STRUCTURE, GATING, AND REGULATION OF THE CFTR ANION CHANNEL

The cystic fibrosis transmembrane conductance regulator (CFTR) belongs to the ATP binding cassette (ABC) transporter superfamily but functions as an anion channel crucial for salt and water transport across epithelial cells. CFTR dysfunction, because of mutations, causes cystic fibrosis (CF). The anion-selective pore of the CFTR protein is formed by its two transmembrane domains (TMDs) and regulated by its cytosolic domains: two nucleotide binding domains (NBDs) and a regulatory (R) domain. Channel activation requires phosphorylation of the R domain by cAMP-dependent protein kinase (PKA), and pore opening and closing (gating) of phosphorylated channels is driven by ATP binding and hydrolysis at the NBDs. This review summarizes available information on structure and mechanism of the CFTR protein, with a particular focus on atomic-level insight gained from recent cryo-electron microscopic structures and on the molecular mechanisms of channel gating and its regulation. The pharmacological mechanisms of small molecules targeting CFTR's ion channel function, aimed at treating patients suffering from CF and other diseases, are briefly discussed

Probing a Complex of Cytochromecand Cardiolipin by Magnetic Circular Dichroism Spectroscopy: Implications for the Initial Events in Apoptosis

Oxidation of cardiolipin (CL) by its complex with cytochrome c (cyt c) plays a crucial role in triggering apoptosis. Through a combination of magnetic circular dichroism spectroscopy and potentiometric titrations, we show that both the ferric and ferrous forms of the heme group of a CL:cyt c complex exist as multiple conformers at a physiologically relevant pH of 7.4. For the ferric state, these conformers are His/Lys- and His/OH–-ligated. The ferrous state is predominantly high-spin and, most likely, His/–. Interconversion of the ferric and ferrous conformers is described by a single midpoint potential of -80 ± 9 mV vs SHE. These results suggest that CL oxidation in mitochondria could occur by the reaction of molecular oxygen with the ferrous CL:cyt c complex in addition to the well-described reaction of peroxides with the ferric form

Regulation of Na+/K+ ATPase Transport Velocity by RNA Editing

Editing of Na+/K+ ATPase mRNAs modulates the Na+/K+ pump's turnover rate by selectively targeting the release of the final sodium to the outside

“Catching your tail and firefighting”: The impact of staffing levels on restraint minimization efforts

Introduction: Safe staffing and coercive practices are of pressing concern for mental health services. These are inter-dependent and the relationship is under-researched. Aim: To explore views on staffing levels in context of attempting to minimise physical restraint practices on mental health wards. Findings emerged from a wider dataset with the broader aim of exploring experiences of a restraint reduction initiative Methods: Thematic analysis of semi-structured interviews with staff (n=130) and service users (n=32). Results: Five themes were identified regarding how staffing levels impact experiences and complicate efforts to minimise physical restraint. We titled the themes – ‘insufficient staff to do the job’; ‘detriment to staff and service users’; ‘a paperwork exercise: the burden of non-clinical tasks’; ‘false economies’; and, ‘you can’t do these interventions’. Discussion: Tendencies detracting from relational aspects of care are not independent of insufficiencies in staffing. The relational, communicative, and organisational developments that would enable reductions in use of restraint are labour intensive and vulnerable to derailment by insufficient and poorly skilled staff. Implications for Practice: Restrictive practices are unlikely to be minimised unless wards are adequately staffed. Inadequate staffing is not independent of restrictive practices and reduces access to alternative interventions for reducing individuals’ distress