A novel conceptual model of heart rate autonomic modulation based on a small-world modular structure of the sinoatrial node

The present view on heartbeat initiation is that a primary pacemaker cell or a group of cells in the sinoatrial node (SAN) center paces the rest of the SAN and the atria. However, recent high-resolution imaging studies show a more complex paradigm of SAN function that emerges from heterogeneous signaling, mimicking brain cytoarchitecture and function. Here, we developed and tested a new conceptual numerical model of SAN organized similarly to brain networks featuring a modular structure with small-world topology. In our model, a lower rate module leads action potential (AP) firing in the basal state and during parasympathetic stimulation, whereas a higher rate module leads during β-adrenergic stimulation. Such a system reproduces the respective shift of the leading pacemaker site observed experimentally and a wide range of rate modulation and robust function while conserving energy. Since experimental studies found functional modules at different scales, from a few cells up to the highest scale of the superior and inferior SAN, the SAN appears to feature hierarchical modularity, i.e., within each module, there is a set of sub-modules, like in the brain, exhibiting greater robustness, adaptivity, and evolvability of network function. In this perspective, our model offers a new mainframe for interpreting new data on heterogeneous signaling in the SAN at different scales, providing new insights into cardiac pacemaker function and SAN-related cardiac arrhythmias in aging and disease

The experience in treatment of dengue fever using antiviral drug riamilovir in the Republic of Guinea (case report)

Dengue fever is classified as one of the most common viral diseases with a transmission mechanism implemented through arthropod vectors. The expansion of of the Aedes aegypti mosquito is leading to a significant increase in the number of cases of dengue fever in more than 100 countries, highlighting the importance of developing and implementing specific prevention and treatment measures. Etiotropic drugs with proven efficacy against the pathogen are not registered, and the use of the vaccine is approved only among seropositive individuals. In this regard, pathogenetic treatment remains the main therapeutic strategy, however, work on the synthesis of antiviral drugs is being actively carried out. Due to the unique functions of non-structural proteins NS3 and NS5 in the viral replication cycle, they have become the main targets for studying the antiviral activity of a number of chemotherapy drugs. Of these proteins, due to the most conserved structure, the NS5 protein is a promising target for inhibition, however, success in obtaining a clinical effect using a number of available antiviral drugs has not been reached. This study describes the positive experience of using the nucleoside analogue riamilovir in the treatment of a patient with dengue fever in the Republic of Guinea

Les droits disciplinaires des fonctions publiques : « unification », « harmonisation » ou « distanciation ». A propos de la loi du 26 avril 2016 relative à la déontologie et aux droits et obligations des fonctionnaires

The production of tt‾ , W+bb‾ and W+cc‾ is studied in the forward region of proton–proton collisions collected at a centre-of-mass energy of 8 TeV by the LHCb experiment, corresponding to an integrated luminosity of 1.98±0.02 fb−1 . The W bosons are reconstructed in the decays W→ℓν , where ℓ denotes muon or electron, while the b and c quarks are reconstructed as jets. All measured cross-sections are in agreement with next-to-leading-order Standard Model predictions.The production of $t\overline{t}$, $W+b\overline{b}$ and $W+c\overline{c}$ is studied in the forward region of proton-proton collisions collected at a centre-of-mass energy of 8 TeV by the LHCb experiment, corresponding to an integrated luminosity of 1.98 $\pm$ 0.02 \mbox{fb}^{-1}. The $W$ bosons are reconstructed in the decays $W\rightarrow\ell\nu$, where $\ell$ denotes muon or electron, while the $b$ and $c$ quarks are reconstructed as jets. All measured cross-sections are in agreement with next-to-leading-order Standard Model predictions

Measurement of forward W→eνW\to e\nu production in pppp collisions at s=8 \sqrt{s}=8\,TeV

A measurement of the cross-section for $W \to e\nu$ production in $pp$ collisions is presented using data corresponding to an integrated luminosity of $2\,$fb$^{-1}$ collected by the LHCb experiment at a centre-of-mass energy of $\sqrt{s}=8\,$TeV. The electrons are required to have more than $20\,$GeV of transverse momentum and to lie between 2.00 and 4.25 in pseudorapidity. The inclusive $W$ production cross-sections, where the $W$ decays to $e\nu$, are measured to be \begin{align*} \begin{split} \sigma_{W^{+} \to e^{+}\nu_{e}}&=1124.4\pm 2.1\pm 21.5\pm 11.2\pm 13.0\,\mathrm{pb},\\ \sigma_{W^{-} \to e^{-}\bar{\nu}_{e}}&=\,\,\,809.0\pm 1.9\pm 18.1\pm\,\,\,7.0\pm \phantom{0}9.4\,\mathrm{pb}, \end{split} \end{align*} where the first uncertainties are statistical, the second are systematic, the third are due to the knowledge of the LHC beam energy and the fourth are due to the luminosity determination. Differential cross-sections as a function of the electron pseudorapidity are measured. The $W^{+}/W^{-}$ cross-section ratio and production charge asymmetry are also reported. Results are compared with theoretical predictions at next-to-next-to-leading order in perturbative quantum chromodynamics. Finally, in a precise test of lepton universality, the ratio of $W$ boson branching fractions is determined to be \begin{align*} \begin{split} \mathcal{B}(W \to e\nu)/\mathcal{B}(W \to \mu\nu)=1.020\pm 0.002\pm 0.019, \end{split} \end{align*} where the first uncertainty is statistical and the second is systematic.A measurement of the cross-section for $W \to e\nu$ production in $pp$ collisions is presented using data corresponding to an integrated luminosity of $2\,$fb$^{-1}$ collected by the LHCb experiment at a centre-of-mass energy of $\sqrt{s}=8\,$TeV. The electrons are required to have more than $20\,$GeV of transverse momentum and to lie between 2.00 and 4.25 in pseudorapidity. The inclusive $W$ production cross-sections, where the $W$ decays to $e\nu$, are measured to be \begin{equation*} \sigma_{W^{+} \to e^{+}\nu_{e}}=1124.4\pm 2.1\pm 21.5\pm 11.2\pm 13.0\,\mathrm{pb}, \end{equation*} \begin{equation*} \sigma_{W^{-} \to e^{-}\bar{\nu}_{e}}=\,\,\,809.0\pm 1.9\pm 18.1\pm\,\,\,7.0\pm \phantom{0}9.4\,\mathrm{pb}, \end{equation*} where the first uncertainties are statistical, the second are systematic, the third are due to the knowledge of the LHC beam energy and the fourth are due to the luminosity determination. Differential cross-sections as a function of the electron pseudorapidity are measured. The $W^{+}/W^{-}$ cross-section ratio and production charge asymmetry are also reported. Results are compared with theoretical predictions at next-to-next-to-leading order in perturbative quantum chromodynamics. Finally, in a precise test of lepton universality, the ratio of $W$ boson branching fractions is determined to be \begin{equation*} \mathcal{B}(W \to e\nu)/\mathcal{B}(W \to \mu\nu)=1.020\pm 0.002\pm 0.019, \end{equation*} where the first uncertainty is statistical and the second is systematic.A measurement of the cross-section for W → eν production in pp collisions is presented using data corresponding to an integrated luminosity of 2 fb$^{−1}$ collected by the LHCb experiment at a centre-of-mass energy of $\sqrt{s}=8$ TeV. The electrons are required to have more than 20 GeV of transverse momentum and to lie between 2.00 and 4.25 in pseudorapidity. The inclusive W production cross-sections, where the W decays to eν, are measured to be ${\sigma}_{W^{+}\to {e}^{+}{\nu}_e}=1124.4\pm 2.1\pm 21.5\pm 11.2\pm 13.0\kern0.5em \mathrm{p}\mathrm{b},$ ${\sigma}_{W^{-}\to {e}^{-}{\overline{\nu}}_e}=809.0\pm 1.9\pm 18.1\pm \kern0.5em 7.0\pm \kern0.5em 9.4\,\mathrm{p}\mathrm{b},$ where the first uncertainties are statistical, the second are systematic, the third are due to the knowledge of the LHC beam energy and the fourth are due to the luminosity determination

LCR activity and background Ca at low and high SR Ca pumping rate Pup of 4 mM/s and 24 mM/s as membrane depolarizes from the MDP (Maximal Diastolic Potential) to -50 mV (a threshold of I_CaL activation).

<p>(A): Local Ca distribution in submembrane cytosol voxels at the scale of 5 μM. The LCR activity increases during diastolic depolarization, but remains much lower at lower Pup. The background Ca does not appear different at this large Ca scale. (B) The same Ca distribution at a smaller scale of 0.25 μM. At low Pup, the cytosol is not efficiently cleared of Ca by the Ca pump after action potential-induced Ca transient and Ca distribution at the MDP (sub-panel a) shows substantially higher background and multiple small LCRs. Conversely, higher SR Ca pumping rate of 24 mM/s efficiently clears cytosol of Ca and the background Ca decreases (black background in sub-panel c). See also <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005675#pcbi.1005675.s001" target="_blank">S1</a> and <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005675#pcbi.1005675.s002" target="_blank">S2</a> Movies for more details and dynamic representation of the numerical model simulation results.</p

Analysis of average and local Ca signals in submembrane cytosol voxel to generate NCX currents during spontaneous action potential firing by our numerical model of sinoatrial node cell at various SR Ca pumping rate (Pup).

<p>(A and B) Overlapped average Ca signals synchronized at the Ca transient peak at different scales of 8 and 0.5 μM, respectively. The noisy rising Ca signal caused by LCR activity is marked by label “LCRs” in panel B. (C) The corresponding NCX currents simulated concurrently with the Ca signals in panels A and B. Occurrence of an earlier and stronger inward NCX current at high Pup is shown by red arrow. Green arrow shows decreasing NCX current at low Pup. (D-F) Examples of noisy local Ca dynamics in a single voxel at various Pup. LCR signals generated nearby are labeled “LCR” and the local Ca transient is marked “T”. Parts of Ca local transient decays with no LCR are outlined by rectangles. (G) Overlapped traces of the local Ca transient decays outlined in panels D-F. The decay is faster at higher Pup.</p

Initial statistical analysis of automatically detected LCRs.

<p>(A and B): Distributions of simple LCR birth times at different SR Ca pumping rates of Pup 4 mM/s and Pup 24 mM/s. Simple LCRs at Pup 4 mM/s appear mainly at the beginning of the diastolic depolarization period. The 0 bin takes all pre-existing LCRs as new and thus should not be taken into consideration. (C and D): Distributions of complex LCR signal mass at different Pup of 24 mM/s (C) and 4 mM/s (D). Powerful complex LCRs emerge at higher Pup (circled in red).</p

Schematic illustration of major components of numerical model of rabbit sinoatrial node cell used in our study.

<p>Abbreviations: Free SR (FSR) collects Ca from cytoplasm and transfers it to the junctional SR (JSR) that releases Ca under cell membrane; Ca_SR, [Ca] in JSR; Ca_cyto, [Ca] in cytoplasm; RyR, Ca release channel, ryanodine receptor; i_CaL, L-type Ca channel; NCX, Na/Ca exchanger. See <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005675#sec011" target="_blank">Methods</a> for details. Modified from [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005675#pcbi.1005675.ref005" target="_blank">5</a>].</p

Key LCR characteristics measured at three SR Ca pumping rates Pup in each representative cycle.

<p>Key LCR characteristics measured at three SR Ca pumping rates Pup in each representative cycle.</p