Multiple Weak Linear Motifs Enhance Recruitment and Processivity in SPOP-Mediated Substrate Ubiquitination

AbstractPrimary sequence motifs, with millimolar affinities for binding partners, are abundant in disordered protein regions. In multivalent interactions, such weak linear motifs can cooperate to recruit binding partners via avidity effects. If linear motifs recruit modifying enzymes, optimal placement of weak motifs may regulate access to modification sites. Weak motifs may thus exert physiological relevance stronger than that suggested by their affinities, but molecular mechanisms of their function are still poorly understood. Herein, we use the N-terminal disordered region of the Hedgehog transcriptional regulator Gli3 (Gli31-90) to determine the role of weak motifs encoded in its primary sequence for the recruitment of its ubiquitin ligase CRL3SPOP and the subsequent effect on ubiquitination efficiency. The substrate adaptor SPOP binds linear motifs through its MATH (meprin and TRAF homology) domain and forms higher-order oligomers through its oligomerization domains, rendering SPOP multivalent for its substrates. Gli3 has multiple weak SPOP binding motifs. We map three such motifs in Gli31-90, the weakest of which has a millimolar dissociation constant. Multivalency of ligase and substrate for each other facilitates enhanced ligase recruitment and stimulates Gli31-90 ubiquitination in in vitro ubiquitination assays. We speculate that the weak motifs enable processivity through avidity effects and by providing steric access to lysine residues that are otherwise not prioritized for polyubiquitination. Weak motifs may generally be employed in multivalent systems to act as gatekeepers regulating post-translational modification

Robust time-varying multivariate coherence estimation: Application to electroencephalogram recordings during general anesthesia

Coherence analysis characterizes frequency-dependent covariance between signals, and is useful for multivariate oscillatory data often encountered in neuroscience. The global coherence provides a summary of coherent behavior in high-dimensional multivariate data by quantifying the concentration of variance in the first mode of an eigenvalue decomposition of the cross-spectral matrix. Practical application of this useful method is sensitive to noise, and can confound coherent activity in disparate neural populations or spatial locations that have a similar frequency structure. In this paper we describe two methodological enhancements to the global coherence procedure that increase robustness of the technique to noise, and that allow characterization of how power within specific coherent modes change through time.National Institutes of Health (U.S.) (Grant DP2-OD006454)National Institutes of Health (U.S.) (Grant K25-NS057580)National Institutes of Health (U.S.) (Grant DP1-OD003646)National Institutes of Health (U.S.) (Grant R01-EB006385)National Institutes of Health (U.S.) (Grant R01-MH071847

Bayesian analysis of trinomial data in behavioral experiments and its application to human studies of general anesthesia

Accurate quantification of loss of response to external stimuli is essential for understanding the mechanisms of loss of consciousness under general anesthesia. We present a new approach for quantifying three possible outcomes that are encountered in behavioral experiments during general anesthesia: correct responses, incorrect responses and no response. We use a state-space model with two state variables representing a probability of response and a conditional probability of correct response. We show applications of this approach to an example of responses to auditory stimuli at varying levels of propofol anesthesia ranging from light sedation to deep anesthesia in human subjects. The posterior probability densities of model parameters and the response probability are computed within a Bayesian framework using Markov Chain Monte Carlo methods.National Institutes of Health (U.S.) (Grant DP2-OD006454)National Institutes of Health (U.S.) (Grant K25-NS057580)National Institutes of Health (U.S.) (Grant DP1-OD003646)National Institutes of Health (U.S.) (Grant R01-EB006385)National Institutes of Health (U.S.) (Grant R01-MH071847

Perspectives on the scientific legacy of J. Philip Grime

Perhaps as much as any other scientist in the 20th century, J.P. Grime transformed the study of plant ecology and helped shepherd the field toward international prominence as a nexus of ideas related to global environmental change. Editors at the Journal of Ecology asked a group of senior plant ecologists to comment on Grime's scientific legacy. This commentary piece includes individual responses of 14 scientists from around the world attesting to Grime's foundational role in plant functional ecology, including his knack for sparking controversy, his unique approach to theory formulation involving clever experiments and standardized trait measurements of large numbers of species, and the continued impact of his work on ecological science and policy

Dynamic Assessment of Baroreflex Control of Heart Rate During Induction of Propofol Anesthesia Using a Point Process Method

In this article, we present a point process method to assess dynamic baroreflex sensitivity (BRS) by estimating the baroreflex gain as focal component of a simplified closed-loop model of the cardiovascular system. Specifically, an inverse Gaussian probability distribution is used to model the heartbeat interval, whereas the instantaneous mean is identified by linear and bilinear bivariate regressions on both the previous R−R intervals (RR) and blood pressure (BP) beat-to-beat measures. The instantaneous baroreflex gain is estimated as the feedback branch of the loop with a point-process filter, while the RRBP feedforward transfer function representing heart contractility and vasculature effects is simultaneously estimated by a recursive least-squares filter. These two closed-loop gains provide a direct assessment of baroreflex control of heart rate (HR). In addition, the dynamic coherence, cross bispectrum, and their power ratio can also be estimated. All statistical indices provide a valuable quantitative assessment of the interaction between heartbeat dynamics and hemodynamics. To illustrate the application, we have applied the proposed point process model to experimental recordings from 11 healthy subjects in order to monitor cardiovascular regulation under propofol anesthesia. We present quantitative results during transient periods, as well as statistical analyses on steady-state epochs before and after propofol administration. Our findings validate the ability of the algorithm to provide a reliable and fast-tracking assessment of BRS, and show a clear overall reduction in baroreflex gain from the baseline period to the start of propofol anesthesia, confirming that instantaneous evaluation of arterial baroreflex control of HR may yield important implications in clinical practice, particularly during anesthesia and in postoperative care.National Institutes of Health (U.S.) (Grant R01-HL084502)National Institutes of Health (U.S.) (Grant K25-NS05758)National Institutes of Health (U.S.) (Grant DP2- OD006454)National Institutes of Health (U.S.) (Grant T32NS048005)National Institutes of Health (U.S.) (Grant T32NS048005)National Institutes of Health (U.S.) (Grant R01-DA015644)Massachusetts General Hospital (Clinical Research Center, UL1 Grant RR025758

Analysis of protein-coding genetic variation in 60,706 humans

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. We describe the aggregation and analysis of high-quality exome (protein-coding region) sequence data for 60,706 individuals of diverse ethnicities generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of truncating variants with 72% having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human “knockout” variants in protein-coding genes

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder