Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects

The adaptor protein-2 sigma subunit (AP2sigma;2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2sigma;2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca<inf>o</inf>²⁺) homeostasis. To elucidate the role of AP2sigma;2 in Ca<inf>o</inf>²⁺ regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2sigma;2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2sigma;2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2sigma;2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2sigma;2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2sigma;2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.

Obsessive-compulsive symptoms and attentional bias: An eye-tracking methodology

Background and objectives: Cognitive models suggest that attentional biases are integral in the maintenance of obsessive-compulsive symptoms (OCS). Such biases have been established experimentally in anxiety disorders; however, the evidence is unclear in Obsessive Compulsive disorder (OCD). In the present study, an eye-tracking methodology was employed to explore attentional biases in relation to OCS.
Methods: A convenience sample of 85 community volunteers was assessed on OCS using the Yale-Brown Obsessive Compulsive Scale-self report. Participants completed an eye-tracking paradigm where they were exposed to OCD, Aversive and Neutral visual stimuli. Indices of attentional bias were derived from the eye-tracking data.
Results: Simple linear regressions were performed with OCS severity as the predictor and eye-tracking measures of the different attentional biases for each of the three stimuli types were the criterion variables. Findings revealed that OCS severity moderately predicted greater frequency and duration of fixations on OCD stimuli, which reflect the maintenance attentional bias. No significant results were found in support of other biases.
Limitations: Interpretations based on a non-clinical sample limit the generalisability of the conclusions, although use of such samples in OCD research has been found to be comparable to clinical populations. Future research would include both clinical and sub-clinical participants.
Conclusions: Results provide some support for the theory of maintained attention in OCD attentional biases, as opposed to vigilance theory. Individuals with greater OCS do not orient to OCD stimuli any faster than individuals with lower OCS, but once a threat is identified, these individuals allocate more attention to OCS-relevant stimuli.

LD Score regression distinguishes confounding from polygenicity in genome-wide association studies

Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.

Comparing lateral bias in dogs and humans using the KongTM ball test

The KongTM ball test has been used extensively to assess lateral bias in the domestic dog. Implicit in this challenge is the assumption that dogs use their dominant paw to stabilise the ball. This study examined whether or not this is the case. A comparative approach was adopted, exploring limb use in dogs and humans. In Experiment 1, the paw preference of 48 dogs was assessed on the KongTM ball test. Analysis revealed an equal distribution of paw use, although significantly more dogs were paw-preferent than ambilateral. Significantly more male dogs were classified as right-pawed, while more females were ambilateral. There was no significant effect of canine sex or castration status on the dogs’ paw preferences. In Experiment 2, 94 adult humans were assessed on their ability to remove a piece of paper from a KongTM ball with their mouth, using their left, right or both hands to stabilise the ball. 76% of the right-handed people used their left hand, and 82% of the left-handed participants used their right hand, to hold the KongTM steady. It is concluded that dogs, like humans, are most likely using their non-dominant limb to stabilise the KongTM ball and their dominant side for postural support. This has potential applied implications from an animal welfare perspective.

Lateral bias and temperament in the domestic cat (Felis silvestris)

Research points to a relationship between lateralization and emotional functioning in humans and many species of animal. The present study explored the association between paw preferences and emotional functioning, specifically temperament, in a species thus far overlooked in this area, the domestic cat. Thirty left-pawed, 30 right-pawed, and 30 ambilateral pet cats were recruited following an assessment of their paw preferences using a food-reaching challenge. The animals’ temperament was subsequently assessed using the Feline Temperament Profile (FTP). Cats’ owners also completed a purpose-designed cat temperament (CAT) scale. Analysis revealed a significant relationship between lateral bias and FTP and CAT scale scores. Ambilateral cats had lower positive (FTP+) scores, and were perceived as less affectionate, obedient, friendly, and more aggressive, than left or right-pawed animals. Left and right pawed cats differed significantly on 1 trait on the CAT scale, namely playfulness. The strength of the cats’ paw preferences was related to the animals’ FTP and CAT scores. Cats with a greater strength of paw preference had higher FTP + scores than those with a weaker strength of paw preference. Animals with stronger paw preferences were perceived as more confident, affectionate, active, and friendly than those with weaker paw preferences. Results suggest that motor laterality in the cat is strongly related to temperament and that the presence or absence of lateralization has greater implications for the expression of emotion in this species than the direction of the lateralized bias.

Measuring persistence in inflation: evidence for Angola

The purpose of this paper is to examine the degree of persistence in five inflation indicators for Angola, and to identify the implications for decision making. Our results suggest that when structural breaks are accounted for, all five inflation indicators are stationary. Second, our findings suggest that persistence is not too high. Moreover, the degree of persistence is similar among the five inflation indicators and throughout the sample period. Finally, our results also show that extracting the most volatile components of the headline inflation indicator does not generate a new inflation indicator that is less volatile and more persistent than the original. These results have important policy implications as the National Bank of Angola is preparing to change its monetary policy focus to a more inflation-targeting regime

Galvanic Vestibular Stimulation Induces a Spatial Bias in Whole-body Position Estimates

Letter to the Editor

Inflation targeting and the consistency of monetary policy decisions in Mexico: an empirical analysis with discrete choice models

This paper examines the nature of monetary policy decisions in Mexico using discrete choice models applied to the Central Bank's explicit monetary policy instrument. We find that monetary policy adjustments in Mexico have been strongly consistent with the CB's inflation targeting strategy. We also find evidence that monetary policy responds in a forward-looking manner to deviations of inflation from the target and that observed policy adjustments exhibit asymmetric features, with stronger responses to positive than to negative deviations of inflation from the target and a greater likelihood of policy persistence during periods when monetary policy is tightened, compared with periods when policy is loosened.

Home bias persistence in foreign direct investments

The purpose of this paper is to analyse the issues related to home bias and foreign direct investments (FDIs). We study the role of physical, cultural, and institutional distances from home on FDI decisions taken by corporations to assess whether the globalization of the past two decades has reduced their influence. Using the ‘home bias’ framework from the finance literature and the gravity model from the economics literature, we utilize a large sample of both developed and emerging markets, using FDI flows of 6263 unique bilateral country pairs over a 30-year period. We find strong empirical evidence of persistent home bias in FDI outflows, and we show that not only physical distance but also cultural and institutional similarities between host and source countries remain a decisive factor in foreign corporate investment decisions. We also show that such home bias is persistent over time and is observed around the world.

Reducing job-irrelevant bias in performance and appraisals: compliance and beyond

Job-irrelevant discrimination seems as ubiquitous as the performance appraisals in which it is commonly detected. This paper explores both compliance-based and more proactive approaches that deal with the various possible sources of discrimination in performance appraisal ratings. The suggestions lead to a code of practice for performance management in firms across cultures and national boundaries.

Improving accuracy of inflation forecasts using macroeconomic information

This thesis examines the effects of macroeconomic factors on inflation level and volatility in the Euro Area to improve the accuracy of inflation forecasts with econometric modelling. Inflation aggregates for the EU as well as inflation levels of selected countries are analysed, and the difference between these inflation estimates and forecasts are documented. The research proposes alternative models depending on the focus and the scope of inflation forecasts. I find that models with a Generalized AutoRegressive Conditional Heteroskedasticity (GARCH) in mean process have better explanatory power for inflation variance compared to the regular GARCH models. The significant coefficients are different in EU countries in comparison to the aggregate EU-wide forecast of inflation. The presence of more pronounced GARCH components in certain countries with more stressed economies indicates that inflation volatility in these countries are likely to occur as a result of the stressed economy. In addition, other economies in the Euro Area are found to exhibit a relatively stable variance of inflation over time. Therefore, when analysing EU inflation one have to take into consideration the large differences on country level and focus on those one by one.

Effort, reward and self-reported mental health: a simulation study on negative affectivity bias.

Background : In the present article, we propose an alternative method for dealing with negative affectivity (NA) biases in research, while investigating the association between a deleterious psychosocial environment at work and poor mental health. First, we investigated how strong NA must be to cause an observed correlation between the independent and dependent variables. Second, we subjectively assessed whether NA can have a large enough impact on a large enough number of subjects to invalidate the observed correlations between dependent and independent variables.Methods : We simulated 10,000 populations of 300 subjects each, using the marginal distribution of workers in an actual population that had answered the Siegrist's questionnaire on effort and reward imbalance (ERI) and the General Health Questionnaire (GHQ).Results : The results of the present study suggested that simulated NA has a minimal effect on the mean scores for effort and reward. However, the correlations between the effort and reward imbalance (ERI) ratio and the GHQ score might be important, even in simulated populations with a limited NA.Conclusions : When investigating the relationship between the ERI ratio and the GHQ score, we suggest the following rules for the interpretation of the results: correlations with an explained variance of 5% and below should be considered with caution; correlations with an explained variance between 5% and 10% may result from NA, although this effect does not seem likely; and correlations with an explained variance of 10% and above are not likely to be the result of NA biases. [Authors]

Male mutation bias and possible long-term effects of human activities.

The ability of a population to adapt to changing environments depends critically on the amount and kind of genetic variability it possesses. Mutations are an important source of new genetic variability and may lead to new adaptations, especially if the population size is large. Mutation rates are extremely variable between and within species, and males usually have higher mutation rates as a result of elevated rates of male germ cell division. This male bias affects the overall mutation rate. We examined the factors that influence male mutation bias, and focused on the effects of classical life-history parameters, such as the average age at reproduction and elevated rates of sperm production in response to sexual selection and sperm competition. We argue that human-induced changes in age at reproduction or in sexual selection will affect male mutation biases and hence overall mutation rates. Depending on the effective population size, these changes are likely to influence the long-term persistence of a population.

Mapping Bias Overestimates Reference Allele Frequencies at the HLA Genes in the 1000 Genomes Project Phase I Data.

Next-generation sequencing (NGS) technologies have become the standard for data generation in studies of population genomics, as the 1000 Genomes Project (1000G). However, these techniques are known to be problematic when applied to highly polymorphic genomic regions, such as the human leukocyte antigen (HLA) genes. Because accurate genotype calls and allele frequency estimations are crucial to population genomics analyses, it is important to assess the reliability of NGS data. Here, we evaluate the reliability of genotype calls and allele frequency estimates of the single-nucleotide polymorphisms (SNPs) reported by 1000G (phase I) at five HLA genes (HLA-A, -B, -C, -DRB1, and -DQB1). We take advantage of the availability of HLA Sanger sequencing of 930 of the 1092 1000G samples and use this as a gold standard to benchmark the 1000G data. We document that 18.6% of SNP genotype calls in HLA genes are incorrect and that allele frequencies are estimated with an error greater than ±0.1 at approximately 25% of the SNPs in HLA genes. We found a bias toward overestimation of reference allele frequency for the 1000G data, indicating mapping bias is an important cause of error in frequency estimation in this dataset. We provide a list of sites that have poor allele frequency estimates and discuss the outcomes of including those sites in different kinds of analyses. Because the HLA region is the most polymorphic in the human genome, our results provide insights into the challenges of using of NGS data at other genomic regions of high diversity.

Correcting Interdevice Bias of Horizontal White-to-White and Sulcus-to-Sulcus Measures Used for Implantable Collamer Lens Sizing.

PURPOSE: To assess the agreement and repeatability of horizontal white-to-white (WTW) and horizontal sulcus-to-sulcus (STS) diameter measurements and use these data in combination with available literature to correct for interdevice bias in preoperative implantable collamer lens (ICL) size selection. DESIGN: Interinstrument reliability and bias assessment study. METHODS: A total of 107 eyes from 56 patients assessed for ICL implantation at our institution were included in the study. This was a consecutive series of all patients with suitable available data. The agreement and bias between WTW (measured with the Pentacam and BioGraph devices) and STS (measured with the HiScan device) were estimated. RESULTS: The mean spherical equivalent was -8.93 ± 5.69 diopters. The BioGraph measures of WTW were wider than those taken with the Pentacam (bias = 0.26 mm, P < .01), and both horizontal WTW measures were wider than the horizontal STS measures (bias >0.91 mm, P < .01). The repeatability (Sr) of STS measured with the HiScan was 0.39 mm, which was significantly reduced (Sr = 0.15 mm) when the average of 2 measures was used. Agreement between the horizontal WTW measures and horizontal STS estimates when bias was accounted for was г = 0.54 with the Pentacam and г = 0.64 with the BioGraph. CONCLUSIONS: Large interdevice bias was observed for WTW and STS measures. STS measures demonstrated poor repeatability, but the average of repeated measures significantly improved repeatability. In order to conform to the US Food and Drug Administration's accepted guidelines for ICL sizing, clinicians should be aware of and account for the inconsistencies between devices.