Order Effects of Ballot Position without Information-Induced Confirmatory Bias

Candidate list positions have been shown to influence decision making when voters have limited candidate information (e.g. Miller and Krosnick, 1998; Brockington, 2003). Here, a primacy advantage is observed due to a greater number of positive arguments generated for early list candidates (Krosnick, 1991). The present study examined list position effects when an absence of information precludes such a confirmatory bias heuristic. We report the first large scale low-information experimental election where candidate position is fully counterbalanced. Seven hundred and twenty participants voted in a mock election where the position of 6 fictitious and meaningless parties was counterbalanced across the electorate. Analysis by position revealed that significantly fewer votes were allocated to the terminal parties (Experiment 1). In addition, Experiment 1 reported preliminary evidence of an alphabetical bias (consistent with Bagley, 1966). However, this positional bias was not present in a methodological replication using six genuine UK political parties (Experiment 2). This suggests that in situations of pure guessing, the heuristic shifts from the primacy benefiting confirmatory bias to an alternative heuristic that prejudices the first and last parties. These findings suggest that whilst the UK general electoral process may be largely immune to positional prejudice, English local elections (in which there can be multiple candidates from the same party) and multiple preference ranking systems (Scottish Local Government and London Mayoral Elections) could be susceptible to both positional and alphabetical biases

Double quick, double click reversible peptide “stapling”

The development of constrained peptides for inhibition of protein–protein interactions is an emerging strategy in chemical biology and drug discovery. This manuscript introduces a versatile, rapid and reversible approach to constrain peptides in a bioactive helical conformation using BID and RNase S peptides as models. Dibromomaleimide is used to constrain BID and RNase S peptide sequence variants bearing cysteine (Cys) or homocysteine (hCys) amino acids spaced at i and i + 4 positions by double substitution. The constraint can be readily removed by displacement of the maleimide using excess thiol. This new constraining methodology results in enhanced α-helical conformation (BID and RNase S peptide) as demonstrated by circular dichroism and molecular dynamics simulations, resistance to proteolysis (BID) as demonstrated by trypsin proteolysis experiments and retained or enhanced potency of inhibition for Bcl-2 family protein–protein interactions (BID), or greater capability to restore the hydrolytic activity of the RNAse S protein (RNase S peptide). Finally, use of a dibromomaleimide functionalized with an alkyne permits further divergent functionalization through alkyne–azide cycloaddition chemistry on the constrained peptide with fluorescein, oligoethylene glycol or biotin groups to facilitate biophysical and cellular analyses. Hence this methodology may extend the scope and accessibility of peptide stapling

The vacuolar-ATPase complex and assembly factors, TMEM199 and CCDC115, control HIF1α prolyl hydroxylation by regulating cellular iron levels.

Hypoxia Inducible transcription Factors (HIFs) are principally regulated by the 2-oxoglutarate and Iron(II) prolyl hydroxylase (PHD) enzymes, which hydroxylate the HIFα subunit, facilitating its proteasome-mediated degradation. Observations that HIFα hydroxylation can be impaired even when oxygen is sufficient emphasise the importance of understanding the complex nature of PHD regulation. Here, we use an unbiased genome-wide genetic screen in near-haploid human cells to uncover cellular processes that regulate HIF1α. We identify that genetic disruption of the Vacuolar H+ ATPase (V-ATPase), the key proton pump for endo-lysosomal acidification, and two previously uncharacterised V-ATPase assembly factors, TMEM199 and CCDC115, stabilise HIF1α in aerobic conditions. Rather than preventing the lysosomal degradation of HIF1α, disrupting the V-ATPase results in intracellular iron depletion, thereby impairing PHD activity and leading to HIF activation. Iron supplementation directly restores PHD catalytic activity following V-ATPase inhibition, revealing important links between the V-ATPase, iron metabolism and HIFs.This work was supported by a Wellcome Trust Senior Clinical Research Fellowship to JAN (102770/Z/13/Z), and an MRC Award to ALM (MR/K50127X/1). The Cambridge Institute for Medical Research is in receipt of a Wellcome Trust Strategic Award (100140)

A Case Study of Eukaryogenesis: The Evolution of Photoreception by Photolyase/Cryptochrome Proteins

Eukaryogenesis, the origin of the eukaryotes, is still poorly understood. Herein, we show how a detailed all-kingdom phylogenetic analysis overlaid with a map of key biochemical features can provide valuable clues. The photolyase/cryptochrome family of proteins are well known to repair DNA in response to potentially harmful effects of sunlight and to entrain circadian rhythms. Phylogenetic analysis of photolyase/cryptochrome protein sequences from a wide range of prokaryotes and eukaryotes points to a number of horizontal gene transfer events between ancestral bacteria and ancestral eukaryotes. Previous experimental research has characterised patterns of tryptophan residues in these proteins that are important for photoreception, specifically a tryptophan dyad, a canonical tryptophan triad, an alternative tryptophan triad, a tryptophan tetrad and an alternative tetrad. Our results suggest that the spread of the different triad and tetrad motifs across the kingdoms of life accompanied the putative horizontal gene transfers and is consistent with multiple bacterial contributions to eukaryogenesis

Your space or mine? : Mapping self in time

Peer reviewedPublisher PD

Biophysical suitability, economic pressure and land-cover change: a global probabilistic approach and insights for REDD+

There has been a concerted effort by the international scientific community to understand the multiple causes and patterns of land-cover change to support sustainable land management. Here, we examined biophysical suitability, and a novel integrated index of “Economic Pressure on Land” (EPL) to explain land cover in the year 2000, and estimated the likelihood of future land-cover change through 2050, including protected area effectiveness. Biophysical suitability and EPL explained almost half of the global pattern of land cover (R 2 = 0.45), increasing to almost two-thirds in areas where a long-term equilibrium is likely to have been reached (e.g. R 2 = 0.64 in Europe). We identify a high likelihood of future land-cover change in vast areas with relatively lower current and past deforestation (e.g. the Congo Basin). Further, we simulated emissions arising from a “business as usual” and two reducing emissions from deforestation and forest degradation (REDD) scenarios by incorporating data on biomass carbon. As our model incorporates all biome types, it highlights a crucial aspect of the ongoing REDD + debate: if restricted to forests, “cross-biome leakage” would severely reduce REDD + effectiveness for climate change mitigation. If forests were protected from deforestation yet without measures to tackle the drivers of land-cover change, REDD + would only reduce 30 % of total emissions from land-cover change. Fifty-five percent of emissions reductions from forests would be compensated by increased emissions in other biomes. These results suggest that, although REDD + remains a very promising mitigation tool, implementation of complementary measures to reduce land demand is necessary to prevent this leakage

Does oral sodium bicarbonate therapy improve function and quality of life in older patients with chronic kidney disease and low-grade acidosis (the BiCARB trial)? Study protocol for a randomized controlled trial

Date of acceptance: 01/07/2015 © 2015 Witham et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Acknowledgements UK NIHR HTA grant 10/71/01. We acknowledge the financial support of NHS Research Scotland in conducting this trial.Peer reviewedPublisher PD

A qualitative study of the views of patients with long-term conditions on family doctors in Hong Kong

<b>Background</b> Primary care based management of long-term conditions (LTCs) is high on the international healthcare agenda, including the Asia-Pacific region. Hong Kong has a 'mixed economy' healthcare system with both public and private sectors with a range of types of primary care doctors. Recent Hong Kong Government policy aims to enhance the management of LTCs in primary care possibly based on a 'family doctor' model. Patients' views on this are not well documented and the aim of the present study was to explore the views of patients with LTCs on family doctors in Hong Kong.<p></p> <b>Methods</b> The views of patients (with a variety of LTCs) on family doctors in Hong Kong were explored. Two groups of participants were interviewed; a) those who considered themselves as having a family doctor, b) those who considered themselves as not having a family doctor (either with a regular primary care doctor but not a family doctor or with no regular primary care doctor). In-depth individual semi-structured interviews were carried out with 28 participants (10 with a family doctor, 10 with a regular doctor, and 8 with no regular doctor) and analysed using the constant comparative method.<p></p> <b>Results</b> Participants who did not have a family doctor were familiar with the concept but regarded it as a 'luxury item' for the rich within the private healthcare system. Those with a regular family doctor (all private) regarded having one as important to their and their family's health. Participants in both groups felt that as well as the more usual family medicine specialist or general practitioner, traditional Chinese medicine practitioners also had the potential to be family doctors. However most participants attended the public healthcare system for management of their LTCs whether they had a family doctor or not. Cost, perceived need, quality, trust, and choice were all barriers to the use of family doctors for the management of their LTCs.<p></p> <b>Conclusions</b> Important barriers to the adoption of a 'family doctor' model of management of LTCs exist in Hong Kong. Effective policy implementation seems unlikely unless these complex barriers are addressed

The depression in visual impairment trial (DEPVIT): trial design and protocol

<b>Background</b> The prevalence of depression in people with a visual disability is high but screening for depression and referral for treatment is not yet an integral part of visual rehabilitation service provision. One reason for this may be that there is no good evidence about the effectiveness of treatments in this patient group. This study is the first to evaluate the effect of depression treatments on people with a visual impairment and co morbid depression.<p></p> <b>Methods/design</b> The study is an exploratory, multicentre, individually randomised waiting list controlled trial. Participants will be randomised to receive Problem Solving Therapy (PST), a ‘referral to the GP’ requesting treatment according to the NICE’s ‘stepped care’ recommendations or the waiting list arm of the trial. The primary outcome measure is change (from randomisation) in depressive symptoms as measured by the Beck’s Depression Inventory (BDI-II) at 6 months. Secondary outcomes include change in depressive symptoms at 3 months, change in visual function as measured with the near vision subscale of the VFQ-48 and 7 item NEI-VFQ at 3 and 6 months, change in generic health related quality of life (EQ5D), the costs associated with PST, estimates of incremental cost effectiveness, and recruitment rate estimation.<p></p> <b>Discussion</b> Depression is prevalent in people with disabling visual impairment. This exploratory study will establish depression screening and referral for treatment in visual rehabilitation clinics in the UK. It will be the first to explore the efficacy of PST and the effectiveness of NICE’s ‘stepped care’ approach to the treatment of depression in people with a visual impairment.<p></p&gt

Selective Affimers Recognise the BCL‐2 Family Proteins BCL‐xL and MCL‐1 through Noncanonical Structural Motifs

The BCL‐2 family is a challenging group of proteins to target selectively due to sequence and structural homologies across the family. Selective ligands for the BCL‐2 family regulators of apoptosis are useful as probes to understand cell biology and apoptotic signalling pathways, and as starting points for inhibitor design. We have used phage display to isolate Affimer reagents (non‐antibody‐binding proteins based on a conserved scaffold) to identify ligands for MCL‐1, BCL‐xL, BCL‐2, BAK and BAX, then used multiple biophysical characterisation methods to probe the interactions. We established that purified Affimers elicit selective recognition of their target BCL‐2 protein. For anti‐apoptotic targets BCL‐xL and MCL‐1, competitive inhibition of their canonical protein‐protein interactions is demonstrated. Co‐crystal structures reveal an unprecedented mode of molecular recognition; where a BH3 helix is normally bound, flexible loops from the Affimer dock into the BH3 binding cleft. Moreover, the Affimers induce a change in the target proteins towards a desirable drug‐bound‐like conformation. These proof‐of‐concept studies indicate that Affimers could be used as alternative templates to inspire the design of selective BCL‐2 family modulators and more generally other protein‐protein interaction inhibitors