Theory and generalization of Monte Carlo models of the BOLD signal source

The dependency of the blood oxygenation level dependent (BOLD) signal on underlying hemodynamics is not well understood. Building a forward biophysical model of this relationship is important for the quantitative estimation of the hemodynamic changes and neural activity underlying functional magnetic resonance imaging (fMRI) signals. We have developed a general model of the BOLD signal which can model both intra- and extravascular signals for an arbitrary tissue model across a wide range of imaging parameters. The model of the BOLD signal was instantiated as a look-up-table (LuT), and was verified against concurrent fMRI and optical imaging measurements of activation induced hemodynamics. Magn Reson Med, 2008. © 2008 Wiley-Liss, Inc.

A SEPALLATA gene is involved in the development and ripening of strawberry (Fragaria X ananassa Duch.) fruit, a non-climacteric tissue

Climacteric and non-climacteric fruits have traditionally been viewed as representing two distinct programmes of ripening associated with differential respiration and ethylene hormone effects. In climacteric fruits, such as tomato and banana, the ripening process is marked by increased respiration and is induced and co-ordinated by ethylene, while in non-climacteric fruits, such as strawberry and grape, it is controlled by an ethylene-independent process with little change in respiration rate. The two contrasting mechanisms, however, both lead to texture, colour, and flavour changes that probably reflect some common programmes of regulatory control. It has been shown that a SEPALLATA(SEP)4-like gene is necessary for normal ripening in tomato. It has been demonstrated here that silencing a fruit-related SEP1/2-like (FaMADS9) gene in strawberry leads to the inhibition of normal development and ripening in the petal, achene, and receptacle tissues. In addition, analysis of transcriptome profiles reveals pleiotropic effects of FaMADS9 on fruit development and ripening-related gene expression. It is concluded that SEP genes play a central role in the developmental regulation of ripening in both climacteric and non-climacteric fruits. These findings provide important information to extend the molecular control of ripening in a non-climacteric fruit beyond the limited genetic and cultural options currently available.

Development and evaluation of an Earth-System model – HadGEM2

We describe here the development and evaluation of an Earth system model suitable for centennial-scale climate prediction. The principal new components added to the physical climate model are the terrestrial and ocean ecosystems and gas-phase tropospheric chemistry, along with their coupled interactions. The individual Earth system components are described briefly and the relevant interactions between the components are explained. Because the multiple interactions could lead to unstable feedbacks, we go through a careful process of model spin up to ensure that all components are stable and the interactions balanced. This spun-up configuration is evaluated against observed data for the Earth system components and is generally found to perform very satisfactorily. The reason for the evaluation phase is that the model is to be used for the core climate simulations carried out by the Met Office Hadley Centre for the Coupled Model Intercomparison Project (CMIP5), so it is essential that addition of the extra complexity does not detract substantially from its climate performance. Localised changes in some specific meteorological variables can be identified, but the impacts on the overall simulation of present day climate are slight. This model is proving valuable both for climate predictions, and for investigating the strengths of biogeochemical feedbacks.

Transcriptional dysregulation of coding and non-coding genes in cellular models of Huntington's disease

HD (Huntington's disease) is a late onset heritable neurodegenerative disorder that is characterized by neuronal dysfunction and death, particularly in the cerebral cortex and medium spiny neurons of the striatum. This is followed by progressive chorea, dementia and emotional dysfunction, eventually resulting in death. HD is caused by an expanded CAG repeat in the first exon of the HD gene that results in an abnormally elongated polyQ (polyglutamine) tract in its protein product, Htt (Huntingtin). Wild-type Htt is largely cytoplasmic; however, in HD, proteolytic N-terminal fragments of Htt form insoluble deposits in both the cytoplasm and nucleus, provoking the idea that mutHtt (mutant Htt) causes transcriptional dysfunction. While a number of specific transcription factors and co-factors have been proposed as mediators of mutHtt toxicity, the causal relationship between these Htt/transcription factor interactions and HD pathology remains unknown. Previous work has highlighted REST [RE1 (repressor element 1)-silencing transcription factor] as one such transcription factor. REST is a master regulator of neuronal genes, repressing their expression. Many of its direct target genes are known or suspected to have a role in HD pathogenesis, including BDNF (brain-derived neurotrophic factor). Recent evidence has also shown that REST regulates transcription of regulatory miRNAs (microRNAs), many of which are known to regulate neuronal gene expression and are dysregulated in HD. Thus repression of miRNAs constitutes a second, indirect mechanism by which REST can alter the neuronal transcriptome in HD. We will describe the evidence that disruption to the REST regulon brought about by a loss of interaction between REST and mutHtt may be a key contributory factor in the widespread dysregulation of gene expression in HD.

Forecasting with vector autoregressive models of data vintages: US output growth and inflation

Vintage-based vector autoregressive models of a single macroeconomic variable are shown to be a useful vehicle for obtaining forecasts of different maturities of future and past observations, including estimates of post-revision values. The forecasting performance of models which include information on annual revisions is superior to that of models which only include the first two data releases. However, the empirical results indicate that a model which reflects the seasonal nature of data releases more closely does not offer much improvement over an unrestricted vintage-based model which includes three rounds of annual revisions.

In vitro and in vivo models of colorectal cancer: antigenotoxic activity of berries.

The etiology of colorectal cancer (CRC), a common cause of cancer-related mortality globally, has strong associations with diet. There is considerable epidemiological evidence that fruits and vegetables are associated with reduced risk of CRC. This paper reviews the extensive evidence, both from in vitro studies and animal models, that components of berry fruits can modulate biomarkers of DNA damage and that these effects may be potentially chemoprotective, given the likely role that oxidative damage plays in mutation rate and cancer risk. Human intervention trials with berries are generally consistent in indicating a capacity to significantly decrease oxidative damage to DNA, but represent limited evidence for anticarcinogenicity, relying as they do on surrogate risk markers. To understand the effects of berry consumption on colorectal cancer risk, future studies will need to be well controlled, with defined berry extracts, using suitable and clinically relevant end points and considering the importance of the gut microbiota.

Development and validation of a parent report measure for detection of cognitive delay in infancy

Aim To develop a brief, parent-completed instrument (‘ERIC’) for detection of cognitive delay in 10-24 month-olds born preterm, or with low birth weight, or with perinatal complications, and to establish its diagnostic properties. Method Scores were collected from parents of 317 children meeting ≥1 inclusion criteria (birth weight <1500g; gestational age <34 completed weeks; 5-minute Apgar <7; presence of hypoxic-ischemic encephalopathy) and meeting no exclusion criteria. Children were assessed for cognitive delay using a criterion score on the Bayley Scales of Infant and Toddler Development Cognitive Scale III1 <80. Items were retained according to their individual associations with delay. Sensitivity, specificity, Positive and Negative Predictive Values were estimated and a truncated ERIC was developed for use <14 months. Results ERIC detected 17 out of 18 delayed children in the sample, with 94.4% sensitivity (95% CI [confidence interval] 83.9-100%), 76.9% specificity (72.1-81.7%), 19.8% positive predictive value (11.4-28.2%); 99.6% negative predictive value (98.7-100%); 4.09 likelihood ratio positive; and 0.07 likelihood ratio negative; the associated Area under the Curve was .909 (.829-.960). Interpretation ERIC has potential value as a quickly-administered diagnostic instrument for the absence of early cognitive delay in preterm or premature infants of 10-24 months, and as a screen for cognitive delay. Further research may be needed before ERIC can be recommended for wide-scale use.

Disparity-driven vs blur-driven models of accommodation and convergence in binocular vision and intermittent strabismus

Background. Current models of concomitant, intermittent strabismus, heterophoria, convergence and accommodation anomalies are either theoretically complex or incomplete. We propose an alternative and more practical way to conceptualize clinical patterns. Methods. In each of three hypothetical scenarios (normal; high AC/A and low CA/C ratios; low AC/A and high CA/C ratios) there can be a disparity-biased or blur-biased “style”, despite identical ratios. We calculated a disparity bias index (DBI) to reflect these biases. We suggest how clinical patterns fit these scenarios and provide early objective data from small illustrative clinical groups. Results. Normal adults and children showed disparity bias (adult DBI 0.43 (95%CI 0.50-0.36), child DBI 0.20 (95%CI 0.31-0.07) (p=0.001). Accommodative esotropes showed less disparity-bias (DBI 0.03). In the high AC/A and low CA/C scenario, early presbyopes had mean DBI of 0.17 (95%CI 0.28-0.06), compared to DBI of -0.31 in convergence excess esotropes. In the low AC/A and high CA/C scenario near exotropes had mean DBI of 0.27, while we predict that non-strabismic, non-amblyopic hyperopes with good vision without spectacles will show lower DBIs. Disparity bias ranged between 1.25 and -1.67. Conclusions. Establishing disparity or blur bias, together with knowing whether convergence to target demand exceeds accommodation or vice versa explains clinical patterns more effectively than AC/A and CA/C ratios alone. Excessive bias or inflexibility in near-cue use increases risk of clinical problems. We suggest clinicians look carefully at details of accommodation and convergence changes induced by lenses, dissociation and prisms and use these to plan treatment in relation to the model.

New models of North West European Holocene palaeogeography and inundation

This paper presents new 500 year interval palaeogeographic models for Britain, Ireland and the North West French coast from 11000 cal. BP to present. These models are used to calculate the varying rates of inundation for different geographical zones over the study period. This allows for consideration of the differential impact that Holocene sea-level rise had across space and time, and on past societies. In turn, consideration of the limitations of the models helps to foreground profitable areas for future research.

On flow reversal boundaries and transpolar voltage in average models of high-latitude convection

The implications of polar cap expansions, contractions and movements for empirical models of high-latitude plasma convection are examined. Some of these models have been generated by directly averaging flow measurements from large numbers of satellite passes or radar scans; others have employed more complex means to combine data taken at different times into large-scale patterns of flow. In all cases, the models have implicitly adopted the assumption that the polar cap is in steady state: they have all characterized the ionospheric flow in terms of the prevailing conditions (e.g. the interplanetary magnetic field and/or some index of terrestrial magnetic activity) without allowance for their history. On long enough time scales, the polar cap is indeed in steady state but on time scales shorter than a few hours it is not and can oscillate in size and position. As a result, the method used to combine the data can influence the nature of the convection reversal boundary and the transpolar voltage in the derived model. This paper discusses a variety of effects due to time-dependence in relation to some ionospheric convection models which are widely applied. The effects are shown to be varied and to depend upon the procedure adopted to compile the model.

Bond graph models of DC-DC converters operating in both CCM and DCM

In this paper, Bond Graphs are employed to develop a novel mathematical model of conventional switched-mode DC-DC converters valid for both continuous and discontinuous conduction modes. A unique causality bond graph model of hybrid models is suggested with the operation of the switch and the diode to be represented by a Modulated Transformer with a binary input and a resistor with fixed conductance causality. The operation of the diode is controlled using an if-then function within the model. The extracted hybrid model is implemented on a Boost and Buck converter with their operations to change from CCM to DCM and to return to CCM. The vector fields of the models show validity in a wide operation area and comparison with the simulation of the converters using PSPICE reveals high accuracy of the proposed model, with the Normalised Root Means Square Error and the Maximum Absolute Error remaining adequately low. The model is also experimentally tested on a Buck topology.

Biomineralisation by earthworms: an investigation into the stability and distribution of amorphous calcium carbonate

Background Many biominerals form from amorphous calcium carbonate (ACC), but this phase is highly unstable when synthesised in its pure form inorganically. Several species of earthworm secrete calcium carbonate granules which contain highly stable ACC. We analysed the milky fluid from which granules form and solid granules for amino acid (by liquid chromatography) and functional group (by Fourier transform infrared (FTIR) spectroscopy) compositions. Granule elemental composition was determined using inductively coupled plasma-optical emission spectroscopy (ICP-OES) and electron microprobe analysis (EMPA). Mass of ACC present in solid granules was quantified using FTIR and compared to granule elemental and amino acid compositions. Bulk analysis of granules was of powdered bulk material. Spatially resolved analysis was of thin sections of granules using synchrotron-based μ-FTIR and EMPA electron microprobe analysis. Results The milky fluid from which granules form is amino acid-rich (≤ 136 ± 3 nmol mg−1 (n = 3; ± std dev) per individual amino acid); the CaCO3 phase present is ACC. Even four years after production, granules contain ACC. No correlation exists between mass of ACC present and granule elemental composition. Granule amino acid concentrations correlate well with ACC content (r ≥ 0.7, p ≤ 0.05) consistent with a role for amino acids (or the proteins they make up) in ACC stabilisation. Intra-granule variation in ACC (RSD = 16%) and amino acid concentration (RSD = 22–35%) was high for granules produced by the same earthworm. Maps of ACC distribution produced using synchrotron-based μ-FTIR mapping of granule thin sections and the relative intensity of the ν2: ν4 peak ratio, cluster analysis and component regression using ACC and calcite standards showed similar spatial distributions of likely ACC-rich and calcite-rich areas. We could not identify organic peaks in the μ-FTIR spectra and thus could not determine whether ACC-rich domains also had relatively high amino acid concentrations. No correlation exists between ACC distribution and elemental concentrations determined by EMPA. Conclusions ACC present in earthworm CaCO3 granules is highly stable. Our results suggest a role for amino acids (or proteins) in this stability. We see no evidence for stabilisation of ACC by incorporation of inorganic components.

Development and validation of the Morphing Fear Questionnaire (MFQ)

Morphing fears (also called transformation obsessions) involve concerns that a person may become contaminated by and acquire undesirable characteristics of others. These symptoms are found in patients with OCD and are thought to be related to mental contamination. Given the high levels of distress and interference morphing fears can cause, a reliable and valid assessment measure is needed. This article describes the development and evaluation of the Morphing Fear Questionnaire (MFQ), a 13-item measure designed to assess for the presence and severity of morphing fears. A sample of 900 participants took part in the research. Of these, 140 reported having a current diagnosis of OCD (SR-OCD) and 760 reported never having had OCD (N-OCD; of whom 24 reported a diagnosis of an anxiety disorder and 23 reported a diagnosis of depression). Factor structure, reliability, and construct and criterion related validity were investigated. Exploratory and confirmatory factor analyses supported a one-factor structure replicable across the N-OCD and SR-OCD group. The MFQ was found to have high internal consistency and good temporal stability, and showed significantly greater associations with convergent measures (assessing obsessive-compulsive symptoms, mental contamination, thought-action fusion and magical thinking) than with divergent measures (assessing depression and anxiety). Moreover, the MFQ successfully discriminated between the SR-OCD sample and the N-OCD group, anxiety disorder sample, and depression sample. These findings suggest that the MFQ has sound psychometric properties and that it can be used to assess morphing fear. Clinical implications are discussed.

Do Cognitive Models of Obsessive Compulsive Disorder Apply to Children and Adolescents?

Cognitive models of obsessive compulsive disorder (OCD) have been influential in understanding and treating the disorder in adults. Cognitive models may also be applicable to children and adolescents and would have important implications for treatment. The aim of this systematic review was to evaluate research that examined the applicability of the cognitive model of OCD to children and adolescents. Inclusion criteria were set broadly but most studies identified included data regarding responsibility appraisals, thought-action fusion or meta-cognitive models of OCD in children or adolescents. Eleven studies were identified in a systematic literature search. Seven studies were with non clinical samples, and 10 studies were cross-sectional. Only one study did not support cognitive models of OCD in children and adolescents and this was with a clinical sample and was the only experimental study. Overall, the results strongly supported the applicability of cognitive models of OCD to children and young people. There were, however, clear gaps in the literature. Future research should include experimental studies, clinical groups, and should test which of the different models provide more explanatory power.