Dynamics of the upper airway microbiome in the pathogenesis of asthma-associated persistent wheeze in preschool children, bioRxiv, 2017-11-21
ABSTRACTRepeated cycles of infection-associated lower airway inflammation drives the pathogenesis of persistent wheezing disease in children. Tracking these events across a birth cohort during their first five years, we demonstrate that >80% of infectious events indeed involve viral pathogens, but are accompanied by a shift in the nasopharyngeal microbiome (NPM) towards dominance by a small range of pathogenic bacterial genera. Unexpectedly, this change in NPM frequently precedes the appearance of viral pathogens and acute symptoms. In non-sensitized children these events are associated only with “transient wheeze” that resolves after age three. In contrast, in children developing early allergic sensitization, they are associated with ensuing development of persistent wheeze, which is the hallmark of the asthma phenotype. This suggests underlying pathogenic interactions between allergic sensitization and antibacterial mechanisms.
biorxiv genetics 0-100-users 2017Eye movement-related confounds in neural decoding of visual working memory representations, bioRxiv, 2017-11-21
AbstractThe study of visual working memory (VWM) has recently seen revitalization with the emergence of new insights and theories regarding its neural underpinnings. One crucial ingredient responsible for this progress is the rise of neural decoding techniques. These techniques promise to uncover the representational contents of neural signals, as well as the underlying code and the dynamic profile thereof. Here, we aimed to contribute to the field by subjecting human volunteers to a combined VWMimagery task, while recording and decoding their neural signals as measured by MEG. At first sight, the results seem to provide evidence for a persistent, stable representation of the memorandum throughout the delay period. However, control analyses revealed that these findings can be explained by subtle, VWM-specific eye movements. As a potential remedy, we demonstrate the use of a functional localizer, which was specifically designed to target bottom-up sensory signals and as such avoids eye movements, to train the neural decoders. This analysis revealed a sustained representation for approximately 1 second, but no longer throughout the entire delay period. We conclude by arguing for more awareness of the potentially pervasive and ubiquitous effects of eye movement-related confounds.Significance statementVisual working memory is an important aspect of higher cognition and has been subject of much investigation within the field of cognitive neuroscience. Over recent years, these studies have increasingly relied on the use of neural decoding techniques. Here, we show that neural decoding may be susceptible to confounds induced by stimulus-specific eye movements. Such eye movements during working memory have been reported before, and may in fact be a common phenomenon. Given the widespread use of neural decoding and the potentially contaminating effects of eye movements, we therefore believe that our results are of significant relevance for the field.
biorxiv neuroscience 0-100-users 2017Genome-wide polygenic score to identify a monogenic risk-equivalent for coronary disease, bioRxiv, 2017-11-21
AbstractIdentification of individuals at increased genetic risk for a complex disorder such as coronary disease can facilitate treatments or enhanced screening strategies. A rare monogenic mutation associated with increased cholesterol is present in ~1250 carriers and confers an up to 4-fold increase in coronary risk when compared with non-carriers. Although individual common polymorphisms have modest predictive capacity, their cumulative impact can be aggregated into a polygenic score. Here, we develop a new, genome-wide polygenic score that aggregates information from 6.6 million common polymorphisms and show that this score can similarly identify individuals with a 4-fold increased risk for coronary disease. In >400,000 participants from UK Biobank, the score conforms to a normal distribution and those in the top 2.5% of the distribution are at 4-fold increased risk compared to the remaining 97.5%. Similar patterns are observed with genome-wide polygenic scores for two additional diseases – breast cancer and severe obesity.One Sentence SummaryA genome-wide polygenic score identifies 2.5% of the population born with a 4-fold increased risk for coronary artery disease.
biorxiv genomics 100-200-users 2017Higher-order inter-chromosomal hubs shape 3-dimensional genome organization in the nucleus, bioRxiv, 2017-11-19
ABSTRACTEukaryotic genomes are packaged into a 3-dimensional structure in the nucleus of each cell. There are currently two distinct views of genome organization that are derived from different technologies. The first view, derived from genome-wide proximity ligation methods (e.g. Hi-C), suggests that genome organization is largely organized around chromosomes. The second view, derived from in situ imaging, suggests a central role for nuclear bodies. Yet, because microscopy and proximity-ligation methods measure different aspects of genome organization, these two views remain poorly reconciled and our overall understanding of how genomic DNA is organized within the nucleus remains incomplete. Here, we develop Split-Pool Recognition of Interactions by Tag Extension (SPRITE), which moves away from proximity-ligation and enables genome-wide detection of higher-order DNA interactions within the nucleus. Using SPRITE, we recapitulate known genome structures identified by Hi-C and show that the contact frequencies measured by SPRITE strongly correlate with the 3-dimensional distances measured by microscopy. In addition to known structures, SPRITE identifies two major hubs of inter-chromosomal interactions that are spatially arranged around the nucleolus and nuclear speckles, respectively. We find that the majority of genomic regions exhibit preferential spatial association relative to one of these nuclear bodies, with regions that are highly transcribed by RNA Polymerase II organizing around nuclear speckles and transcriptionally inactive and centromere-proximal regions organizing around the nucleolus. Together, our results reconcile the two distinct pictures of nuclear structure and demonstrate that nuclear bodies act as inter-chromosomal hubs that shape the overall 3-dimensional packaging of genomic DNA in the nucleus.
biorxiv genomics 100-200-users 2017The Generation and Propagation of the Human Alpha Rhythm, bioRxiv, 2017-11-19
AbstractThe alpha rhythm is the longest studied brain oscillation and has been theorized to play a key role in cognition. Still, its physiology is poorly understood. In this study, we used micro and macro electrodes in surgical epilepsy patients to measure the intracortical and thalamic generators of the alpha rhythm during quiet wakefulness. We first found that alpha in posterior cortex propagates from higher-order anterosuperior areas towards the occipital pole, consistent with alpha effecting top-down processing. This cortical alpha leads pulvinar alpha, complicating prevailing theories of a thalamic pacemaker. Finally, alpha is dominated by currents and firing in supragranular cortical layers. Together, these results suggest that the alpharhythm likely reflects short-range supragranular feedback which propagates from higher to lower-order cortex and cortex to thalamus. These physiological insights suggest how alpha could mediate feedback throughout the thalamocortical system.
biorxiv neuroscience 0-100-users 2017Transcription start site analysis reveals widespread divergent transcription in D. melanogaster and core promoter-encoded enhancer activities, bioRxiv, 2017-11-19
ABSTRACTMammalian gene promoters and enhancers share many properties. They are composed of a unified promoter architecture of divergent transcripton initiation and gene promoters may exhibit enhancer function. However, it is currently unclear how expression strength of a regulatory element relates to its enhancer strength and if the unifying architecture is conserved across Metazoa. Here we investigate the transcription initiation landscape and its associated RNA decay in D. melanogaster. Surprisingly, we find that the majority of active gene-distal enhancers and a considerable fraction of gene promoters are divergently transcribed. We observe quantitative relationships between enhancer potential, expression level and core promoter strength, providing an explanation for indirectly related histone modifications that are reflecting expression levels. Lowly abundant unstable RNAs initiated from weak core promoters are key characteristics of gene-distal developmental enhancers, while the housekeeping enhancer strengths of gene promoters reflect their expression strengths. The different layers of regulation mediated by gene-distal enhancers and gene promoters are also reflected in chromatin interaction data. Our results suggest a unified promoter architecture of many D. melanogaster regulatory elements, that is universal across Metazoa, whose regulatory functions seem to be related to their core promoter elements.
biorxiv genomics 0-100-users 2017