Benefits and costs of introducing tariff choice in uncontested markets – A Report for Ofwat

1. Theoretical models indicate that allowing a regulated company to introduce optional (or self selecting) tariffs can make individual consumers (and consumers on average) better off and be profitable for the company, as long as the original (regulated) tariff remains available to all consumers. 2. The models contain some restrictive assumptions and limitations and may be difficult to apply in practice. 3. One particular assumption crucial to the benefits is that consumers choose the best tariff for themselves. More recent research on consumer behaviour in general and in utilities in particular show that this may not be the case. Much of the market literature has been concerned with the telecoms and energy markets. 4. There may be distributional concerns if some consumer groups are less likely to choose well, particularly if there are likely to be long term effects on the ‘base’ tariff. Such concerns are reflected in the current British energy regulator’s consultation on reducing tariff choice for both suppliers and consumers as a response to perceived failure of competition. This experience raises questions about the intrinsic value of choice for consumers. 5. Experience of optional metering in England and Wales provides some evidence of how residential water consumers have responded to that particular tariff choice. Other evidence on water consumer perceptions indicates that the assumptions made in theoretical models of tariff choice may not be applicable to this market. This may affect the applicability of welfare assessments made in the models. 6. We conclude by identifying some questions about the circumstances in which allowing optional tariffs (alongside a regulated base) is likely to be beneficial

Varenicline Interactions at the 5-HT3 Receptor Ligand Binding Site are Revealed by 5-HTBP.

Cys-loop receptors are the site of action of many therapeutic drugs. One of these is the smoking cessation agent varenicline, which has its major therapeutic effects at nicotinic acetylcholine (nACh) receptors but also acts at 5-HT3 receptors. Here, we report the X-ray crystal structure of the 5-HT binding protein (5-HTBP) in complex with varenicline, and test the predicted interactions by probing the potency of varenicline in a range of mutant 5-HT3 receptors expressed in HEK293 cells and Xenopus oocytes. The structure reveals a range of interactions between varenicline and 5-HTBP. We identified residues within 5 Å of varenicline and substituted the equivalent residues in the 5-HT3 receptor with Ala or a residue with similar chemical properties. Functional characterization of these mutant 5-HT3 receptors, using a fluorescent membrane potential dye in HEK cells and voltage clamp in oocytes, supports interactions between varenicline and the receptor that are similar to those in 5-HTBP. The structure also revealed C-loop closure that was less than in the 5-HT-bound 5-HTBP, and hydrogen bonding between varenicline and the complementary face of the binding pocket via a water molecule, which are characteristics consistent with partial agonist behavior of varenicline in the 5-HT3 receptor. Together, these data reveal detailed insights into the molecular interaction of varenicline in the 5-HT3 receptor.Supported by grants from the Wellcome Trust (81925) and the MRC to S.C.R.L.This is the final published version. It first appeared at http://pubs.acs.org/doi/abs/10.1021/cn500369

The Proton Responsiveness in the Extracellular Domain of GLIC Differs in the Presence of the ELIC Transmembrane Domain

Prokaryotic homologues of Cys-loop receptors have proven to be useful in understanding their eukaryotic counterparts, but even the best studied of these, Gloeobacter ligand-gated ion channel (GLIC), is still not yet fully understood. GLIC is activated by protons with a pH$_{50}$ between 5 and 6, implicating a histidine residue in its activation, but although a histidine residue (His11′) in the pore-forming α-helix (M2) is known to be involved in gating, the His in the extracellular domain (ECD), His127, is not. Nevertheless, there is evidence from a GLIC–glycine chimera for a proton sensitive residue or region in the GLIC extracellular domain. Here we create a novel chimeric receptor with the ECD of GLIC and the transmembrane domain of ELIC (GELIC). Expression of this receptor in oocytes reveals proton activation, although the pH$_{50}$ (6.7) differs from that of GLIC (5.4). Exploration of protonatable residues in the ECD reveals that the pK$_{a}$s of five Asp residues (31, 49, 91, 136, and 178) differ between the open and closed states of GLIC. Substitution of these residues with Ala or Asn shows somewhat similar effects for GLIC and GELIC in Asp91 mutants, but different effects for the others. Overall, the data suggest that protonation of residues in the ECD is a requirement for channel opening in GELIC but plays only a minor role in GLIC, where gating may be largely driven via protonation of the His residue in its pore.S.C.R.L. and K.L.P. were supported by an MRC grant (MR L02/676). M.A.A. was funded by a Yousef Jameel Scholarship

An atypical residue in the pore of Varroa destructor GABA-activated RDL receptors affects picrotoxin block and thymol modulation.

GABA-activated RDL receptors are the insect equivalent of mammalian GABAA receptors, and play a vital role in neurotransmission and insecticide action. Here we clone the pore lining M2 region of the Varroa mite RDL receptor and show that it has 4 atypical residues when compared to M2 regions of most other insects, including bees, which are the major host of Varroa mites. We create mutant Drosophila RDL receptors containing these substitutions and characterise their effects on function. Using two electrode voltage clamp electrophysiology we show that one substitution (T6'M) ablates picrotoxin inhibition and increases the potency of GABA. This mutation also alters the effect of thymol, which enhances both insect and mammalian GABA responses, and is widely used as a miticide. Thymol decreases the GABA EC50 of WT receptors, enhancing responses, but in T6'M-containing receptors it is inhibitory. The other 3 atypical residues have no major effects on either the GABA EC50, the picrotoxin potency or the effect of thymol. In conclusion we show that the RDL 6' residue is important for channel block, activation and modulation, and understanding its function also has the potential to prove useful in the design of Varroa-specific insecticidal agents.This project was supported by the Wellcome Trust (grant 81925 to SCRL). SCRL is a Wellcome Trust Senior Research Fellow in Basic Biomedical Studies.This is the final published version, which first appeared at http://www.sciencedirect.com/science/article/pii/S0965174814001684

Phenylalanine in the pore of the Erwinia ligand-gated ion channel modulates picrotoxinin potency but not receptor function.

The Erwinia ligand-gated ion channel (ELIC) is a bacterial homologue of eukaryotic Cys-loop ligand-gated ion channels. This protein has the potential to be a useful model for Cys-loop receptors but is unusual in that it has an aromatic residue (Phe) facing into the pore, leading to some predictions that this protein is incapable of ion flux. Subsequent studies have shown this is not the case, so here we probe the role of this residue by examining the function of the ELIC in cases in which the Phe has been substituted with a range of alternative amino acids, expressed in Xenopus oocytes and functionally examined. Most of the mutations have little effect on the GABA EC50, but the potency of the weak pore-blocking antagonist picrotoxinin at F16'A-, F16'D-, F16'S-, and F16'T-containing receptors was increased to levels comparable with those of Cys-loop receptors, suggesting that this antagonist can enter the pore only when residue 16' is small. T6'S has no effect on picrotoxinin potency when expressed alone but abolishes the increased potency when combined with F16'S, indicating that the inhibitor binds at position 6', as in Cys-loop receptors, if it can enter the pore. Overall, the data support the proposal that the ELIC pore is a good model for Cys-loop receptor pores if the role of F16' is taken into consideration.This project was supported by the Wellcome Trust Grant 81925 to S.C.R.L. S.C.R.L. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Studies. M.A. is funded by a Yousef Jameel Scholarship. D.A.W. was funded by an MRC studentship.This is the final published version. It first appeared at http://pubs.acs.org/doi/abs/10.1021/bi5008035

Associations Between Case, Staff, and Agency Characteristics and the Decision to Place a Child in Out-of-Home Care

Typically, when children are placed into out-of-home care due to child maltreatment concerns, people assume that this decision is based on action or inaction on behalf of the child’s caregivers. While such elements are likely the main drivers of the decision, a growing body of research suggests that other factors contribute to caseworkers’ decisions on the child welfare cases they serve. Drawing from the decision-making ecology (DME), this study examines the extent to which caseworker and organizational factors, in addition to case characteristics, play a role in decisions to remove a child from their home. Survey data from 118 investigation or assessment workers in a southeastern state were paired with administrative data from 10,568 child protective services (CPS) responses assigned to the surveyed workers for analysis. Multi-level modeling (cases, and cases within workers) results identified that, controlling for case characteristics and using 95% confidence intervals, workers who were male (aOR: 0.71 [0.50–0.998]), perceived the agency as more supportive (aOR: 0.87 [0.80–0.94]), and those indicating a strong orientation towards family preservation compared to child safety (aOR: 0.58 [0.42–0.81]) were associated with lower odds of placing children into out-of-home care. Staff who felt more cohesion with their co-workers (aOR: 1.37 [1.19–1.57]) were more likely to place children on their caseloads. These results indicate that the current system of decision-making and case trajectories are prone to influences from caseworkers’ personal biases and perceptions of support. Implications for CPS workforce selection, development, support, and case assignment are discussed