Mental health and debt collection: a story of progress? Exploring changes in debt collectors' attitudes and practices when working with customers with mental health problems, 2010-2016.

BACKGROUND: In recent years, the UK debt collection industry has taken steps to improve its policies and practices in relation to customers with mental health problems. Little data, however, have been collected to evidence change. AIMS: This paper examines whether the reported attitudes and practices of debt collection staff when working with customers with mental health problems have changed between 2010 and 2016. METHOD: This paper draws on descriptive and regression analyses of two cross-sectional surveys of debt collection staff: one conducted in 2010 and one conducted in 2016. RESULTS: All variables analysed show statistically significant changes between 2010 and 2016 indicative of improved reported attitudes and practices. CONCLUSIONS: While results suggest an improvement in attitudes and practice may have occurred between 2010 and 2016, research is required to understand this potential shift, its likely causes, and concrete impact on customers.

Behavioral effects of peripheral corticotropin-releasing factor during maternal separation may be mediated by proinflammatory activity.

When guinea pig pups are separated from their mothers in a novel environment, an initial period of active behavior (vocalizing, locomotor activity) wanes after an hour or so and is replaced by a second, passive stage characterized by a crouched stance, closed eyes, and extensive piloerection. If pups are given a peripheral injection of 7-14µg of corticotropin-releasing factor (CRF) prior to testing, the passive behaviors occur immediately upon separation. We found that intracerebroventricular infusion of 1-10µg of CRF did not increase passive behavior relative to vehicle infusion, but that peripheral injection of the anti-inflammatory cytokine, interleukin-10, attenuated the passive behavior induced by peripheral CRF injection. These results together with previous findings suggest that peripheral CRF administration affects behavior of separated guinea pig pups through a mechanism that involves peripheral proinflammatory activity. The possible role of endogenous peripheral CRF in the behavioral response of untreated pups during maternal separation is considered.

An antibody loop replacement design feasibility study and a loop-swapped dimer structure.

A design approach was taken to investigate the feasibility of replacing single complementarity determining region (CDR) antibody loops. This approach may complement simpler mutation-based strategies for rational antibody design by expanding conformation space. Enormous crystal structure diversity is available, making CDR loops logical targets for structure-based design. A detailed analysis for the L1 loop shows that each loop length takes a distinct conformation, thereby allowing control on a length scale beyond that accessible to simple mutations. The L1 loop in the anti-VLA1 antibody was replaced with the L2 loop residues longer in an attempt to add an additional hydrogen bond and fill space on the antibody-antigen interface. The designs expressed well, but failed to improve affinity. In an effort to learn more, one design was crystallized and data were collected at 1.9 A resolution. The designed L1 loop takes the qualitatively desired conformation; confirming that loop replacement by design is feasible. The crystal structure also shows that the outermost loop (residues Leu51-Ser68) is domain swapped with another monomer. Tryptophan fluorescence measurements were used to monitor unfolding as a function of temperature and indicate that the loop involved in domain swapping does not unfold below 60 degrees C. The domain-swapping is not directly responsible for the affinity loss, but is likely a side-effect of the structural instability which may contribute to affinity loss. A second round of design was successful in eliminating the dimerization through mutation of a residue (Leu51Ser) at the joint of the domain-swapped loop.

Affinity enhancement of an in vivo matured therapeutic antibody using structure-based computational design.

Improving the affinity of a high-affinity protein-protein interaction is a challenging problem that has practical applications in the development of therapeutic biomolecules. We used a combination of structure-based computational methods to optimize the binding affinity of an antibody fragment to the I-domain of the integrin VLA1. Despite the already high affinity of the antibody (Kd approximately 7 nM) and the moderate resolution (2.8 A) of the starting crystal structure, the affinity was increased by an order of magnitude primarily through a decrease in the dissociation rate. We determined the crystal structure of a high-affinity quadruple mutant complex at 2.2 A. The structure shows that the design makes the predicted contacts. Structural evidence and mutagenesis experiments that probe a hydrogen bond network illustrate the importance of satisfying hydrogen bonding requirements while seeking higher-affinity mutations. The large and diverse set of interface mutations allowed refinement of the mutant binding affinity prediction protocol and improvement of the single-mutant success rate. Our results indicate that structure-based computational design can be successfully applied to further improve the binding of high-affinity antibodies.