Building KCNQ1/KCNE1 Channel Models and Probing their Interactions by Molecular-Dynamics Simulations

The slow delayed rectifier (IKs) channel is composed of KCNQ1 (pore-forming) and KCNE1 (auxiliary) subunits, and functions as a repolarization reserve in the human heart. Design of IKs-targeting anti-arrhythmic drugs requires detailed three-dimensional structures of the KCNQ1/KCNE1 complex, a task made possible by Kv channel crystal structures (templates for KCNQ1 homology-modeling) and KCNE1 NMR structures. Our goal was to build KCNQ1/KCNE1 models and extract mechanistic information about their interactions by molecular-dynamics simulations in an explicit lipid/solvent environment. We validated our models by confirming two sets of model-generated predictions that were independent from the spatial restraints used in model-building. Detailed analysis of the molecular-dynamics trajectories revealed previously unrecognized KCNQ1/KCNE1 interactions, whose relevance in IKs channel function was confirmed by voltage-clamp experiments. Our models and analyses suggest three mechanisms by which KCNE1 slows KCNQ1 activation: by promoting S6 bending at the Pro hinge that closes the activation gate; by promoting a downward movement of gating charge on S4; and by establishing a network of electrostatic interactions with KCNQ1 on the extracellular surface that stabilizes the channel in a pre-open activated state. Our data also suggest how KCNE1 may affect the KCNQ1 pore conductance

Gibbs-non-Gibbs transitions via large deviations: computable examples

We give new and explicitly computable examples of Gibbs-non-Gibbs transitions of mean-field type, using the large deviation approach introduced in [4]. These examples include Brownian motion with small variance and related diffusion processes, such as the Ornstein-Uhlenbeck process, as well as birth and death processes. We show for a large class of initial measures and diffusive dynamics both short-time conservation of Gibbsianness and dynamical Gibbs-non-Gibbs transitions

Long-Term Fish Oil Supplementation Induces Cardiac Electrical Remodeling by Changing Channel Protein Expression in the Rabbit Model

Clinical trials and epidemiological studies have suggested that dietary fish oil (FO) supplementation can provide an anti-arrhythmic benefit in some patient populations. The underlying mechanisms are not entirely clear. We wanted to understand how FO supplementation (for 4 weeks) affected the action potential configuration/duration of ventricular myocytes, and the ionic mechanism(s)/molecular basis for these effects. The experiments were conducted on adult rabbits, a widely used animal model for cardiac electrophysiology and pathophysiology. We used gas chromatography - mass spectroscopy to confirm that FO feeding produced a marked increase in the content of n-3 polyunsaturated fatty acids in the phospholipids of rabbit hearts. Left ventricular myocytes were used in current and voltage clamp experiments to monitor action potentials and ionic currents, respectively. Action potentials of myocytes from FO-fed rabbits exhibited much more positive plateau voltages and prolonged durations. These changes could be explained by an increase in the L-type Ca current (ICaL) and a decrease in the transient outward current (Ito) in these myocytes. FO feeding did not change the delayed rectifier or inward rectifier current. Immunoblot experiments showed that the FO-feeding induced changes in ICaL and Ito were associated with corresponding changes in the protein levels of major pore-forming subunits of these channels: increase in Cav1.2 and decrease in Kv4.2 and Kv1.4. There was no change in other channel subunits (Cav1.1, Kv4.3, KChIP2, and ERG1). We conclude that long-term fish oil supplementation can impact on cardiac electrical activity at least partially by changing channel subunit expression in cardiac myocytes

Preserving Both Privacy and Utility in Network Trace Anonymization

As network security monitoring grows more sophisticated, there is an increasing need for outsourcing such tasks to third-party analysts. However, organizations are usually reluctant to share their network traces due to privacy concerns over sensitive information, e.g., network and system configuration, which may potentially be exploited for attacks. In cases where data owners are convinced to share their network traces, the data are typically subjected to certain anonymization techniques, e.g., CryptoPAn, which replaces real IP addresses with prefix-preserving pseudonyms. However, most such techniques either are vulnerable to adversaries with prior knowledge about some network flows in the traces, or require heavy data sanitization or perturbation, both of which may result in a significant loss of data utility. In this paper, we aim to preserve both privacy and utility through shifting the trade-off from between privacy and utility to between privacy and computational cost. The key idea is for the analysts to generate and analyze multiple anonymized views of the original network traces; those views are designed to be sufficiently indistinguishable even to adversaries armed with prior knowledge, which preserves the privacy, whereas one of the views will yield true analysis results privately retrieved by the data owner, which preserves the utility. We present the general approach and instantiate it based on CryptoPAn. We formally analyze the privacy of our solution and experimentally evaluate it using real network traces provided by a major ISP. The results show that our approach can significantly reduce the level of information leakage (e.g., less than 1\% of the information leaked by CryptoPAn) with comparable utility

Endoscopic sinus surgery for maxillary sinus mucoceles

BACKGROUND: Maxillary sinus mucoceles are relatively rare among all paranasal sinus mucoceles. With the introduction of endoscopic sinus surgical techniques, rhinologic surgeons prefer transnasal endoscopic management of sinus mucoceles. The aim of this study is to describe the clinical presentation of maxillary sinus mucoceles and to establish the efficacy of endoscopic management of sinus mucoceles. METHODS: Between 2003 and 2005, 14 patients underwent endoscopic sinus surgery for maxillary sinus mucocele. The presenting sign and symptoms, radiological findings, surgical management and need for revision surgery were reviewed. RESULTS: There were eight males and six females with an age range of 14 to 65. Ten patients complained of nasal obstruction, five of nasal drainage, five of cheek pressure or pain and one of proptosis of the eye and cheek swelling. The maxillary sinus and ipsilateral ethmoid sinus involvement on computed tomographic studies was seen in 4 patients. Four patients had history of endoscopic ethmoidectomy surgery for ethmoid sinusitis and one had Caldwell-Luc operation in the past. Ethmoidectomy with middle meatal antrostomy and marsupialization of the mucocele was performed in all patients. Postoperative follow-up ranged between 8 to 48 months. All patients had a patent middle meatal antrostomy and healthy maxillary sinus mucosa. No patients need revision surgery. CONCLUSION: The most common causes of mucoceles are chronic infection, allergic sinonasal disease, trauma and previous surgery. In 64% of the patients of our study cause remains uncertain. Endoscopic sinus surgery is an effective treatment for maxillary sinus mucoceles with a favorable long-term outcome

Intervention effects of Ganoderma lucidum spores on epileptiform discharge hippocampal neurons and expression of Neurotrophin-4 and N-Cadherin

Epilepsy can cause cerebral transient dysfunctions. Ganoderma lucidum spores (GLS), a traditional Chinese medicinal herb, has shown some antiepileptic effects in our previous studies. This was the first study of the effects of GLS on cultured primary hippocampal neurons, treated with Mg2+ free medium. This in vitro model of epileptiform discharge hippocampal neurons allowed us to investigate the anti-epileptic effects and mechanism of GLS activity. Primary hippocampal neurons from <1 day old rats were cultured and their morphologies observed under fluorescence microscope. Neurons were confirmed by immunofluorescent staining of neuron specific enolase (NSE). Sterile method for GLS generation was investigated and serial dilutions of GLS were used to test the maximum non-toxic concentration of GLS on hippocampal neurons. The optimized concentration of GLS of 0.122 mg/ml was identified and used for subsequent analysis. Using the in vitro model, hippocampal neurons were divided into 4 groups for subsequent treatment i) control, ii) model (incubated with Mg2+ free medium for 3 hours), iii) GLS group I (incubated with Mg2+ free medium containing GLS for 3 hours and replaced with normal medium and incubated for 6 hours) and iv) GLS group II (neurons incubated with Mg2+ free medium for 3 hours then replaced with a normal medium containing GLS for 6 hours). Neurotrophin-4 and N-Cadherin protein expression were detected using Western blot. The results showed that the number of normal hippocampal neurons increased and the morphologies of hippocampal neurons were well preserved after GLS treatment. Furthermore, the expression of neurotrophin-4 was significantly increased while the expression of N-Cadherin was decreased in the GLS treated group compared with the model group. This data indicates that GLS may protect hippocampal neurons by promoting neurotrophin-4 expression and inhibiting N-Cadherin expression

Predatory Bacteria: A Potential Ally against Multidrug-Resistant Gram-Negative Pathogens

Multidrug-resistant (MDR) Gram-negative bacteria have emerged as a serious threat to human and animal health. Bdellovibrio spp. and Micavibrio spp. are Gram-negative bacteria that prey on other Gram-negative bacteria. In this study, the ability of Bdellovibrio bacteriovorus and Micavibrio aeruginosavorus to prey on MDR Gram-negative clinical strains was examined. Although the potential use of predatory bacteria to attack MDR pathogens has been suggested, the data supporting these claims is lacking. By conducting predation experiments we have established that predatory bacteria have the capacity to attack clinical strains of a variety of ß-lactamase-producing, MDR Gram-negative bacteria. Our observations indicate that predatory bacteria maintained their ability to prey on MDR bacteria regardless of their antimicrobial resistance, hence, might be used as therapeutic agents where other antimicrobial drugs fail. © 2013 Kadouri et al

Waist-to-Height Ratio Is More Predictive of Years of Life Lost than Body Mass Index

Objective: Our aim was to compare the effect of central obesity (measured by waist-to-height ratio, WHtR) and total obesity (measured by body mass index, BMI) on life expectancy expressed as years of life lost (YLL), using data on British adults. Methods: A Cox proportional hazards model was applied to data from the prospective Health and Lifestyle Survey (HALS) and the cross sectional Health Survey for England (HSE). The number of years of life lost (YLL) at three ages (30, 50, 70 years) was found by comparing the life expectancies of obese lives with those of lives at optimum levels of BMI and WHtR. Results: Mortality risk associated with BMI in the British HALS survey was similar to that found in US studies. However, WHtR was a better predictor of mortality risk. For the first time, YLL have been quantified for different values of WHtR. This has been done for both sexes separately and for three representative ages. Conclusion: This study supports the simple message ‘‘Keep your waist circumference to less than half your height’’. The use of WHtR in public health screening, with appropriate action, could help add years to life

Microarray Analyses of Gene Expression during the Tetrahymena thermophila Life Cycle

The model eukaryote, Tetrahymena thermophila, is the first ciliated protozoan whose genome has been sequenced, enabling genome-wide analysis of gene expression.A genome-wide microarray platform containing the predicted coding sequences (putative genes) for T. thermophila is described, validated and used to study gene expression during the three major stages of the organism's life cycle: growth, starvation and conjugation.Of the approximately 27,000 predicted open reading frames, transcripts homologous to only approximately 5900 are not detectable in any of these life cycle stages, indicating that this single-celled organism does indeed contain a large number of functional genes. Transcripts from over 5000 predicted genes are expressed at levels >5x corrected background and 95 genes are expressed at >250x corrected background in all stages. Transcripts homologous to 91 predicted genes are specifically expressed and 155 more are highly up-regulated in growing cells, while 90 are specifically expressed and 616 are up-regulated during starvation. Strikingly, transcripts homologous to 1068 predicted genes are specifically expressed and 1753 are significantly up-regulated during conjugation. The patterns of gene expression during conjugation correlate well with the developmental stages of meiosis, nuclear differentiation and DNA elimination. The relationship between gene expression and chromosome fragmentation is analyzed. Genes encoding proteins known to interact or to function in complexes show similar expression patterns, indicating that co-ordinate expression with putative genes of known function can identify genes with related functions. New candidate genes associated with the RNAi-like process of DNA elimination and with meiosis are identified and the late stages of conjugation are shown to be characterized by specific expression of an unexpectedly large and diverse number of genes not involved in nuclear functions