Direct activation of KCC2 arrests benzodiazepine refractory status epilepticus and limits the subsequent neuronal injury in mice

Hyperpolarizing GABAAR currents, the unitary events that underlie synaptic inhibition, are dependent upon efficient Cl− extrusion, a process that is facilitated by the neuronal specific K+/Cl− co-transporter KCC2. Its activity is also a determinant of the anticonvulsant efficacy of the canonical GABAAR-positive allosteric: benzodiazepines (BDZs). Compromised KCC2 activity is implicated in the pathophysiology of status epilepticus (SE), a medical emergency that rapidly becomes refractory to BDZ (BDZ-RSE). Here, we have identified small molecules that directly bind to and activate KCC2, which leads to reduced neuronal Cl− accumulation and excitability. KCC2 activation does not induce any overt effects on behavior but prevents the development of and terminates ongoing BDZ-RSE. In addition, KCC2 activation reduces neuronal cell death following BDZ-RSE. Collectively, these findings demonstrate that KCC2 activation is a promising strategy to terminate BDZ-resistant seizures and limit the associated neuronal injury

A photo‐thermoelectric twist to wireless energy transfer: radial flexible thermoelectric device powered by a high‐power laser beam

Systems for wireless energy transmission (WET) are gaining prominence nowadays. This work presents a WET system based on the photo-thermoelectric effect. With an incident laser beam at λ = 1450 nm, a temperature gradient is generated in the radial flexible thermoelectric (TE) device, with a carbon-based light collector in its center to enhance the photoheating. The three-part prototype presents a unique approach by using a radial TE device with one simple manufacturing process - screen-printing. A TE ink with a polymeric matrix of poly(3,4-ethylenedioxythiophene) polystyrene sulfonate and doped-Poly(vinyl alcohol) with Sb-Bi-Te microparticles is developed (S∽33 µVK−1 and s∽10.31 Sm−1), presenting mechanical and electrical stability. Regarding the device, a full electrical analysis is performed, and the influence of the light collector is investigated using thermal tests, spectrophotometry, and numerical simulations. A maximum output voltage (Vout) of ∽16 mV and maximum power density of ∽25 µWm−2 are achieved with Plaser = 2 W. Moreover, the device's viability under extreme conditions is explored. At T∽180 K, a 25% increase in Vout compared to room-temperature conditions is achieved, and at low pressures (∽10‒6 Torr), an increase of 230% is obtained. Overall, this prototype allows the supply of energy at long distances and remote places, especially for space exploration.Federación Española de Enfermedades Raras | Ref. UID/NAN/50024/2019Federación Española de Enfermedades Raras | Ref. NORTE‐01‐0145‐FEDER022096Fundação para a Ciência e a Tecnologia | Ref. UIDB/04968/2020Fundação para a Ciência e a Tecnologia | Ref. UIDP/04968/202

Deciphering the role of coumarin as a novel quorum sensing inhibitor suppressing virulence phenotypes in bacterial pathogens

© 2015, Springer-Verlag Berlin Heidelberg. The rapid unchecked rise in antibiotic resistance over the last few decades has led to an increased focus on the need for alternative therapeutic strategies for the treatment and clinical management of microbial infections. In particular, small molecules that can suppress microbial virulence systems independent of any impact on growth are receiving increased attention. Quorum sensing (QS) is a cell-to-cell signalling communication system that controls the virulence behaviour of a broad spectrum of bacterial pathogens. QS systems have been proposed as an effective target, particularly as they control biofilm formation in pathogens, a key driver of antibiotic ineffectiveness. In this study, we identified coumarin, a natural plant phenolic compound, as a novel QS inhibitor, with potent anti-virulence activity in a broad spectrum of pathogens. Using a range of biosensor systems, coumarin was active against short, medium and long chain N-acyl-homoserine lactones, independent of any effect on growth. To determine if this suppression was linked to anti-virulence activity, key virulence systems were studied in the nosocomial pathogen Pseudomonas aeruginosa. Consistent with suppression of QS, coumarin inhibited biofilm, the production of phenazines and swarming motility in this organism potentially linked to reduced expression of the rhlI and pqsA quorum sensing genes. Furthermore, coumarin significantly inhibited biofilm formation and protease activity in other bacterial pathogens and inhibited bioluminescence in Aliivibrio fischeri. In light of these findings, coumarin would appear to have potential as a novel quorum sensing inhibitor with a broad spectrum of action