A role for consolidation in cross-modal category learning

The ability to categorize objects and events is a fundamental human skill that depends upon the representation of multimodal conceptual knowledge. This study investigated the acquisition and consolidation of categorical information that required participants to integrate information across visual and auditory dimensions. The impact of wake- and sleep-dependent consolidation were investigated using a paradigm in which training and testing were separated by a delay spanning either an evening of sleep or daytime wakefulness, with a paired-associate episodic memory task used as a measure of classic sleep-dependent consolidation. Participants displayed good evidence of category learning, but did not show any wake- or sleep-dependent changes in memory for category information immediately following the delay. This is in contrast to paired-associate learning, where a sleep-dependent benefit was observed in memory recall. To replicate real-world concept learning, in which knowledge is acquired across multiple distinct episodes, participants were given a second opportunity for category learning following the consolidation delay. Here we found an interaction between consolidation and learning; with greater improvements in category knowledge as a result of the second session learning for those participants who had a sleep filled delay. These results suggest a role for sleep in the consolidation of recently acquired categorical knowledge; however this benefit does not emerge as an immediate benefit in memory recall, but by enhancing the effectiveness of future learning. This study therefore provides insights into the processes responsible for the formation and development of conceptual representations

The Role of Consolidation in Conceptual Memory

Concepts allow us to bring meaning to the world; they require the integration of information from across multiple episodes and events, and the abstraction of statistical patterns and regularities from both new and existing knowledge. Processes during consolidation have been shown to benefit the extraction of gist, the detection of hidden rules and the integration of memory elements into coherent representations. Consolidation may therefore play an important role in the development of conceptual memory. To explore this, we used a range of consolidation delay manipulations and two paradigms that assessed the development of concept-based representations. In Chapter 2 and 3 we used an abstract cross-modal information-integration categorisation task, which allowed us to investigate the integration of information from across modalities (visual and auditory) and the extraction of an underlying category structure. In these experiments we did not find any immediate consolidation benefits on categorisation performance. However, post-consolidation improvements in category learning were observed, if participants had a sleep-filled delay; suggesting that processes during sleep may enhance the effectiveness of future concept-based learning. In Chapters 4 and 5, we used an associative memory task that allowed us to dissociate the impact of consolidation on generalised concept-based representations from trained item knowledge. In this task we found sleep-associated improvements in memory; however, these were specific to trained-item knowledge, with no sleep-associated benefits in measures of memory generalisation. An investigation into intrinsic brain connectivity in Chapter 5 suggests that general variations in functional connectivity can in part explain individual differences in long-term memory performance; with decoupling between heteromodal and sensory-motor brain regions supporting memory generalisation and the formation of concepts. Our results provide new insights into the role of consolidation in the development of conceptual memory and highlight important directions for future research

tDCS to temporoparietal cortex during familiarisation enhances the subsequent phonological coherence of nonwords in immediate serial recall

Research has shown that direct current stimulation (tDCS) over left temporoparietal cortex - a region implicated in phonological processing - aids new word learning. The locus of this effect remains unclear since (i) experiments have not empirically separated the acquisition of phonological forms from lexical-semantic links and (ii) outcome measures have focused on learnt associations with a referent rather than phonological stability. We tested the hypothesis that left temporoparietal tDCS would strengthen the acquisition of phonological forms, even in the absence of the opportunity to acquire lexical-semantic associations. Participants were familiarised with nonwords paired with (i) photographs of concrete referents or (ii) blurred images where no clear features were visible. Nonword familiarisation proceeded under conditions of anodal tDCS and sham stimulation in different sessions. We examined the impact of these manipulations on the stability of the phonological trace in an immediate serial recall (ISR) task the following day, ensuring that any effects were due to the influence of tDCS on long-term learning and not a direct consequence of short-term changes in neural excitability. We found that only a few exposures to the phonological forms of nonwords were sufficient to enhance nonword ISR overall compared to entirely novel items. Anodal tDCS during familiarisation further enhanced the acquisition of phonological forms, producing a specific reduction in the frequency of phoneme migrations when sequences of nonwords were maintained in verbal short-term memory. More of the phonemes that were recalled were bound together as a whole correct nonword following tDCS. These data show that tDCS to left temporoparietal cortex can facilitate word learning by strengthening the acquisition of long-term phonological forms, irrespective of the availability of a concrete referent, and that the consequences of this learning can be seen beyond the learning task as strengthened phonological coherence in verbal short-term memory

Incidence of community-acquired lower respiratory tract infections and pneumonia among older adults in the United Kingdom: a population-based study.

Community-acquired lower respiratory tract infections (LRTI) and pneumonia (CAP) are common causes of morbidity and mortality among those aged ≥65 years; a growing population in many countries. Detailed incidence estimates for these infections among older adults in the United Kingdom (UK) are lacking. We used electronic general practice records from the Clinical Practice Research Data link, linked to Hospital Episode Statistics inpatient data, to estimate incidence of community-acquired LRTI and CAP among UK older adults between April 1997-March 2011, by age, sex, region and deprivation quintile. Levels of antibiotic prescribing were also assessed. LRTI incidence increased with fluctuations over time, was higher in men than women aged ≥70 and increased with age from 92.21 episodes/1000 person-years (65-69 years) to 187.91/1000 (85-89 years). CAP incidence increased more markedly with age, from 2.81 to 21.81 episodes/1000 person-years respectively, and was higher among men. For both infection groups, increases over time were attenuated after age-standardisation, indicating that these rises were largely due to population aging. Rates among those in the most deprived quintile were around 70% higher than the least deprived and were generally higher in the North of England. GP antibiotic prescribing rates were high for LRTI but lower for CAP (mostly due to immediate hospitalisation). This is the first study to provide long-term detailed incidence estimates of community-acquired LRTI and CAP in UK older individuals, taking person-time at risk into account. The summary incidence commonly presented for the ≥65 age group considerably underestimates LRTI/CAP rates, particularly among older individuals within this group. Our methodology and findings are likely to be highly relevant to health planners and researchers in other countries with aging populations

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes