participant in any included trial suffered a fatal asthma exacerbation. We did not perform a subgroup analysis to determine whether the effect of vitamin D on risk of severe exacerbation was modified by baseline vitamin D status, due to unavailability of suitably disaggregated data. We assessed two trials as being at high risk of bias in at least one domain; neither trial contributed data to the analysis of the outcomes reported above. Authors' conclusions Meta-analysis of a modest number of trials in people with predominantly mild to moderate asthma suggests that vitamin D is likely to reduce both the risk of severe asthma exacerbation and healthcare use. It is as yet unclear whether these effects are confined to people with lower baseline vitamin D status; further research, including individual patient data meta-analysis of existing datasets, is needed to clarify this issue. Children and people with frequent severe asthma exacerbations were under-represented; additional primary trials are needed to establish whether vitamin D can reduce the risk of severe asthma exacerbation in these groups

Joint Radar and Communication Design: Applications, State-of-the-Art, and the Road Ahead

Sharing of the frequency bands between radar and communication systems has attracted substantial attention, as it can avoid under-utilization of otherwise permanently allocated spectral resources, thus improving efficiency. Further, there is increasing demand for radar and communication systems that share the hardware platform as well as the frequency band, as this not only decongests the spectrum, but also benefits both sensing and signaling operations via the full cooperation between both functionalities. Nevertheless, the success of spectrum and hardware sharing between radar and communication systems critically depends on high-quality joint radar and communication designs. In the first part of this paper, we overview the research progress in the areas of radar-communication coexistence and dual-functional radar-communication (DFRC) systems, with particular emphasis on application scenarios and technical approaches. In the second part, we propose a novel transceiver architecture and frame structure for a DFRC base station (BS) operating in the millimeter wave (mmWave) band, using the hybrid analog-digital (HAD) beamforming technique. We assume that the BS is serving a multi-antenna user equipment (UE) over a mmWave channel, and at the same time it actively detects targets. The targets also play the role of scatterers for the communication signal. In that framework, we propose a novel scheme for joint target search and communication channel estimation, which relies on omni-directional pilot signals generated by the HAD structure. Given a fully-digital communication precoder and a desired radar transmit beampattern, we propose to design the analog and digital precoders under non-convex constant-modulus (CM) and power constraints, such that the BS can formulate narrow beams towards all the targets, while pre-equalizing the impact of the communication channel. Furthermore, we design a HAD receiver that can simultaneously process signals from the UE and echo waves from the targets. By tracking the angular variation of the targets, we show that it is possible to recover the target echoes and mitigate the resulting interference to the UE signals, even when the radar and communication signals share the same signal-to-noise ratio (SNR). The feasibility and efficiency of the proposed approaches in realizing DFRC are verified via numerical simulations. Finally, the paper concludes with an overview of the open problems in the research field of communication and radar spectrum sharing (CRSS)

Hidden Disunities and Uncanny Resemblances: Connections and Disconnections in the Music of Lera Auerbach and Michael Nyman

Does stylistic appropriation serve to create a sense of unity or disunity, continuity or fragmentation? Taking George Lipsitz's notion of �families of resemblance� and intertextuality's dialogic qualities (as shown in the writings of Mikhail Bakhtin and Julia Kristeva), this article will put forward the argument that certain forms of quotation result in a kind of halfway house�an in-between state�where the text seemingly announces its own independence despite its (inter)dependence on a whole host of other intertexts. Unlike the collage-like, so-called polystylistic compositions of the late 1960s, which also used quotation, an altogether different and more deeply embedded form has developed since then, where the quoted material is integrated to a much greater extent on the surface, only to lay bare its �difference� at a deeper level. Such �hidden discontinuities� will be examined in relation to a single work, Lera Auerbach's Sogno di Stabat Mater (2005/2008), before applying Lipsitz's principle as a case study to Michael Nyman's oeuvre

On Flux Quantization in F-Theory

We study the problem of four-form flux quantization in F-theory compactifications. We prove that for smooth, elliptically fibered Calabi-Yau fourfolds with a Weierstrass representation, the flux is always integrally quantized. This implies that any possible half-integral quantization effects must come from 7-branes, i.e. from singularities of the fourfold. We subsequently analyze the quantization rule on explicit fourfolds with Sp(N) singularities, and connect our findings via Sen's limit to IIB string theory. Via direct computations we find that the four-form is half-integrally quantized whenever the corresponding 7-brane stacks wrap non-spin complex surfaces, in accordance with the perturbative Freed-Witten anomaly. Our calculations on the fourfolds are done via toric techniques, whereas in IIB we rely on Sen's tachyon condensation picture to treat bound states of branes. Finally, we give general formulae for the curvature- and flux-induced D3 tadpoles for general fourfolds with Sp(N) singularities.Comment: 46 page

An epigenetic clock for human skeletal muscle.

BACKGROUND: Ageing is associated with DNA methylation changes in all human tissues, and epigenetic markers can estimate chronological age based on DNA methylation patterns across tissues. However, the construction of the original pan-tissue epigenetic clock did not include skeletal muscle samples and hence exhibited a strong deviation between DNA methylation and chronological age in this tissue. METHODS: To address this, we developed a more accurate, muscle-specific epigenetic clock based on the genome-wide DNA methylation data of 682 skeletal muscle samples from 12 independent datasets (18-89 years old, 22% women, 99% Caucasian), all generated with Illumina HumanMethylation (HM) arrays (HM27, HM450, or HMEPIC). We also took advantage of the large number of samples to conduct an epigenome-wide association study of age-associated DNA methylation patterns in skeletal muscle. RESULTS: The newly developed clock uses 200 cytosine-phosphate-guanine dinucleotides to estimate chronological age in skeletal muscle, 16 of which are in common with the 353 cytosine-phosphate-guanine dinucleotides of the pan-tissue clock. The muscle clock outperformed the pan-tissue clock, with a median error of only 4.6 years across datasets (vs. 13.1 years for the pan-tissue clock, P < 0.0001) and an average correlation of ρ = 0.62 between actual and predicted age across datasets (vs. ρ = 0.51 for the pan-tissue clock). Lastly, we identified 180 differentially methylated regions with age in skeletal muscle at a false discovery rate < 0.005. However, gene set enrichment analysis did not reveal any enrichment for gene ontologies. CONCLUSIONS: We have developed a muscle-specific epigenetic clock that predicts age with better accuracy than the pan-tissue clock. We implemented the muscle clock in an r package called Muscle Epigenetic Age Test available on Bioconductor to estimate epigenetic age in skeletal muscle samples. This clock may prove valuable in assessing the impact of environmental factors, such as exercise and diet, on muscle-specific biological ageing processes

Profiling cytotoxic microRNAs in pediatric and adult glioblastoma cells by high-content screening, identification, and validation of miR-1300

MicroRNAs play an important role in the regulation of mRNA translation and have therapeutic potential in cancer and other diseases. To profile the landscape of microRNAs with significant cytotoxicity in the context of glioblastoma (GBM), we performed a high-throughput screen in adult and pediatric GBM cells using a synthetic oligonucleotide library representing all known human microRNAs. Bioinformatics analysis was used to refine this list and the top seven microRNAs were validated in a larger panel of GBM cells using state-of-the-art in vitro assays. The cytotoxic effect of our most relevant candidate was assessed in a preclinical model. Our screen identified ~100 significantly cytotoxic microRNAs with 70% concordance between cell lines. MicroRNA-1300 (miR-1300) was the most potent and robust candidate. We observed a striking binucleated phenotype in miR-1300 transfected cells due to cytokinesis failure followed by apoptosis. This was also observed in two stem-like patient-derived cultures. We identified the physiological role of miR-1300 as a regulator of endomitosis in megakaryocyte differentiation where blockade of cytokinesis is an essential step. In GBM cells, where miR-1300 is normally not expressed, the oncogene Epithelial Cell Transforming 2 (ECT2) was validated as a direct key target. ECT2 siRNA phenocopied the effects of miR-1300, and ECT2 overexpression led to rescue of miR-1300 induced binucleation. We showed that ectopic expression of miR-1300 led to decreased tumor growth in an orthotopic GBM model. Our screen provides a resource for the neuro-oncology community and identified miR-1300 as a novel regulator of endomitosis with translatable potential for therapeutic application

Intravesicle Isothermal DNA Replication

<p>Abstract</p> <p>Background</p> <p>Bacterial and viral DNA replication was previously reconstituted <it>in vitro </it>from component parts <abbrgrp><abbr bid="B1">1</abbr><abbr bid="B2">2</abbr><abbr bid="B3">3</abbr><abbr bid="B4">4</abbr></abbrgrp>. Significant advances in building minimal cell-like structures also have been made recently <abbrgrp><abbr bid="B5">5</abbr><abbr bid="B6">6</abbr><abbr bid="B7">7</abbr></abbrgrp>. Combining the two approaches would further attempts to build a minimal cell-like structure capable of undergoing evolution by combining membrane encapsulation and genome replication. Towards this end, we attempted to use purified genomic replication protein components from thermophilic bacterial sources to copy strands of DNA isothermally within lipid vesicles.</p> <p>Findings</p> <p>Bacterial replication components (such as helicases and DNA polymerases) are compatible with methods for the generation of lipid vesicles. Encapsulation inside phospholipid vesicles does not inhibit the activity of bacterial DNA genome replication machinery. Further the described system is efficient at isothermally amplifying short segments of DNA within phospholipid vesicles.</p> <p>Conclusions</p> <p>Herein we show that bacterial isothermal DNA replication machinery is functional inside of phospholipid vesicles, suggesting that replicating cellular mimics can be built from purified bacterial components.</p

Mitochondrial ROS regulate oxidative damage and mitophagy but not age-related muscle fiber atrophy

Age-related loss of skeletal muscle mass and function is a major contributor to morbidity and has a profound effect on the quality of life of older people. The potential role of age-dependent mitochondrial dysfunction and cumulative oxidative stress as the underlying cause of muscle aging remains a controversial topic. Here we show that the pharmacological attenuation of age-related mitochondrial redox changes in muscle with SS31 is associated with some improvements in oxidative damage and mitophagy in muscles of old mice. However, this treatment failed to rescue the age-related muscle fiber atrophy associated with muscle atrophy and weakness. Collectively, these data imply that the muscle mitochondrial redox environment is not a key regulator of muscle fiber atrophy during sarcopenia but may play a key role in the decline of mitochondrial organelle integrity that occurs with muscle aging