Molecular Basis for the Interactions of Human Thioredoxins with Their Respective Reductases

The mammalian cytosolic thioredoxin (Trx) system consists of Trx1 and its reductase, the NADPH-dependent seleno-enzyme TrxR1. These proteins function as electron donor for metabolic enzymes, for instance in DNA synthesis, and the redox regulation of numerous processes. In this work, we analysed the interactions between these two proteins. We proposed electrostatic complementarity as major force controlling the formation of encounter complexes between the proteins and thus the efficiency of the subsequent electron transfer reaction. If our hypothesis is valid, formation of the encounter complex should be independent of the redox reaction. In fact, we were able to confirm that also a redox inactive mutant of Trx1 lacking both active site cysteinyl residues (C32,35S) binds to TrxR1 in a similar manner and with similar kinetics as the wild-type protein. We have generated a number of mutants with alterations in electrostatic properties and characterised their interaction with TrxR1 in kinetic assays. For human Trx1 and TrxR1, complementary electrostatic surfaces within the area covered in the encounter complex appear to control the affinity of the reductase for its substrate Trx. Electrostatic compatibility was even observed in areas that do not form direct molecular interactions in the encounter complex, and our results suggest that the electrostatic complementarity in these areas influences the catalytic efficiency of the reduction. The human genome encodes ten cytosolic Trx-like or Trx domain-containing proteins. In agreement with our hypothesis, the proteins that have been characterised as TrxR1 substrates also show the highest similarity in their electrostatic properties.

Optimal administration of bronchodilators with valved holding chambers in preschool children: a review of literature

Our aim was to synthesize the published literature on factors that potentially affect the delivery of bronchodilators using valved holding chambers (VHC) in preschool children. We also aimed to identify those attributes that are not yet incorporated or clearly stated in the guidelines and those topics that are still lacking sufficient data. There is strong evidence supporting several recommendations in current guidelines. Based on present knowledge, bronchodilators should be delivered by VHC administering each puff separately. Face mask should be omitted as soon as the child can hold the mouthpiece of the VHC tightly between the lips and teeth. Based on the review, we suggest adding a specific note to current guidelines about the effect of chamber volume and the impact of co-operation during drug administration. Calming the child and securing a tight face-to-mask seal is critical for successful drug delivery. There is not enough evidence to make specific recommendations on the most reliable VHC and face mask for children. There is an urgent need for studies that evaluate and compare the effectiveness of VHCs in various clinical settings in wide age-groups and respiratory patterns. In addition, there is insufficient data on ideal chamber volume, material, and effective antistatic treatment. What is Known:• Valved holding chambers (VHC) should not be considered interchangeable when used with pressurized metered dose inhalers (pMDI).• Drug delivery is influenced by VHC volume, aerodynamic and electrostatic properties; mask fit; respiratory pattern and co-operation during inhalation; and the number of puffs actuated.What is New:• The impact of co-operation, VHC volume, and good mask-to-face fit during drug inhalation is not stressed enough in the guidelines.• Studies are urgently needed to evaluate the effectiveness of different VHCs in various clinical settings focusing on VHC electrostatic properties, respiratory patters, face masks, and ideal pMDI+VHC combinations.

Effect of Bjerrum pairs on electrostatic properties in an electrolyte solution near charged surfaces: A mean-field approach

In this paper, we investigate the consequences of ion association, coupled with the considerations of finite size effects and orientational ordering of Bjerrum pairs as well as ions and water...

γ-Ray irradiation-induced unprecedent optical, frictional and electrostatic performances on CVD-prepared monolayer WSe2

Our work showed a new defect inducing technique to engineer the bandgap and control the optical, frictional and electrostatic properties of atomically thin WSe2.

Salt-in-water and water-in-salt electrolytes: The effects of the asymmetry in cation and anion valence on its properties

We investigated the structural, dynamic, energetic, and electrostatic properties of electrolytes based on the ion pairs LiCl and Li2SO4. Atomistic molecular dynamics simulations were used to simulate these aqueous electrolytic...