Searching for the causal effects of BMI in over 300 000 individuals, using Mendelian randomization, bioRxiv, 2017-12-20
ABSTRACTMendelian randomization (MR) has been used to estimate the causal effect of body mass index (BMI) on particular traits thought to be affected by BMI. However, BMI may also be a modifiable, causal risk factor for outcomes where there is no prior reason to suggest that a causal effect exists. We perform a MR phenome-wide association study (MR-pheWAS) to search for the causal effects of BMI in UK Biobank (n=334 968), using the PHESANT open-source phenome scan tool. Of the 20 461 tests performed, our MR-pheWAS identified 519 associations below a stringent P value threshold corresponding to a 5% estimated false discovery rate, including many previously identified causal effects. We also identified several novel effects, including protective effects of higher BMI on a set of psychosocial traits, identified initially in our preliminary MR-pheWAS and replicated in an independent subset of UK Biobank. Such associations need replicating in an independent sample.
biorxiv epidemiology 0-100-users 2017Social interactions impact on the dopaminergic system and drive individuality, bioRxiv, 2017-12-20
SummaryIndividuality is a ubiquitous and well-conserved feature among animal species. The behavioral patterns of individual animals affect their respective role in the ecosystem and their prospects for survival. Even though some of the factors shaping individuality have been identified, the mechanisms underlying individuation are poorly understood and are generally considered to be genetics-based. Here we devised a large environment where mice live continuously, and observed that individuality, measured by both social and individual traits, emerged and settled within the group. Midbrain dopamine neurons underwent neurophysiological adaptations that mirrored this phenotypic divergence in individual behaviors. Strikingly, modifying the social environment resulted in a fast re-adaptation of both the animal’s personality and its dopaminergic signature. These results indicate that individuality can rapidly evolve upon social challenges, and does not just depend on the genetic or epigenetic initial status of the animal.
biorxiv neuroscience 0-100-users 2017Coherent representations of subjective spatial position in primary visual cortex and hippocampus, bioRxiv, 2017-12-19
A major role of vision is to guide navigation, and navigation is strongly driven by vision1-4. Indeed, the brain’s visual and navigational systems are known to interact5, 6, and signals related to position in the environment have been suggested to appear as early as in visual cortex6, 7. To establish the nature of these signals we recorded in primary visual cortex (V1) and in the CA1 region of the hippocampus while mice traversed a corridor in virtual reality. The corridor contained identical visual landmarks in two positions, so that a purely visual neuron would respond similarly in those positions. Most V1 neurons, however, responded solely or more strongly to the landmarks in one position. This modulation of visual responses by spatial location was not explained by factors such as running speed. To assess whether the modulation is related to navigational signals and to the animal’s subjective estimate of position, we trained the mice to lick for a water reward upon reaching a reward zone in the corridor. Neuronal populations in both CA1 and V1 encoded the animal’s position along the corridor, and the errors in their representations were correlated. Moreover, both representations reflected the animal’s subjective estimate of position, inferred from the animal’s licks, better than its actual position. Indeed, when animals licked in a given location – whether correct or incorrect – neural populations in both V1 and CA1 placed the animal in the reward zone. We conclude that visual responses in V1 are tightly controlled by navigational signals, which are coherent with those encoded in hippocampus, and reflect the animal’s subjective position in the environment. The presence of such navigational signals as early as in a primary sensory area suggests that these signals permeate sensory processing in the cortex.
biorxiv neuroscience 100-200-users 2017Correction of the Framingham Risk Score Data Reported in SPRINT, bioRxiv, 2017-12-19
This report describes an error in the Framingham Risk Score data presented in the original SPRINT publication.1 The data, presented in Table 1 of the main SPRINT publication in the New England Journal of Medicine and made available to SPRINT Challenge participants, incorrectly calculated the level of baseline cardiovascular risk of the study participants using the Framingham Risk Score. The correct calculation increased the number of participants identified as having >15% 10-year risk from 5737 to 7089, a change from 61% to 76% of the total study population. This information is important for researchers attempting to validate and extend the trial’s findings and is particularly germane because the recently released American Heart AssociationAmerican College of Cardiology blood pressure guidelines changed blood pressure targets for pharmacologic therapy only for high-risk individuals.
biorxiv clinical-trials 0-100-users 2017Long-read sequencing of nascent RNA reveals coupling among RNA processing events, bioRxiv, 2017-12-19
AbstractPre-mRNA splicing is accomplished by the spliceosome, a megadalton complex that assembles de novo on each intron. Because spliceosome assembly and catalysis occur co-transcriptionally, we hypothesized that introns are removed in the order of their transcription in genomes dominated by constitutive splicing. Remarkably little is known about splicing order and the regulatory potential of nascent transcript remodeling by splicing, due to the limitations of existing methods that focus on analysis of mature splicing products (mRNAs) rather than substrates and intermediates. Here, we overcome this obstacle through long-read RNA sequencing of nascent, multi-intron transcripts in the fission yeast Schizosaccharomyces pombe. Most multi-intron transcripts were fully spliced, consistent with rapid co-transcriptional splicing. However, an unexpectedly high proportion of transcripts were either fully spliced or fully unspliced, suggesting that splicing of any given intron is dependent on the splicing status of other introns in the transcript. Supporting this, mild inhibition of splicing by a temperature-sensitive mutation in Prp2, the homolog of vertebrate U2AF65, increased the frequency of fully unspliced transcripts. Importantly, fully unspliced transcripts displayed transcriptional read-through at the polyA site and were degraded co-transcriptionally by the nuclear exosome. Finally, we show that cellular mRNA levels were reduced in genes with a high number of unspliced nascent transcripts during caffeine treatment, showing regulatory significance of co-transcriptional splicing. Therefore, overall splicing of individual nascent transcripts, 3’ end formation, and mRNA half-life depend on the splicing status of neighboring introns, suggesting crosstalk among spliceosomes and the polyA cleavage machinery during transcription elongation.
biorxiv molecular-biology 0-100-users 2017Muscle specific stress fibers give rise to sarcomeres and are mechanistically distinct from stress fibers in non-muscle cells, bioRxiv, 2017-12-19
AbstractThe sarcomere is the basic contractile unit within cardiomyocytes driving heart muscle contraction. We sought to test the mechanisms regulating thin (i.e., actin) and thick (i.e., myosin) filament assembly during sarcomere formation. Thus, we developed an assay using human cardiomyocytes to test de novo sarcomere assembly. Using this assay, we report a population of muscle-specific stress fibers are essential sarcomere precursors. We show sarcomeric actin filaments arise directly from these muscle stress fibers. This process requires formin-mediated but not Arp23-mediated actin polymerization and nonmuscle myosin IIB but not non-muscle myosin IIA. Furthermore, we show a short species of β cardiac myosin II filaments grows to form ~1.5 long filaments that then “stitch” together to form the stack of filaments at the core of the sarcomere (i.e., A-band). Interestingly, these are different from mechanisms that have previously been reported during stress fiber assembly in non-muscle cells. Thus, we provide a new model of cardiac sarcomere assembly based on distinct mechanisms of stress fiber regulation between non-muscle and muscle cells.
biorxiv cell-biology 100-200-users 2017