A cognitive approach to identifying measurable milestones for programming skill acquisition

Mead, J., Gray, S., Hamer, J., James, R., Sorva, J., Clair, C. S., and Thomas, L. 2006. A cognitive approach to identifying measurable milestones for programming skill acquisition. SIGCSE Bull. 38, 4 (Dec. 2006), 182-194.

The Ontogeny of Mucosal and Systemic Antibody Responses to HIV-1 Infection

The humoral immune system plays a critical role in the clearance of numerous pathogens. In the setting of HIV-1 infection, the virus infects, integrates its genome into the host's cells, replicates, and establishes a reservoir of virus-infected cells. The initial antibody response to HIV-1 infection is targeted to non-neutralizing epitopes on HIV-1 Env gp41, and when a neutralizing response does develop months after transmission, it is specific for the autologous founder virus and the virus escapes rapidly. After continuous waves of antibody mediated neutralization and viral escape, a small subset of infected individuals eventually develop broad and potent heterologous neutralizing antibodies years after infection. In this dissertation, I have studied the ontogeny of mucosal and systemic antibody responses to HIV-1 infection by means of three distinct aims: 1. Determine the origin of the initial antibody response to HIV-1 infection. 2. Characterize the role of restricted VH and VL gene segment usage in shaping the antibody response to HIV-1 infection. 3. Determine the role of persistence of B cell clonal lineages in shaping the mutation frequencies of HIV-1 reactive antibodies.

After the introduction (Chapter 1) and methods (Chapter 2), Chapter 3 of this dissertation describes a study of the antibody response of terminal ileum B cells to HIV-1 envelope (Env) in early and chronic HIV-1 infection and provides evidence for the role of environmental antigens in shaping the repertoire of B cells that respond to HIV-1 infection. Previous work by Liao et al. demonstrated that the initial plasma cell response in the blood to acute HIV-1 infection is to gp41 and is derived from a polyreactive memory B cell pool. Many of these antibodies cross-reacted with commensal bacteria, Therefore, in Chapter 3, the relationship of intestinal B cell reactivity with commensal bacteria to HIV-1 infection-induced antibody response was probed using single B cell sorting, reverse transcription and nested polymerase chain reaction (RT- PCR) methods, and recombinant antibody technology. The dominant B cell response in the terminal ileum was to HIV-1 envelope (Env) gp41, and 82% of gp41- reactive antibodies cross-reacted with commensal bacteria whole cell lysates. Pyrosequencing of blood B cells revealed HIV-1 antibody clonal lineages shared between ileum and blood. Mutated IgG antibodies cross-reactive with both Env gp41 and commensal bacteria could also be isolated from the terminal ileum of HIV-1 uninfected individuals. Thus, the antibody response to HIV-1 can be shaped by intestinal B cells stimulated by commensal bacteria prior to HIV-1 infection to develop a pre-infection pool of memory B cells cross-reactive with HIV-1 gp41.

Chapter 4 details the study of restricted VH and VL gene segment usage for gp41 and gp120 antibody induction following acute HIV-1 infection; mutations in gp41 lead to virus enhanced neutralization sensitivity. The B cell repertoire of antibodies induced in a HIV-1 infected African individual, CAP206, who developed broadly neutralizing antibodies (bnAbs) directed to the HIV-1 envelope gp41 membrane proximal external region (MPER), is characterized. Understanding the selection of virus mutants by neutralizing antibodies is critical to understanding the role of antibodies in control of HIV-1 replication and prevention from HIV-1 infection. Previously, an MPER neutralizing antibody, CAP206-CH12, with the binding footprint identical to that of MPER broadly neutralizing antibody 4E10, that like 4E10 utilized the VH1-69 and VK3-20 variable gene segments was isolated from this individual (Morris et al., 2011). Using single B cell sorting, RT- PCR methods, and recombinant antibody technology, Chapter 4 describes the isolation of a VH1-69, Vk3-20 glycan-dependent clonal lineage from CAP206, targeted to gp120, that has the property of neutralizing a neutralization sensitive CAP206 transmitted/founder (T/F) and heterologous viruses with mutations at amino acids 680 or 681 in the MPER 4E10/CH12 binding site. These data demonstrate sites within the MPER bnAb epitope (aa 680-681) in which mutations can be selected that lead to viruses with enhanced sensitivity to autologous and heterologous neutralizing antibodies.

In Chapter 5, I have completed a comparison of evolution of B cell clonal lineages in two HIV-1 infected individuals who have a predominant VH1-69 response to HIV-1 infection--one who produces broadly neutralizing MPER-reactive mAbs and one who does not. Autologous neutralization in the plasma takes ~12 weeks to develop (Gray et al., 2007; Tomaras et al., 2008b). Only a small subset of HIV-1 infected individuals develops high plasma levels of broad and potent heterologous neutralization, and when it does occur, it typically takes 3-4 years to develop (Euler et al., 2010; Gray et al., 2007; 2011; Tomaras et al., 2011). The HIV-1 bnAbs that have been isolated to date have a number of unusual characteristics including, autoreactivity and high levels of somatic hypermutations, which are typically tightly regulated by immune control mechanisms (Haynes et al., 2005; 2012b; Kwong and Mascola, 2012; Scheid et al., 2009a). The VH mutation frequencies of bnAbs average ~15% but have been shown to be as high as 32% (reviewed in Mascola and Haynes, 2013; Kwong and Mascola, 2012). The high frequency of somatic hypermutations suggests that the B cell clonal lineages that eventually produce bnAbs undergo high-levels of affinity maturation, implying prolonged germinal center (GC) reactions and high levels of T cell help. To study the duration of HIV-1- reactive B cell clonal persistence, HIV-1 reactive and non HIV-1- reactive B cell clonal lineages were isolated from an HIV-1 infected individual that produces bnAbs, CAP206, and an HIV-1 infected individual who does not produce bnAbs, 004-0. Single B cell sorting, RT-PCR and recombinant antibody technology was used to isolate and produce monoclonal antibodies from multiple time points from each individual. B cell sequences clonally related to mAbs isolated by single cell PCR were identified within pyrosequences of longitudinal samples of these two individuals. Both individuals produced long-lived B cell clones that persisted from 0-232 weeks in CAP206, and 0-238 weeks in 004-0. The average length of persistence of clones containing members isolated from two separate time points was 91.5 weeks both individuals. Examples of the continued evolution of clonal lineages were observed in both the bnAb and non-bnAb individual. These data indicated that the ability to generate persistent and evolving B cell clonal lineages occurs in both bnAb and non-bnAb individuals, suggesting that some alternative host or viral factor is critical for the generation of highly mutated broadly neutralizing antibodies.

Together the studies described in Chapter 3-5 show that multiple factors influence the antibody response to HIV-1 infection. The initial antibody response to HIV-1 Env gp41 can be shaped by a B cell response to intestinal commensal bacteria prior to HIV-1 infection. VH and VL gene segment restriction can impact the B cell response to multiple HIV-1 antigens, and virus escape mutations in the MPER can confer enhanced neutralization sensitivity to autologous and heterologous antibodies. Finally, the ability to generate long-lived HIV-1 clonal lineages in and of itself does not confer on the host the ability to produce bnAbs.

Priority research questions for the UK food system

The rise of food security up international political, societal and academic agendas has led to increasing interest in novel means of improving primary food production and reducing waste. There are however, also many 'post-farm gate' activities that are critical to food security, including processing, packaging, distributing, retailing, cooking and consuming. These activities all affect a range of important food security elements, notably availability, affordability and other aspects of access, nutrition and safety. Addressing the challenge of universal food security, in the context of a number of other policy goals (e.g. social, economic and environmental sustainability), is of keen interest to a range of UK stakeholders but requires an up-to-date evidence base and continuous innovation. An exercise was therefore conducted, under the auspices of the UK Global Food Security Programme, to identify priority research questions with a focus on the UK food system (though the outcomes may be broadly applicable to other developed nations). Emphasis was placed on incorporating a wide range of perspectives ('world views') from different stakeholder groups: policy, private sector, non-governmental organisations, advocacy groups and academia. A total of 456 individuals submitted 820 questions from which 100 were selected by a process of online voting and a three-stage workshop voting exercise. These 100 final questions were sorted into 10 themes and the 'top' question for each theme identified by a further voting exercise. This step also allowed four different stakeholder groups to select the top 7-8 questions from their perspectives. Results of these voting exercises are presented. It is clear from the wide range of questions prioritised in this exercise that the different stakeholder groups identified specific research needs on a range of post-farm gate activities and food security outcomes. Evidence needs related to food affordability, nutrition and food safety (all key elements of food security) featured highly in the exercise. While there were some questions relating to climate impacts on production, other important topics for food security (e.g. trade, transport, preference and cultural needs) were not viewed as strongly by the participants.

ALES: a multi-mission adaptive sub-waveform retracker for coastal and open ocean altimetry

Satellite altimetry has revolutionized our understanding of ocean dynamics thanks to frequent sampling and global coverage. Nevertheless, coastal data have been flagged as unreliable due to land and calm water interference in the altimeter and radiometer footprint and uncertainty in the modelling of high-frequency tidal and atmospheric forcing. Our study addresses the first issue, i.e. altimeter footprint contamination, via retracking, presenting ALES, the Adaptive Leading Edge Subwaveform retracker. ALES is potentially applicable to all the pulse-limited altimetry missions and its aim is to retrack both open ocean and coastal data with the same accuracy using just one algorithm. ALES selects part of each returned echo and models it with a classic ”open ocean” Brown functional form, by means of least square estimation whose convergence is found through the Nelder-Mead nonlinear optimization technique. By avoiding echoes from bright targets along the trailing edge, it is capable of retrieving more coastal waveforms than the standard processing. By adapting the width of the estimation window according to the significant wave height, it aims at maintaining the accuracy of the standard processing in both the open ocean and the coastal strip. This innovative retracker is validated against tide gauges in the Adriatic Sea and in the Greater Agulhas System for three different missions: Envisat, Jason-1 and Jason-2. Considerations of noise and biases provide a further verification of the strategy. The results show that ALES is able to provide more reliable 20-Hz data for all three missions in areas where even 1-Hz averages are flagged as unreliable in standard products. Application of the ALES retracker led to roughly a half of the analysed tracks showing a marked improvement in correlation with the tide gauge records, with the rms difference being reduced by a factor of 1.5 for Jason-1 and Jason-2 and over 4 for Envisat in the Adriatic Sea (at the closest point to the tide gauge).

Prioritization of knowledge needs for sustainable aquaculture: a national and global perspective

Aquaculture is currently the fastest expanding global animal food production sector and is a key future contributor to food security. An increase in food security will be dependent upon the development and improvement of sustainable practices. A prioritization exercise was undertaken, focusing on the future knowledge needs to underpin UK sustainable aquaculture (both domestic and imported products) using a ‘task force’ group of 36 ‘practitioners’ and 12 ‘research scientists’ who have an active interest in sustainable aquaculture. A long list of 264 knowledge needs related to sustainable aquaculture was developed in conjunction with the task force. The long list was further refined through a three stage process of voting and scoring, including discussions of each knowledge need. The top 25 knowledge needs are presented, as scored separately by ‘practitioners’ or ‘research scientists’. There was similar agreement in priorities identified by these two groups. The priority knowledge needs will provide guidance to structure ongoing work to make science accessible to practitioners and help to prioritize future science policy needs and funding. The process of knowledge exchange, and the mechanisms by which this can be achieved, effectively emerged as the top priority for sustainable aquaculture. Viable alternatives to wild fish-based aquaculture feeds, resource constraints that will potentially limit expansion of aquaculture, sustainable offshore aquaculture and the treatment of sea lice also emerged as strong priorities. Although the exercise was focused on UK needs for sustainable aquaculture, many of the emergent issues are considered to have global application.

Patrimonio e Identidad en la Investigación Educativa Basada en las Artes desde un Enfoque Multimodal

Este artículo describe dos experiencias de investigación de nuestro grupo interconectadas, la primera desarrollada durante el año 2007 a través del proyecto internacional CALVINO del Programa Cultura 2000 de la Unión Europea, y la segunda implementada durante el año 2014 en el marco del Proyecto Investigación e Innovación en Secundaria en Andalucía (PIIISA). Ambos proyectos tienen en común el eje temático de la identidad a partir de una idea de patrimonio y el hecho de haber puesto en práctica metodologías de investigación basadas en las artes visuales con un enfoque multimodal. Desde estos dos puntos de anclaje relativos a la temática (qué) y a la metodología (cómo) analizamos lo acontecido para obtener conclusiones relevantes que, por una parte, pongan en valor estas prácticas significativas y, por otra, aporten nuestra experiencia para futuras propuestas de investigación en el ámbito temático y/o metodológico.

Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease

We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 x 10(-157)) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 x 10(-9)) and 5. to the PICALM gene (rs3851179, P = 1.9 x 10(-8)). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 x 10(-10), odds ratio = 0.86; rs3851179, P = 1.3 x 10(-9), odds ratio = 0.86).

Language-universal Sensory Deficits in Developmental Dyslexia: English, Spanish, and Chinese

Studies in sensory neuroscience reveal the critical importance of accurate sensory perception for cognitive development. There is considerable debate concerning the possible sensory correlates of phonological processing, the primary cognitive risk factor for developmental dyslexia. Across languages, children with dyslexia have a specific difficulty with the neural representation of the phonological structure of speech. The identification of a robust sensory marker of phonological difficulties would enable early identification of risk for developmental dyslexia and early targeted intervention. Here, we explore whether phonological processing difficulties are associated with difficulties in processing acoustic cues to speech rhythm. Speech rhythm is used across languages by infants to segment the speech stream into words and syllables. Early difficulties in perceiving auditory sensory cues to speech rhythm and prosody could lead developmentally to impairments in phonology. We compared matched samples of children with and without dyslexia, learning three very different spoken and written languages, English, Spanish, and Chinese. The key sensory cue measured was rate of onset of the amplitude envelope (rise time), known to be critical for the rhythmic timing of speech. Despite phonological and orthographic differences, for each language, rise time sensitivity was a significant predictor of phonological awareness, and rise time was the only consistent predictor of reading acquisition. The data support a language-universal theory of the neural basis of developmental dyslexia on the basis of rhythmic perception and syllable segmentation. They also suggest that novel remediation strategies on the basis of rhythm and music may offer benefits for phonological and linguistic development.

Rise time and formant transition duration in the discrimination of speech sounds: The Ba–Wa distinction in developmental dyslexia

Across languages, children with developmental dyslexia have a specific difficulty with the neural representation of the sound structure (phonological structure) of speech. One likely cause of their difficulties with phonology is a perceptual difficulty in auditory temporal processing (Tallal, 1980). Tallal (1980) proposed that basic auditory processing of brief, rapidly successive acoustic changes is compromised in dyslexia, thereby affecting phonetic discrimination (e.g. discriminating /b/ from /d/) via impaired discrimination of formant transitions (rapid acoustic changes in frequency and intensity). However, an alternative auditory temporal hypothesis is that the basic auditory processing of the slower amplitude modulation cues in speech is compromised (Goswami , 2002). Here, we contrast children's perception of a synthetic speech contrast (ba/wa) when it is based on the speed of the rate of change of frequency information (formant transition duration) versus the speed of the rate of change of amplitude modulation (rise time). We show that children with dyslexia have excellent phonetic discrimination based on formant transition duration, but poor phonetic discrimination based on envelope cues. The results explain why phonetic discrimination may be allophonic in developmental dyslexia (Serniclaes , 2004), and suggest new avenues for the remediation of developmental dyslexia. © 2010 Blackwell Publishing Ltd.

Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer's Disease

Background: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. Methodology: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset.

Music, rhythm, rise time perception and developmental dyslexia: Perception of musical meter predicts reading and phonology

Introduction: Rhythm organises musical events into patterns and forms, and rhythm perception in music is usually studied by using metrical tasks. Metrical structure also plays an organisational function in the phonology of language, via speech prosody, and there is evidence for rhythmic perceptual difficulties in developmental dyslexia. Here we investigate the hypothesis that the accurate perception of musical metrical structure is related to basic auditory perception of rise time, and also to phonological and literacy development in children. Methods: A battery of behavioural tasks was devised to explore relations between musical metrical perception, auditory perception of amplitude envelope structure, phonological awareness (PA) and reading in a sample of 64 typically-developing children and children with developmental dyslexia. Results: We show that individual differences in the perception of amplitude envelope rise time are linked to musical metrical sensitivity, and that musical metrical sensitivity predicts PA and reading development, accounting for over 60% of variance in reading along with age and I.Q. Even the simplest metrical task, based on a duple metrical structure, was performed significantly more poorly by the children with dyslexia. Conclusions: The accurate perception of metrical structure may be critical for phonological development and consequently for the development of literacy. Difficulties in metrical processing are associated with basic auditory rise time processing difficulties, suggesting a primary sensory impairment in developmental dyslexia in tracking the lower-frequency modulations in the speech envelope. © 2010 Elsevier.

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P = 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).

No Evidence that Extended Tracts of Homozygosity are Associated with Alzheimer’s Disease.

We sought to investigate the contribution of extended runs of homozygosity in a genome-wide association dataset of 1,955 Alzheimer's disease cases and 955 elderly screened controls genotyped for 529,205 autosomal single nucleotide polymorphisms. Tracts of homozygosity may mark regions inherited from a common ancestor and could reflect disease loci if observed more frequently in cases than controls. We found no excess of homozygous tracts in Alzheimer's disease cases compared to controls and no individual run of homozygosity showed association to Alzheimer's disease.

Auditory sensory deficits in developmental dyslexia: A longitudinal ERP study

The core difficulty in developmental dyslexia across languages is a "phonological deficit", a specific difficulty with the neural representation of the sound structure of words. Recent data across languages suggest that this phonological deficit arises in part from inefficient auditory processing of the rate of change of the amplitude envelope at syllable onset (inefficient sensory processing of rise time). Rise time is a complex percept that also involves changes in duration and perceived intensity. Understanding the neural mechanisms that give rise to the phonological deficit in dyslexia is important for optimising educational interventions. In a three-deviant passive 'oddball' paradigm and a corresponding blocked 'deviant-alone' control condition we recorded ERPs to tones varying in rise time, duration and intensity in children with dyslexia and typically developing children longitudinally. We report here results from test Phases 1 and 2, when participants were aged 8-10. years. We found an MMN to duration, but not to rise time nor intensity deviants, at both time points for both groups. For rise time, duration and intensity we found group effects in both the Oddball and Blocked conditions. There was a slower fronto-central P1 response in the dyslexic group compared to controls. The amplitude of the P1 fronto-centrally to tones with slower rise times and lower intensity was smaller compared to tones with sharper rise times and higher intensity in the Oddball condition, for children with dyslexia only. The latency of this ERP component for all three stimuli was shorter on the right compared to the left hemisphere, only for the dyslexic group in the Blocked condition. Furthermore, we found decreased N1c amplitude to tones with slower rise times compared to tones with sharper rise times for children with dyslexia, only in the Oddball condition. Several other effects of stimulus type, age and laterality were also observed. Our data suggest that neuronal responses underlying some aspects of auditory sensory processing may be impaired in dyslexia. © 2011 Elsevier Inc.