Negative emotional reactivity as a marker of vulnerability in the development of borderline personality disorder symptoms

Negative emotionality is a distinguishing feature of borderline personality disorder (BPD). However, this person-level characteristic has not been examined as a marker of vulnerability in the development of this disorder. The current study utilized a multi-method approach to examine the interplay between negative emotional reactivity and cumulative exposure to family adversity on the development of BPD symptoms across three years (ages 16–18) in a diverse, at-risk sample of adolescent girls (N=113). A latent variable of negative emotional reactivity was created from multiple assessments at age 16: (1) self-report, (2) emotion ratings to stressors from ecological assessments across one week, and (3) observer-rated negative affectivity during a mother-daughter conflict discussion task. Exposure to family adversity was measured cumulatively between ages 5 and 16 from annual assessments of family poverty, single parent household, and difficult life circumstances. Results from latent growth curve models demonstrated a significant interaction between negative emotional reactivity and family adversity, such that exposure to adversity strengthened the association between negative emotional reactivity and BPD symptoms. Additionally, family adversity predicted increasing BPD symptoms during late adolescence. These findings highlight negative emotional reactivity as a marker of vulnerability that ultimately increases risk for the development of BPD symptoms

GeneLink: a database to facilitate genetic studies of complex traits

BACKGROUND: In contrast to gene-mapping studies of simple Mendelian disorders, genetic analyses of complex traits are far more challenging, and high quality data management systems are often critical to the success of these projects. To minimize the difficulties inherent in complex trait studies, we have developed GeneLink, a Web-accessible, password-protected Sybase database. RESULTS: GeneLink is a powerful tool for complex trait mapping, enabling genotypic data to be easily merged with pedigree and extensive phenotypic data. Specifically designed to facilitate large-scale (multi-center) genetic linkage or association studies, GeneLink securely and efficiently handles large amounts of data and provides additional features to facilitate data analysis by existing software packages and quality control. These include the ability to download chromosome-specific data files containing marker data in map order in various formats appropriate for downstream analyses (e.g., GAS and LINKAGE). Furthermore, an unlimited number of phenotypes (either qualitative or quantitative) can be stored and analyzed. Finally, GeneLink generates several quality assurance reports, including genotyping success rates of specified DNA samples or success and heterozygosity rates for specified markers. CONCLUSIONS: GeneLink has already proven an invaluable tool for complex trait mapping studies and is discussed primarily in the context of our large, multi-center study of hereditary prostate cancer (HPC). GeneLink is freely available at

The effect of a monetary incentive on return of a postal health and development questionnaire: a randomised trial [ISRCTN53994660]

BACKGROUND: Postal questionnaires are widely used to collect data in healthcare research but a poor response rate may reduce the validity and reliability of results. There was a lack of evidence available relating to use of a monetary incentive to improve the response rate in the healthcare setting. METHODS: The MRC ORACLE Children Study is assessing the health and development of nearly 9000 seven year old children whose mothers' joined the MRC ORACLE Trial. We carried out a randomised controlled trial of inclusion of monetary incentive (five pound voucher redeemable at many high street stores) with the reminder questionnaire to parents. This trial took place between April 2002 and November 2003. When the parents were sent the reminder questionnaire about their child's health and development they were randomly assigned by concealed computer-generated allocation stratified by week of birthday to receive a five pound voucher or no incentive. The population were 722 non-responders to the initial mailing of a 12-page questionnaire. Main outcome measures: Difference in response rate between the two groups. RESULTS: Inclusion of the voucher with the reminder questionnaire resulted in a 11.7%(95% CI 4.7% to 18.6%) improvement in the response rate between the two groups. CONCLUSION: This improvement in response rate and hence the validity and reliability of results obtained appears to be justified ethically and financially

Reserve sizes needed to protect coral reef fishes

Marine reserves are a commonly applied conservation tool, but their size is often chosen based on considerations of socioeconomic rather than ecological impact. Here, we use a simple individual-based model together with the latest empirical information on home ranges, densities and schooling behaviour in 66 coral reef fishes to quantify the conservation effectiveness of various reserve sizes. We find that standard reserves with a diameter of 1-2 km can achieve partial protection (50% of the maximum number of individuals) of 56% of all simulated species. Partial protection of the most important fishery species, and of species with diverse functional roles, required 2-10 km wide reserves. Full protection of nearly all simulated species required 100 km wide reserves. Linear regressions based on the mean home range and density, and even just the maximum length, of fish species approximated these results reliably, and can therefore be used to support locally effective decision making

Covariance Clustering: Modelling Covariance in Designed Experiments When the Number of Variables is Greater than Experimental Units

The size and complexity of datasets resulting from comparative research experiments in the agricultural domain is constantly increasing. Often the number of variables measured in an experiment exceeds the number of experimental units composing the experiment. When there is a necessity to model the covariance relationships that exist between variables in these experiments, estimation difficulties can arise due to the resulting covariance structure being of reduced rank. A statistical method, based in a linear mixed model framework, is presented for the analysis of designed experiments where datasets are characterised by a greater number of variables than experimental units, and for which the modelling of complex covariance structures between variables is desired. Aided by a clustering algorithm, the method enables the estimation of covariance through the introduction of covariance clusters as random effects into the modelling framework, providing an extension of the traditional variance components model for building covariance structures. The method was applied to a multi-phase mass spectrometry-based proteomics experiment, with the aim of exploring changes in the proteome of barley grain over time during the malting process. The modelling approach provides a new linear mixed model-based method for the estimation of covariance structures between variables measured from designed experiments, when there are a small number of experimental units, or observations, informing covariance parameter estimates

Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and cerine residues in the Epstein-Barr Virus lytic switch protein

Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with various malignancies, including Burkitt's lymphoma and nasopharyngeal carcinoma. Like all herpesviruses, the EBV life cycle alternates between latency and lytic replication. During latency, the viral genome is largely silenced by host-driven methylation of CpG motifs and, in the switch to the lytic cycle, this epigenetic silencing is overturned. A key event is the activation of the viral BRLF1 gene by the immediate-early protein Zta. Zta is a bZIP transcription factor that preferentially binds to specific response elements (ZREs) in the BRLF1 promoter (Rp) when these elements are methylated. Zta's ability to trigger lytic cycle activation is severely compromised when a cysteine residue in its bZIP domain is mutated to serine (C189S), but the molecular basis for this effect is unknown. Here we show that the C189S mutant is defective for activating Rp in a Burkitt's lymphoma cell line. The mutant is compromised both in vitro and in vivo for binding two methylated ZREs in Rp (ZRE2 and ZRE3), although the effect is striking only for ZRE3. Molecular modeling of Zta bound to methylated ZRE3, together with biochemical data, indicate that C189 directly contacts one of the two methyl cytosines within a specific CpG motif. The motif's second methyl cytosine (on the complementary DNA strand) is predicted to contact S186, a residue known to regulate methyl-ZRE recognition. Our results suggest that C189 regulates the enhanced interaction of Zta with methylated DNA in overturning the epigenetic control of viral latency. As C189 is conserved in many bZIP proteins, the selectivity of Zta for methylated DNA may be a paradigm for a more general phenomenon

Bayesian inversion of pressure diffusivity from microseismicity

We have considered the problem of using microseismic data to characterize the flow of injected fluid during hydraulic fracturing. We have developed a simple probabilistic physical model that directly ties the fluid pressure in the subsurface during the injection to observations of induced microseismicity. This tractable model includes key physical parameters that affect fluid pressure, rock failure, and seismic wave propagation. It is also amenable to a rigorous uncertainty quantification analysis of the forward model and the inversion. We have used this probabilistic rock failure model to invert for fluid pressure during injection from synthetically generated microseismicity and to quantify the uncertainty of this inversion. The results of our analysis can be used to assess the effectiveness of microseismic monitoring in a given experiment and even to suggest ways to improve the quality and value of monitoring

Predictors of training-related improvement in visuomotor performance in patients with multiple sclerosis: a behavioural and MRI study

Background: The development of tailored recovery-oriented strategies in multiple sclerosis requires early identification of an individual’s potential for functional recovery. Objective: To identify predictors of visuomotor performance improvements, a proxy of functional recovery, using a predictive statistical model that combines demographic, clinical and magnetic resonance imaging (MRI) data. Methods: Right-handed multiple sclerosis patients underwent baseline disability assessment and MRI of the brain structure, function and vascular health. They subsequently undertook 4 weeks of right upper limb visuomotor practice. Changes in performance with practice were our outcome measure. We identified predictors of improvement in a training set of patients using lasso regression; we calculated the best performing model in a validation set and applied this model to a test set. Results: Patients improved their visuomotor performance with practice. Younger age, better visuomotor abilities, less severe disease burden and concurrent use of preventive treatments predicted improvements. Neuroimaging localised outcome-relevant sensory motor regions, the microstructure and activity of which correlated with performance improvements. Conclusion: Initial characteristics, including age, disease duration, visuo-spatial abilities, hand dexterity, self-evaluated disease impact and the presence of disease-modifying treatments, can predict functional recovery in individual patients, potentially improving their clinical management and stratification in clinical trials. MRI is a correlate of outcome, potentially supporting individual prognosis

Tumour cell CD99 regulates transendothelial migration via CDC42 and actin remodelling

Metastasis requires tumour cells to cross endothelial cell (EC) barriers using pathways similar to those used by leucocytes during inflammation. Cell surface CD99 is expressed by healthy leucocytes and ECs, and participates in inflammatory transendothelial migration (TEM). Tumour cells also express CD99, and we have analysed its role in tumour progression and cancer cell TEM. Tumour cell CD99 was required for adhesion to ECs but inhibited invasion of the endothelial barrier and migratory activity. Furthermore, CD99 depletion in tumour cells caused redistribution of the actin cytoskeleton and increased activity of the Rho GTPase CDC42, known for its role in actin remodelling and cell migration. In a xenograft model of breast cancer, tumour cell CD99 expression inhibited metastatic progression, and patient samples showed reduced expression of the CD99 gene in brain metastases compared to matched primary breast tumours. We conclude that CD99 negatively regulates CDC42 and cell migration. However, CD99 has both pro- and anti-tumour activity, and our data suggest that this results in part from its functional linkage to CDC42 and the diverse signalling pathways downstream of this Rho GTPase. This article has an associated First Person interview with the first author of the paper