Development and validation of a novel non-contact monitor of nocturnal respiration for identifying sleep-disordered breathing in patients with heart failure

© 2016 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology. Aims: At least 50% of patients with heart failure (HF) may have sleep-disordered breathing (SDB). Overnight in-hospital polysomnography (PSG) is considered the gold standard for diagnosis, but a lack of access to such testing contributes to under-diagnosis of SDB. Therefore, there is a need for simple and reliable validated methods to aid diagnosis in patients with HF. The aim of this study was to investigate the accuracy of a non-contact type IV screening device, SleepMinderTM (SM), compared with in-hospital PSG for detecting SDB in patients with HF. Methods and results: The study included 75 adult patients with systolic HF and suspected SDB who underwent simultaneous PSG and SM recordings. An algorithm was developed from the SM signals, using digital signal processing and pattern recognition techniques to calculate the SM apnoea-hypopnoea index (AHI). This was then compared with expert-scored PSGAHI. The SM algorithm had 70% sensitivity and 89% specificity for identifying patients with clinically significant SDB (AHI ≥ 15/h). At this threshold, it had a positive likelihood ratio of 6.3 and a negative likelihood ratio of 0.16. The overall accuracy of the SMAHI algorithm was 85.8% as shown by the area under a receiver operator characteristic curve. The mean AHI with SM was 3.8/h (95% confidence interval 0.5–7.1) lower than that with PSG. Conclusions: The accuracy of the non-contact type IV screening device SM is good for clinically significant SDB in patients with systolic HF and could be considered as a simple first step in the diagnostic pathway

Unilateral interactions in granular packings: A model for the anisotropy modulus

Unilateral interparticle interactions have an effect on the elastic response of granular materials due to the opening and closing of contacts during quasi-static shear deformations. A simplified model is presented, for which constitutive relations can be derived. For biaxial deformations the elastic behavior in this model involves three independent elastic moduli: bulk, shear, and anisotropy modulus. The bulk and the shear modulus, when scaled by the contact density, are independent of the deformation. However, the magnitude of the anisotropy modulus is proportional to the ratio between shear and volumetric strain. Sufficiently far from the jamming transition, when corrections due to non-affine motion become weak, the theoretical predictions are qualitatively in agreement with simulation results.Comment: 6 pages, 5 figure

Regulation of Hepatitis C Virion Production via Phosphorylation of the NS5A Protein

Hepatitis C virus (HCV) is a significant pathogen, infecting some 170 million people worldwide. Persistent virus infection often leads to cirrhosis and liver cancer. In the infected cell many RNA directed processes must occur to maintain and spread infection. Viral genomic RNA is constantly replicating, serving as template for translation, and being packaged into new virus particles; processes that cannot occur simultaneously. Little is known about the regulation of these events. The viral NS5A phosphoprotein has been proposed as a regulator of events in the HCV life cycle for years, but the details have remained enigmatic. NS5A is a three-domain protein and the requirement of domains I and II for RNA replication is well documented. NS5A domain III is not required for RNA replication, and the function of this region in the HCV lifecycle is unknown. We have identified a small deletion in domain III that disrupts the production of infectious virus particles without altering the efficiency of HCV RNA replication. This deletion disrupts virus production at an early stage of assembly, as no intracellular virus is generated and no viral RNA and nucleocapsid protein are released from cells. Genetic mapping has indicated a single serine residue within the deletion is responsible for the observed phenotype. This serine residue lies within a casein kinase II consensus motif, and mutations that mimic phosphorylation suggest that phosphorylation at this position regulates the production of infectious virus. We have shown by genetic silencing and chemical inhibition experiments that NS5A requires casein kinase II phosphorylation at this position for virion production. A mutation that mimics phosphorylation at this position is insensitive to these manipulations of casein kinase II activity. These data provide the first evidence for a function of the domain III of NS5A and implicate NS5A as an important regulator of the RNA replication and virion assembly of HCV. The ability to uncouple virus production from RNA replication, as described herein, may be useful in understanding HCV assembly and may be therapeutically important

DNA glycosylases: in DNA repair and beyond

The base excision repair machinery protects DNA in cells from the damaging effects of oxidation, alkylation, and deamination; it is specialized to fix single-base damage in the form of small chemical modifications. Base modifications can be mutagenic and/or cytotoxic, depending on how they interfere with the template function of the DNA during replication and transcription. DNA glycosylases play a key role in the elimination of such DNA lesions; they recognize and excise damaged bases, thereby initiating a repair process that restores the regular DNA structure with high accuracy. All glycosylases share a common mode of action for damage recognition; they flip bases out of the DNA helix into a selective active site pocket, the architecture of which permits a sensitive detection of even minor base irregularities. Within the past few years, it has become clear that nature has exploited this ability to read the chemical structure of DNA bases for purposes other than canonical DNA repair. DNA glycosylases have been brought into context with molecular processes relating to innate and adaptive immunity as well as to the control of DNA methylation and epigenetic stability. Here, we summarize the key structural and mechanistic features of DNA glycosylases with a special focus on the mammalian enzymes, and then review the evidence for the newly emerging biological functions beyond the protection of genome integrity

Human CD1c+ dendritic cells secrete high levels of IL-12 and potently prime cytotoxic T-cell responses

Dendritic cells (DC) have the unique capacities to induce primary T-cell responses. In mice, CD8 alpha+DC are specialized to cross-prime CD8(+) T cells and produce interleukin-12 (IL-12) that promotes cytotoxicity. Human BDCA-3(+) DC share several relevant characteristics with CD8 alpha+DC, but the capacities of human DC subsets to induce CD8(+) T-cell responses are incompletely understood. Here we compared CD1c(+) myeloid DC (mDC) 1, BDCA-3(+)mDC2, and plasmacytoid DC(pDC) in peripheral blood and lymphoid tissues for phenotype, cytokine production, and their capacities to prime cytotoxic T cells. mDC1 were surprisingly the only human DC that secreted high amounts of IL-12p70, but they required combinational Toll-like receptor (TLR) stimulation. mDC2 and pDC produced interferon-lambda and interferon-alpha, respectively. Importantly, mDC1 and mDC2 required different combinations of TLR ligands to cross-present protein antigens to CD8(+) T cells. pDC were inefficient and also expressed lower levels of major histocompatibility complex and co-stimulatory molecules. Nevertheless, all DC induced CD8(+) memory T-cell expansions upon licensing by CD4(+) T cells, and primed naive CD8(+) T cells following appropriate TLR stimulation. However, because mDC1 produced IL-12, they induced the highest levels of cytotoxic molecules. In conclusion, CD1c(+) mDC1 are the relevant source of IL-12 for naive T cells and are fully equipped to cross-prime cytotoxic T-cell responses

The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites

In addition to its well-documented effects on gene silencing, cytosine methylation is a prominent cause of mutations. In humans, the mutation rate from 5-methylcytosine (m5C) to thymine (T) is 10-50-fold higher than other transitions and the methylated sequence CpG is consequently under-represented. Over one-third of germline point mutations associated with human genetic disease and many somatic mutations leading to cancer involve loss of CpG. The primary cause of mutability appears to be hydrolytic deamination. Cytosine deamination produces mismatched uracil (U), which can be removed by uracil glycosylase, whereas m5C deamination generates a G x T mispair that cannot be processed by this enzyme. Correction of m5CpG x TpG mismatches may instead be initiated by the thymine DNA glycosylase, TDG. Here we show that MBD4, an unrelated mammalian protein that contains a methyl-CpG binding domain, can also efficiently remove thymine or uracil from a mismatches CpG site in vitro. Furthermore, the methyl-CpG binding domain of MBD4 binds preferentially to m5CpG x TpG mismatches-the primary product of deamination at methyl-CpG. The combined specificities of binding and catalysis indicate that this enzyme may function to minimize mutation at methyl-CpG