Constitutively active acetylcholine-dependent potassium current increases atrial defibrillation threshold by favoring post-shock re-initiation

Electrical cardioversion (ECV), a mainstay in atrial fibrillation (AF) treatment, is unsuccessful in up to 10-20% of patients. An important aspect of the remodeling process caused by AF is the constitutive activition of the atrium-specific acetylcholine-dependent potassium current (I-K,I-ACh -> I-K,I-ACh-c), which is associated with ECV failure. This study investigated the role of I-K,I-ACh-c in ECV failure and setting the atrial defibrillation threshold (aDFT) in optically mapped neonatal rat cardiomyocyte monolayers. AF was induced by burst pacing followed by application of biphasic shocks of 25-100 V to determine aDFT. Blocking I-K,I-ACh-c by tertiapin significantly decreased DFT, which correlated with a significant increase in wavelength during reentry. Genetic knockdown experiments, using lentiviral vectors encoding a Kcnj5-specific shRNA to modulate I-K,I-ACh-c, yielded similar results. Mechanistically, failed ECV was attributed to incomplete phase singularity (PS) removal or reemergence of PSs (i.e. re-initiation) through unidirectional propagation of shock-induced action potentials. Re-initiation occurred at significantly higher voltages than incomplete PS-removal and was inhibited by I-K,I-ACh-c blockade. Whole-heart mapping confirmed our findings showing a 60% increase in ECV success rate after I-K,I-ACh-c blockade. This study provides new mechanistic insight into failing ECV of AF and identifies I-K,I-ACh-c as possible atrium-specific target to increase ECV effectiveness, while decreasing its harmfulness

Cell-penetrating peptide conjugates of peptide nucleic acids (PNA) as inhibitors of HIV-1 Tat-dependent trans-activation in cells

The trans-activation response (TAR) RNA stem–loop that occurs at the 5′ end of HIV RNA transcripts is an important antiviral target and is the site of interaction of the HIV-1 Tat protein together with host cellular factors. Oligonucleotides and their analogues targeted to TAR are potential antiviral candidates. We have investigated a range of cell penetrating peptide (CPP) conjugates of a 16mer peptide nucleic acid (PNA) analogue targeted to the apical stem–loop of TAR and show that disulfide-linked PNA conjugates of two types of CPP (Transportan or a novel chimeric peptide R(6)-Penetratin) exhibit dose-dependent inhibition of Tat-dependent trans-activation in a HeLa cell assay when incubated for 24 h. Activity is reached within 6 h if the lysosomotropic reagent chloroquine is co-administered. Fluorescein-labelled stably-linked conjugates of Tat, Transportan or Transportan TP10 with PNA were inactive when delivered alone, but attained trans-activation inhibition in the presence of chloroquine. Confocal microscopy showed that such fluorescently labelled CPP–PNA conjugates were sequestered in endosomal or membrane-bound compartments of HeLa cells, which varied in appearance depending on the CPP type. Co-administration of chloroquine was seen in some cases to release fluorescence from such compartments into the nucleus, but with different patterns depending on the CPP. The results show that CPP–PNA conjugates of different types can inhibit Tat-dependent trans-activation in HeLa cells and have potential for development as antiviral agents. Endosomal or membrane release is a major factor limiting nuclear delivery and trans-activation inhibition

Evolutionary multiobjective optimization of the multi-location transshipment problem

We consider a multi-location inventory system where inventory choices at each location are centrally coordinated. Lateral transshipments are allowed as recourse actions within the same echelon in the inventory system to reduce costs and improve service level. However, this transshipment process usually causes undesirable lead times. In this paper, we propose a multiobjective model of the multi-location transshipment problem which addresses optimizing three conflicting objectives: (1) minimizing the aggregate expected cost, (2) maximizing the expected fill rate, and (3) minimizing the expected transshipment lead times. We apply an evolutionary multiobjective optimization approach using the strength Pareto evolutionary algorithm (SPEA2), to approximate the optimal Pareto front. Simulation with a wide choice of model parameters shows the different trades-off between the conflicting objectives

Postsynaptic Signals Mediating Induction of Long-Term Synaptic Depression in the Entorhinal Cortex

The entorhinal cortex receives a large projection from the piriform cortex, and synaptic plasticity in this pathway may affect olfactory processing. In vitro whole cell recordings have been used here to investigate postsynaptic signalling mechanisms that mediate the induction of long-term synaptic depression (LTD) in layer II entorhinal cortex cells. To induce LTD, pairs of pulses, using a 30-millisecond interval, were delivered at 1 Hz for 15 minutes. Induction of LTD was blocked by the NMDA receptor antagonist APV and by the calcium chelator BAPTA, consistent with a requirement for calcium influx via NMDA receptors. Induction of LTD was blocked when the FK506 was included in the intracellular solution to block the phosphatase calcineurin. Okadaic acid, which blocks activation of protein phosphatases 1 and 2a, also prevented LTD. Activation of protein phosphatases following calcium influx therefore contributes to induction of LTD in layer II of the entorhinal cortex

Clinico-radiological criteria versus GeneXpert for diagnosis of pediatric tuberculosis

Background: Diagnosing tuberculosis in children remains a challenge especially in low-income countries. The aim of this study was to assess the performance of the scoring system combined to chest x-ray images compared to GeneXpert for diagnosis of pediatric tuberculosis.Methods: A retrospective diagnostic accuracy study was carried out on hospitalized children aged 0 to 14 years old, tuberculosis suspect in the pediatric department of the Tsaralalana mother child university hospital center from August 2018 to June 2020.Results: Fifty-one medical files were retained. The mean age was 4±2 years old with a sex ratio of 1.55. The reason for consultation was dominated by respiratory signs (56.9%). The GeneXpert was positive in 58.9% of cases. The chest X-ray images were pathological in all cases, dominated by images of condensation or infiltration (72.5%). WHO score was positive (≥7) in 72.5% of cases. The clinico-radiological criteria had a sensitivity of 13.3-63.3%, a specificity of 61.9-95.2%, positive predictive values of 1.5-6.9% and negative predictive values of 98.8-99.3%.Conclusion: Clinico-radiological criteria could be useful in individual diagnosis of pediatric tuberculosis

Shear strength properties of wet granular materials

We investigate shear strength properties of wet granular materials in the pendular state (i.e. the state where the liquid phase is discontinuous) as a function of water content. Sand and glass beads were wetted and tested in a direct shear cell and under various confining pressures. In parallel, we carried out three-dimensional molecular dynamics simulations by using an explicit equation expressing capillary force as a function of interparticle distance, water bridge volume and surface tension. We show that, due to the peculiar features of capillary interactions, the major influence of water content over the shear strength stems from the distribution of liquid bonds. This property results in shear strength saturation as a function of water content. We arrive at the same conclusion by a microscopic analysis of the shear strength. We propose a model that accounts for the capillary force, the granular texture and particle size polydispersity. We find fairly good agreement of the theoretical estimate of the shear strength with both experimental data and simulations. From numerical data, we analyze the connectivity and anisotropy of different classes of liquid bonds according to the sign and level of the normal force as well as the bond direction. We find that weak compressive bonds are almost isotropically distributed whereas strong compressive and tensile bonds have a pronounced anisotropy. The probability distribution function of normal forces is exponentially decreasing for strong compressive bonds, a decreasing power-law function over nearly one decade for weak compressive bonds and an increasing linear function in the range of tensile bonds. These features suggest that different bond classes do not play the same role with respect to the shear strength.Comment: 12 page

Structural and elastic properties of BiOCu0.875S with Cu vacancies : A First principles study

The  structural and elastic properties of BiOCu0.875S with Cu vacancies have been investigated by using the first-principles density functional theory within the generalized gradient approximation. Population  analysis  suggests  that  the  chemical  bonding  in  BiOCu0.875S  has  predominantly  ionic  character  with  mixed covalent−ionic character. Basic physical properties, such as lattice constant, elastic constants Cij, bulk modulus B, shear modulus G, were calculated.  The  elastic  modulus E and  Poisson  ratio ν  the ratio B/G, shear anisotropy  and elastic anisotropy βc/βa  were  also  predicted.  The  results  show  that  tetragonal  phase  BiOCu0.875S  is mechanically stable and behaves in a ductile manner.

Prevalence of ABCA4 Deep-Intronic Variants and Related Phenotype in An Unsolved "One-Hit" Cohort with Stargardt Disease

We investigated the prevalence of reported deep-intronic variants in a French cohort of 70 patients with Stargardt disease harboring a monoallelic pathogenic variant on the exonic regions of ABCA4. Direct Sanger sequencing of selected intronic regions of ABCA4 was conducted. Complete phenotypic analysis and correlation with the genotype was performed in case a known intronic pathogenic variant was identified. All other variants found on the analyzed sequences were queried for minor allele frequency and possible pathogenicity by in silico predictions. The second mutated allele was found in 14 (20%) subjects. The three known deep-intronic variants found were c.5196+1137G>A in intron 36 (6 subjects), c.4539+2064C>T in intron 30 (4 subjects) and c.4253+43G>A in intron 28 (4 subjects). Even though the phenotype depends on the compound effect of the biallelic variants, a genotype-phenotype correlation suggests that the c.5196+1137G>A was mostly associated with a mild phenotype and the c.4539+2064C>T with a more severe one. A variable effect was instead associated with the variant c.4253+43G>A. In addition, two novel variants, c.768+508A>G and c.859-245_859-243delinsTGA never associated with Stargardt disease before, were identified and a possible splice defect was predicted in silico. Our study calls for a larger cohort analysis including targeted locus sequencing and 3D protein modeling to better understand phenotype-genotype correlations associated with deep-intronic changes and patients' selection for clinical trials

The impact of fire on habitat use by the short-snouted elephant shrew ('Elephantulus brachyrhynchus') in North West Province, South Africa

Several studies have investigated the response of small mammal populations to fire, but few have investigated behavioural responses to habitat modification. In this study we investigated the impact of fire on home range, habitat use and activity patterns of the short-snouted elephant shrew (Elephantulus brachyrhynchus) by radio-tracking individuals before and after a fire event. All animals survived the passage of fire in termite mound refugia. Before the fire, grassland was used more than thickets, but habitat utilization shifted to thickets after fire had removed the grass cover. Thickets were an important refuge both pre- and post-fire, but the proportion of thicket within the home range was greater post-fire. We conclude that fire-induced habitat modification resulted in a restriction of E. brachyrhynchus movements to patches of unburned vegetation. This may be a behavioural response to an increase in predation pressure associated with a reduction in cover, rather than a lack of food. This study highlights the importance of considering the landscape mosaic in fire management and allowing sufficient island patches to remain post-fire ensures the persistence of the small mammal fauna