The neural correlates of reading impairment in adults with developmental dyslexia:evidence from fMRI between group analyses and an fMRI multiple-case study

The goal of this project was to investigate the neural correlates of reading impairment in dyslexia as hypothesised by the main theories – the phonological deficit, visual magnocellular deficit and cerebellar deficit theories, with emphasis on individual differences. This research took a novel approach by: 1) contrasting the predictions in one sample of participants with dyslexia (DPs); 2) using a multiple-case study (and between-group comparisons) to investigate differences in BOLD between each DP and the controls (CPs); 3) demonstrating a possible relationship between reading impairment and its hypothesised neural correlates by using fMRI and a reading task. The multiple-case study revealed that the neural correlates of reading in dyslexia in all cases are not in agreement with the predictions of a single theory. The results show striking individual differences - even, where the neural correlates of reading in two DPs are consistent with the same theory, the areas can differ. A DP can exhibit under-engagement in an area in word, but not in pseudoword reading and vice versa, demonstrating that underactivation in that area cannot be interpreted as a ‘developmental lesion’. Additional analyses revealed complex results. Within-group analyses between behavioural measures and BOLD showed correlations in the predicted regions, areas outside ROI, and lack of correlations in some predicted areas. Comparisons of subgroups which differed on Orthography Composite supported the MDT, but only for Words. The results suggest that phonological scores are not a sufficient predictor of the under-engagement of phonological areas during reading. DPs and CPs exhibited correlations between Purdue Pegboard Composite and BOLD in cerebellar areas only for Pseudowords. Future research into reading in dyslexia should use a more holistic approach, involving genetic and environmental factors, gene by environment interaction, and comorbidity with other disorders. It is argued that multidisciplinary research, within the multiple-deficit model holds significant promise here.

Modulation of glucagon receptor pharmacology by Receptor Activity-modifying Protein-2 (RAMP2)

The glucagon and glucagon-like peptide-1 (GLP-1) receptors play important, opposing roles in regulating blood glucose levels. Consequently, these receptors have been identified as targets for novel diabetes treatments. However, drugs acting at the GLP-1 receptor, whilst having clinical efficacy, have been associated with severe adverse side-effects and targeting of the glucagon receptor has yet to be successful. Here we use a combination of yeast reporter assays and mammalian systems, to provide a more complete understanding of glucagon receptor signaling considering the effect of multiple ligands, association with the receptor-interacting protein, receptor activity modifying protein-2 (RAMP2) and individual G protein α-subunits. We demonstrate that RAMP2 alters both ligand selectivity and G protein preference of the glucagon receptor. Importantly, we also uncover novel cross-reactivity of therapeutically used GLP-1 receptor ligands at the glucagon receptor that is abolished by RAMP2 interaction. This study reveals the glucagon receptor as a previously unidentified target for GLP-1 receptor agonists and highlights a role for RAMP2 in regulating its pharmacology. Such previously unrecognized functions of RAMPs highlight the need to consider all receptor-interacting proteins in future drug development.

Knowledge based improvement:simulation and artificial intelligence for identifying and improving human decision-making in an operations systems

The performance of most operations systems is significantly affected by the interaction of human decision-makers. A methodology, based on the use of visual interactive simulation (VIS) and artificial intelligence (AI), is described that aims to identify and improve human decision-making in operations systems. The methodology, known as 'knowledge-based improvement' (KBI), elicits knowledge from a decision-maker via a VIS and then uses AI methods to represent decision-making. By linking the VIS and AI representation, it is possible to predict the performance of the operations system under different decision-making strategies and to search for improved strategies. The KBI methodology is applied to the decision-making surrounding unplanned maintenance operations at a Ford Motor Company engine assembly plant.

Use of a solvent-free dry matrix coating for quantitative matrix-assisted laser desorption ionization imaging of 4-bromophenyl-1,4-diazabicyclo(3.2.2)nonane-4-carboxylate in rat brain and quantitative analysis of the drug from laser microdissected tissue regions

A dry matrix application for matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) was used to profile the distribution of 4-bromophenyl-1,4-diazabicyclo(3.2.2)nonane-4-carboxylate, monohydrochloride (BDNC, SSR180711) in rat brain tissue sections. Matrix application involved applying layers of finely ground dry alpha-cyano-4-hydroxycinnamic acid (CHCA) to the surface of tissue sections thaw mounted onto MALDI targets. It was not possible to detect the drug when applying matrix in a standard aqueous-organic solvent solution. The drug was detected at higher concentrations in specific regions of the brain, particularly the white matter of the cerebellum. Pseudomultiple reaction monitoring imaging was used to validate that the observed distribution was the target compound. The semiquantitative data obtained from signal intensities in the imaging was confirmed by laser microdissection of specific regions of the brain directed by the imaging, followed by hydrophilic interaction chromatography in combination with a quantitative high-resolution mass spectrometry method. This study illustrates that a dry matrix coating is a valuable and complementary matrix application method for analysis of small polar drugs and metabolites that can be used for semiquantitative analysis.

The use of flow control devices to improve the flow pattern and throughput of sieve trays

Compared to packings trays are more cost effective column internals because they create a large interfacial area for mass transfer by the interaction of the vapour on the liquid. The tray supports a mass of froth or spray which on most trays (including the most widely used sieve trays) is not in any way controlled. The two important results of the gas/liquid interaction are the tray efficiency and the tray throughput or capacity. After many years of practical experience, both may be predicted by empirical correlations, despite the lack of understanding. It is known that the tray efficiency is in part determined by the liquid flow pattern and the throughput by the liquid froth height which in turn depends on the liquid hold-up and vapour velocity. This thesis describes experimental work on sieve trays in an air-water simulator, 2.44 m in diameter. The liquid flow pattern, for flow rates similar to those used in commercial scale distillation, was observed experimentally by direct observation; by water-cooling, to simulate mass transfer; use of potassium permanganate dye to observe areas of longer residence time; and by height of clear liquid measurements across the tray and in the downcomer using manometers. This work presents experiments designed to evaluate flow control devices proposed to improve the gas liquid interaction and hence improve the tray efficiency and throughput. These are (a) the use of intermediate weirs to redirect liquid to the sides of the tray so as to remove slow moving/stagnant liquid and (b) the use of vapour-directing slots designed to use the vapour to cause liquid to be directed towards the outlet weir thus reducing the liquid hold-up at a given rate i.e. increased throughput. This method also has the advantage of removing slow moving/stagnant liquid. In the experiments using intermediate weirs, which were placed in the centre of the tray. it was found that in general the effect of an intermediate weir depends on the depth of liquid downstream of the weir. If the weir is deeper than the downstream depth it will cause the upstream liquid to be deeper than the downstream liquid. If the weir is not as deep as deep as the downstream depth it may have little or no effect on the upstream depth. An intermediate weir placed at an angle to the direction of flow of liquid increases the liquid towards the sides of the tray without causing an increase in liquid hold-up/ froth height. The maximum proportion of liquid caused to flow sideways by the weir is between 5% and 10%. Experimental work using vapour-directing slots on a rectangular sieve tray has shown that the horizontal momentum that is imparted to the liquid is dependent upon the size of the slot. If too much momentum is transferred to the liquid it causes hydraulic jumps to occur at the mouth of the slot coupled with liquid being entrained, The use of slots also helps to eliminate the hydraulic gradient across sieve trays and provides a more uniform froth height on the tray. By comparing the results obtained of the tray and point efficiencies, it is shown that a slotted tray reduces both values by approximately 10%. This reduction is due to the fact that with a slotted tray the liquid has a reduced residence time Ion the tray coupled also with the fact that large size bubbles are passing through the slots. The effectiveness of using vapour-directing slots on a full circular tray was investigated by using dye to completely colour the biphase. The removal of the dye by clear liquid entering the tray was monitored using an overhead camera. Results obtained show that the slots are successful in their aim of reducing slow moving liquid from the sides of the tray, The net effect of this is an increase in tray efficiency. Measurements of slot vapour-velocity found it to be approximately equal to the hole velocity.

Oral uptake and distribution of microspheres

There is a growing body of experimental evidence suggesting that the gastrointestinal tract (GIT) may be penetrated by sub-micron sized polymeric particles which have the capacity to deliver therapeutic compounds. We investigated this, initially with Fluoresbrite™ carboxylate latex microspheres (0.87 m diameter) which were administered orally to rats. Microsphere numbers within blood samples were then quantified using fluorescence microscopy or FACS technology. These studies were prone to quantitative error, but indicated that increased microsphere translocation occurred if particles were administered in conjunction with large volumes of hypotonic liquid, and that uptake was very rapid. Test particles were detected in blood, only a few minutes after dosing. To improve quantification, GPC technology was adopted. 0.22 m latex particles were found to accumulate in greatest numbers within the Mononuclear phagocyte system tissues after gavage. Again translocation was rapid. The ability of test particles to leave the intestinal lumen and access systemic compartments was found to be highly dependent on their size and hydrophobicity, determined by hydrophobic interaction chromatography. Considerably lower numbers of 0.97 m diameter latex microspheres were detectable within extra-intestinal tissue locations after gavage. Histological studies showed that Fluoresbrite™ microspheres accumulate within the liver, spleen, Mesenteric lymph node and vasculature of rats after oral administration. Fluorescent particles were observed in both the Peyer's patches (PPs), and non lymphoid regions of rat intestinal mucosa after gavage, conductive to the acceptance that more than one mechanism of particle absorption may operate.

Liposomes as carriers for polymyxins in the treatment of cystic fibrosis lung infections

Cystic fibrosis (CF) is the most common autosomal recessive disorder affecting Caucasian populations. The pathophysiology of this disorder predisposes the lungs of affected patients to chronic infection, typically by Pseudomonas aeruginosa, which is the main cause of morbidity and mortality. Recently, attention has focused on aerosolised polymyxins, which are given prophylactically in an effort to limit infection and subsequent lung damage. This class of antimicrobial compounds is highly active against P. aeruginosa and possess the advantage that resistance rarely develops. However, the rapid lung clearance of antibiotics is a well documented phenomenon and it was postulated that polymyxin treatment could be further improved by liposomal encapsulation. As part of the development of liposomal polymyxin B, analytical methodology (radiolabelling, HPLC and protein assay) applicable to liposomal formulations was established. Liposomes were prepared by the dehydration-rehydration method and encapsulation efficiencies were determined for a number of phospholipid compositions. Vesicles were characterised with respect to size, zeta potential, morphology and release characteristics. The surface hydrophobicity of vesicles was quantified by hydrophobic interaction chromatography and it was found that this method produced comparable results to techniques conventionally used to assess this property. In vivo testing of liposomal polymyxins demonstrated that encapsulation successfully prevented the rapid pulmonary clearance of PXB. Antimicrobial activity of liposomal formulations was quantified and found to be dependent on both the vesicle surface characteristics and their release profile. Investigation of the interaction of PXB with lipopolysaccharide was undertaken and results demonstrated that PXB caused significant structural distortion of the lipid A region. This may be sufficient to abrogate the potentiating action of LPS in the inflammatory cascade.

Vibration in electromagnetically heated steel

When a ferromagnetic steel billet was heated by induction a large increase in the amplitude of longitudinal vibration frequently occurred as a result of resonance. This happened when a natural frequency of the bar coincided with twice the heating frequency or multiples thereof. The temperature at which resonance occurred depended on a number of factors including billet length and heating power. Resonance was most often observed when the surface temperature of the billet reached the Curie point. It is well established that magnetostrictive vibrations occur in a ferromagnetic material subjected to an alternating electromagnetic field, but existing data suggests that linear magnetostriction decreases towards the Curie point. Linear magnetostriction was measured in a sample of mild steel up to 800ºC using a high temperature strain gauge. The magnetostriction constant 100 was calculated assuming an average grain orientation in mild steel. The data was found to be comparable to that published for single crystals of iron. It was discovered that linear magnetostriction was responsible for resonance below 600ºC but not for temperatures near the Curie point. Other possible causes of resonance such as forces produced by the interaction between eddy currents and the alternating electromagnetic field, the alpha to gamma phase transformation and the existence of a thin ferromagnetic layer were investigated. None were found to account for resonance in bars of mild steel heated by induction. Experimental work relating to the induction heating of steel is compared to previous work on the subject of electromagnetic generation of ultrasound where a similar increase of the amplitude of longitudinal waves in steel is reported at the Curie point. It is concluded that the two phenomena are related as they show strong similarities.

Oxidized phospholipid inhibition of toll-like receptor (TLR) signaling is restricted to TLR2 and TLR4 roles for cd14, lps-binding protein, and md2 as targets for specificity of inhibition

The generation of reactive oxygen species is a central feature of inflammation that results in the oxidation of host phospholipids. Oxidized phospholipids, such as 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (OxPAPC), have been shown to inhibit signaling induced by bacterial lipopeptide or lipopolysac-charide (LPS), yet the mechanisms responsible for the inhibition of Toll-like receptor (TLR) signaling by OxPAPC remain incompletely understood. Here, we examined the mechanisms by which OxPAPC inhibits TLR signaling induced by diverse ligands in macrophages, smooth muscle cells, and epithelial cells. OxPAPC inhibited tumor necrosis factor- production, IB degradation, p38 MAPK phosphorylation, and NF-B-dependent reporter activation induced by stimulants of TLR2 and TLR4 (Pam3CSK4 and LPS) but not by stimulants of other TLRs (poly(I·C), flagellin, loxoribine, single-stranded RNA, or CpG DNA) in macrophages and HEK-293 cells transfected with respective TLRs and significantly reduced inflammatory responses in mice injected subcutaneously or intraperitoneally with Pam3CSK4. Serum proteins, including CD14 and LPS-binding protein, were identified as key targets for the specificity of TLR inhibition as supplementation with excess serum or recombinant CD14 or LBP reversed TLR2 inhibition by OxPAPC, whereas serum accessory proteins or expression of membrane CD14 potentiated signaling via TLR2 and TLR4 but not other TLRs. Binding experiments and functional assays identified MD2 as a novel additional target of OxPAPC inhibition of LPS signaling. Synthetic phospholipid oxidation products 1-palmitoyl-2-(5-oxovaleryl)-sn-glycero-3-phosphocholine and 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine inhibited TLR2 signaling from 30 µM. Taken together, these results suggest that oxidized phospholipid-mediated inhibition of TLR signaling occurs mainly by competitive interaction with accessory proteins that interact directly with bacterial lipids to promote signaling via TLR2 or TLR4.

Sex differences in bipolar disorder:a review of neuroimaging findings and new evidence

Objectives: The sex of an individual is known to modulate the clinical presentation of bipolar disorder (BD), but little is known as to whether there are significant sex-by-diagnosis interactions on the brain structural and functional correlates of BD. Methods: We conducted a literature review of magnetic resonance imaging (MRI) studies in BD, published between January 1990 and December 2010, reporting on the effects of sex and diagnosis. In the absence of any functional MRI (fMRI) studies, this review was supplemented by original data analyses focusing on sex-by-diagnosis interactions on patterns of brain activation obtained during tasks of working memory, incentive decision-making, and facial affect processing. Results: We found no support for a sex-by-diagnosis interaction in global gray or white matter volume. Evidence regarding regional volumetric measures is limited, but points to complex interactions between sex and diagnosis with developmental and temperamental factors within limbic and prefrontal regions. Sex-by-diagnosis interactions were noted in the pattern of activation within the basal ganglia during incentive decision-making and within ventral prefrontal regions during facial affect processing. Conclusions: Potential sex-by-diagnosis interactions influencing the brain structural and functional correlates of disease expression in BD have received limited attention. Our data suggest that the sex of an individual modulates structure and function within subcortical and cortical regions implicated in disease expression. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S.

Does maternal control during feeding moderate early infant weight gain?

OBJECTIVE. Our objective with this study was to examine whether observed maternal control during feeding at 6 months of age moderates the development of early infant weight gain during the first year of life. METHODS. Sixty-nine women were observed feeding their 6-month-old infants during a standard meal. Mealtimes were coded for maternal use of controlling feeding behavior. All infants were weighed at birth and at 6 and 12 months of age, and weight gain was calculated from birth to 6 months and from 6 to 12 months. Weight scores and weight gain scores were standardized for prematurity, age, and gender. RESULTS. Infant weight gain between 6 and 12 months of age was predicted by an interaction between early infant weight gain (birth to 6 months) and observed maternal control during feeding at 6 months. When maternal control was moderate or low, there was a significant interaction with weight gain from birth to 6 months in the prediction of later infant weight gain from 6 to 12 months, such that infants who showed slow early weight gain accelerated in their subsequent weight gain, and those with greater early weight gain decelerated. Conversely, when maternal control was high, infant weight gain followed the opposite pattern. CONCLUSION. Maternal control of solid feeding can moderate infant weight gain.

Relationship between sunlight and the age of onset of bipolar disorder:an international multisite study

Background - The onset of bipolar disorder is influenced by the interaction of genetic and environmental factors. We previously found that a large increase in sunlight in springtime was associated with a lower age of onset. This study extends this analysis with more collection sites at diverse locations, and includes family history and polarity of first episode. Methods - Data from 4037 patients with bipolar I disorder were collected at 36 collection sites in 23 countries at latitudes spanning 3.2 north (N) to 63.4 N and 38.2 south (S) of the equator. The age of onset of the first episode, onset location, family history of mood disorders, and polarity of first episode were obtained retrospectively, from patient records and/or direct interview. Solar insolation data were obtained for the onset locations. Results - There was a large, significant inverse relationship between maximum monthly increase in solar insolation and age of onset, controlling for the country median age and the birth cohort. The effect was reduced by half if there was no family history. The maximum monthly increase in solar insolation occurred in springtime. The effect was one-third smaller for initial episodes of mania than depression. The largest maximum monthly increase in solar insolation occurred in northern latitudes such as Oslo, Norway, and warm and dry areas such as Los Angeles, California. Limitations - Recall bias for onset and family history data. Conclusions - A large springtime increase in sunlight may have an important influence on the onset of bipolar disorder, especially in those with a family history of mood disorders.

Designing immunogenic peptides

Peptides fulfill many roles in immunology, yet none are more important than their role as immunogenic epitopes driving the adaptive immune response, our ultimate bulwark against infectious disease. Peptide epitopes are mediated primarily by their interaction with major histocompatibility complexes (T-cell epitopes) and antibodies (B-cell epitopes). As pathogen genomes continue to be revealed, both experimental and computational epitope mapping are becoming crucial tools in vaccine discovery1,2. Immunoinformatics offers many tools, techniques and approaches for in silico epitope characterization, which is capable of greatly accelerating epitope design. © 2013 Nature America, Inc. All rights reserved.