Enzyme-catalyzed mechanism of isoniazid activation in class I and class III peroxidases.

There is an urgent need to understand the mechanism of activation of the frontline anti-tuberculosis drug isoniazid by the Mycobacterium tuberculosis catalase-peroxidase. To address this, a combination of NMR spectroscopic, biochemical, and computational methods have been used to obtain a model of the frontline anti-tuberculosis drug isoniazid bound to the active site of the class III peroxidase, horseradish peroxidase C. This information has been used in combination with the new crystal structure of the M. tuberculosis catalase-peroxidase to predict the mode of INH binding across the class I heme peroxidase family. An enzyme-catalyzed mechanism for INH activation is proposed that brings together structural, functional, and spectroscopic data from a variety of sources. Collectively, the information not only provides a molecular basis for understanding INH activation by the M. tuberculosis catalase-peroxidase but also establishes a new conceptual framework for testing hypotheses regarding the enzyme-catalyzed turnover of this compound in a number of heme peroxidases

Crack formation and prevention in colloidal drops

Crack formation is a frequent result of residual stress release from colloidal films made by the evaporation of colloidal droplets containing nanoparticles. Crack prevention is a significant task in industrial applications such as painting and inkjet printing with colloidal nanoparticles. Here, we illustrate how colloidal drops evaporate and how crack generation is dependent on the particle size and initial volume fraction, through direct visualization of the individual colloids with confocal laser microscopy. To prevent crack formation, we suggest use of a versatile method to control the colloid-polymer interactions by mixing a nonadsorbing polymer with the colloidal suspension, which is known to drive gelation of the particles with short-range attraction. Gelation-driven crack prevention is a feasible and simple method to obtain crack-free, uniform coatings through drying-mediated assembly of colloidal nanoparticlesopen0

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22–25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None

Tonks-Frenkel instability in electrolyte under high-frequency AC electric fields

The instability of an electrolyte surface to a high-frequency, 10 to 200kHz, electric field, normal to the interface is investigated theoretically. From a practical viewpoint, such a high frequency leads to the absence of undesired electrochemical reactions and provides an additional control parameter. The theory of unsteady electric double layer by Barrero and Ramos is exploited. At such a high frequency, which is much larger than the eigenfrequency of the mechanical system, the nonlinear mechanical term does not “feel” the fast part of the Coulomb force, but it feels its slower component. In fact, the system behaves as if the electric field were a DC field. The observed instability is qualitatively close to the Tonks-Frenkel instability. The problem of the linear stability of the 1D quiescent stationary solution is solved analytically. For the important limiting cases, simple analytical formulas are derived. The linear stability analysis is complemented by the DNS of the full nonlinear system of equations with broadband low-amplitude white-noise initial conditions. After a transition period, the linear instability mechanism filters out the broad spectrum except for a narrow band near the maximum growth rate in rather good agreement with the linear stability analysis. If the external field is large enough, the nonlinear evolution results in coherent structures with sharp tips resembling to a Taylor cone. An evaluation of the cone angle for different conditions gives its value of about 30° to 60° , which is smaller than the angle of 98.6° for DC field and qualitatively corresponds to the experiments (L.Y. Yeo et al., Phys. Rev. Lett. 92, 133902 (2004)) for the high-frequency AC field and to the theoretical evaluation of the AC Taylor cones in E.A. Demekhin et al., Phys. Rev. E 84, 035301(R) (2011)

Impact of Fluorocarbon Gaseous Environments on the Permeability of Foam Films to Air

International audienceA foam film, free to move and stabilized with tetradecyltrimethylammo-nium bromide or sodium dodecylsulfate surfactants, is deposited inside of a cylindrical tube. It separates the tube into two distinct gaseous compartments. The first compartmentisfilled with air, while the second one contains a mixture of air and perfluorohexane vapor(C6F14), which is a barely water-solublefluorinated compound. This foam film thus acts as a liquid semipermeable membrane for gases equivalent to the solid semipermeable membranes conventionally used in fluid separation processes. To infer the rate of air transfer through the membrane, we measure the displacement of the mobile foam film.From this, we deduce the instantaneous permeability of the membrane. In contrast to the permeability of solid membranes, which inexorably decreases over time because they become clogged, an anticlogging effect is observed with a permeability that systematically increases over time. Because the thickness of thefilm is constant over time, we attribute this to the possibility of adsorbing or desorbing fluorinated gas molecules on the liquid membrane. Indeed, because the partial pressure of the fluorinated gas is high at the beginning of the experiment, the density of the adsorbed molecules is also high, which leads to a low permeability to air transfer. On the contrary, at the end of the experiment, the partial pressure in fluorinated gas and thus the density of the adsorbed molecules are low. This leads to a higher permeability and a less clogged membrane

Sclérose en plaques et grossesse [Multiple sclerosis and pregnancy]

International audienceThe question of pregnancy in patients with multiple sclerosis is regularly raised due to the prevalence of the disease in middle age women. The multiple sclerosis think tank (Groupe de Réflexion sur la Sclérose en Plaques [GRESEP]) decided to develop recommendations on this issue, with consideration to both the impact of multiple sclerosis on pregnancy, and that of pregnancy on the disease. As with topics of previous works, the formal expert consensus method was used. The working group was composed of hospital-based and private practice neurologists. The reading group was composed of neurologists, anaesthetists and obstetricians. Each recommendation is presented with the relevant level of consensus