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Studies on multisite phosphorylation networks of cyclin-dependent kinase (CDK) targets have opened a new level of signaling complexity by revealing signal processing routes encoded into disordered proteins. A model target, the CDK inhibitor Sic1, contains linear phosphorylation motifs, docking sites, and phosphodegrons to empower an N-to-C terminally directed phosphorylation process. Here, we uncover a signal processing mechanism involving multi-step competition between mutually diversional phosphorylation routes within the S-CDK-Sic1 inhibitory complex. Intracomplex phosphorylation plays a direct role in controlling Sic1 degradation, and provides a mechanism to sequentially integrate both the G1- and S-CDK activities while keeping S-CDK inhibited towards other targets. The competing phosphorylation routes prevent premature Sic1 degradation and demonstrate how integration of MAPK from the pheromone pathway allows one to tune the competition of alternative phosphorylation paths. The mutually diversional phosphorylation circuits may be a general way for processing multiple kinase signals to coordinate cellular decisions in eukaryotes.Production of reactive oxygen species (ROS) is critical for successful activation of immune responses against pathogen infection. The plant NADPH oxidase RBOHD is a primary player in ROS production during innate immunity. However, how RBOHD is negatively regulated remains elusive. Here we show that RBOHD is regulated by C-terminal phosphorylation and ubiquitination. Genetic and biochemical analyses reveal that the PBL13 receptor-like cytoplasmic kinase phosphorylates RBOHD's C-terminus and two phosphorylated residues (S862 and T912) affect RBOHD activity and stability, respectively. Using protein array technology, we identified an E3 ubiquitin ligase PIRE (PBL13 interacting RING domain E3 ligase) that interacts with both PBL13 and RBOHD. Mimicking phosphorylation of RBOHD (T912D) results in enhanced ubiquitination and decreased protein abundance. PIRE and PBL13 mutants display higher RBOHD protein accumulation, increased ROS production, and are more resistant to bacterial infection. Thus, our study reveals an intricate post-translational network that negatively regulates the abundance of a conserved NADPH oxidase.Heterogeneous catalysts are complex materials with multiple interfaces. A critical proposition in exploiting bifunctionality in alloy catalysts is to achieve surface migration across interfaces separating functionally dissimilar regions. Herein, we demonstrate the enhancement of more than 104 in the rate of molecular hydrogen reduction of a silver surface oxide in the presence of palladium oxide compared to pure silver oxide resulting from the transfer of atomic hydrogen from palladium oxide islands onto the surrounding surface formed from oxidation of a palladium-silver alloy. The palladium-silver interface also dynamically restructures during reduction, resulting in silver-palladium intermixing. This study clearly demonstrates the migration of reaction intermediates and catalyst material across surface interfacial boundaries in alloys with a significant effect on surface reactivity, having broad implications for the catalytic function of bimetallic materials.Quantifying the dependence of thermal conductivity on grain boundary (GB) structure is critical for controlling nanoscale thermal transport in many technologically important materials. A major obstacle to determining such a relationship is the lack of a robust and physically intuitive structure descriptor capable of distinguishing between disparate GB structures. We demonstrate that a microscopic structure metric, the local distortion factor, correlates well with atomically decomposed thermal conductivities obtained from perturbed molecular dynamics for a wide variety of MgO GBs. Based on this correlation, a model for accurately predicting thermal conductivity of GBs is constructed using machine learning techniques. The model reveals that small distortions to local atomic environments are sufficient to reduce overall thermal conductivity dramatically. The method developed should enable more precise design of next-generation thermal materials as it allows GB structures exhibiting the desired thermal transport behaviour to be identified with small computational overhead.Much of our world changes smoothly in time, yet the allocation of attention is typically studied with sudden changes - transients. A sizeable lag in selecting feature information is seen when stimuli change smoothly. Yet this lag is not seen with temporally uncorrelated rapid serial visual presentation (RSVP) stimuli. This suggests that temporal autocorrelation of a feature paradoxically increases the latency at which information is sampled. To test this, participants are asked to report the color of a disk when a cue was presented. There is an increase in selection latency when the disk's color changed smoothly compared to randomly. This increase is due to the smooth color change presented after the cue rather than extrapolated predictions based on the color changes presented before. These results support an attentional drag theory, whereby attentional engagement is prolonged when features change smoothly. A computational model provides insights into the potential underlying neural mechanisms.Genetically encoded Förster Resonance Energy Transfer (FRET)-based biosensors are powerful tools to illuminate spatiotemporal regulation of cell signaling in living cells, but the utility of the red spectrum for biosensing was limited due to a lack of bright and stable red fluorescent proteins. Here, we rationally improve the photophysical characteristics of the coral-derived fluorescent protein TagRFP-T. We show that a new single-residue mutant, super-TagRFP (stagRFP) has nearly twice the molecular brightness of TagRFP-T and negligible photoactivation. stagRFP facilitates significant improvements on multiple green-red biosensors as a FRET acceptor and is an efficient FRET donor that supports red/far-red FRET biosensing. Capitalizing on the ability of stagRFP to couple with multiple FRET partners, we develop a novel multiplex method to examine the confluence of signaling activities from three kinases simultaneously in single living cells, providing evidence for a role of Src family kinases in regulating growth factor induced Akt and ERK activities.Photo-activated resin composites are widely used in industry and medicine. Despite extensive chemical characterisation, the micro-scale pattern of resin matrix reactive group conversion between filler particles is not fully understood. Using an advanced synchrotron-based wide-field IR imaging system and state-of-the-art Mie scattering corrections, we observe how the presence of monodispersed silica filler particles in a methacrylate based resin reduces local conversion and chemical bond strain in the polymer phase. Here we show that heterogeneity originates from a lower converted and reduced bond strain boundary layer encapsulating each particle, whilst at larger inter-particulate distances light attenuation and monomer mobility predominantly influence conversion. Increased conversion corresponds to greater bond strain, however, strain generation appears sensitive to differences in conversion rate and implies subtle distinctions in the final polymer structure. We expect these findings to inform current predictive models of mechanical behaviour in polymer-composite materials, particularly at the resin-filler interface.Asthma is a chronic and genetically complex respiratory disease that affects over 300 million people worldwide. Here, we report a genome-wide analysis for asthma using data from the UK Biobank and the Trans-National Asthma Genetic Consortium. We identify 66 previously unknown asthma loci and demonstrate that the susceptibility alleles in these regions are, either individually or as a function of cumulative genetic burden, associated with risk to a greater extent in men than women. Bioinformatics analyses prioritize candidate causal genes at 52 loci, including CD52, and demonstrate that asthma-associated variants are enriched in regions of open chromatin in immune cells. Lastly, we show that a murine anti-CD52 antibody mimics the immune cell-depleting effects of a clinically used human anti-CD52 antibody and reduces allergen-induced airway hyperreactivity in mice. These results further elucidate the genetic architecture of asthma and provide important insight into the immunological and sex-specific relevance of asthma-associated risk variants.Complex tumor microenvironmental (TME) features influence the outcome of cancer immunotherapy (IO). Here we perform immunogenomic analyses on 67 intratumor sub-regions of a PD-1 inhibitor-resistant melanoma tumor and 2 additional metastases arising over 8 years, to characterize TME interactions. We identify spatially distinct evolution of copy number alterations influencing local immune composition. Sub-regions with chromosome 7 gain display a relative lack of leukocyte infiltrate but evidence of neutrophil activation, recapitulated in The Cancer Genome Atlas (TCGA) samples, and associated with lack of response to IO across three clinical cohorts. Whether neutrophil activation represents cause or consequence of local tumor necrosis requires further study. Analyses of T-cell clonotypes reveal the presence of recurrent priming events manifesting in a dominant T-cell clonotype over many years. Our findings highlight the links between marked levels of genomic and immune heterogeneity within the physical space of a tumor, with implications for biomarker evaluation and immunotherapy response.Gravity sensing provides a robust verticality signal for three-dimensional navigation. selleck chemicals Head direction cells in the mammalian limbic system implement an allocentric neuronal compass. Here we show that head-direction cells in the rodent thalamus, retrosplenial cortex and cingulum fiber bundle are tuned to conjunctive combinations of azimuth and tilt, i.e. pitch or roll. Pitch and roll orientation tuning is anchored to gravity and independent of visual landmarks. When the head tilts, azimuth tuning is affixed to the head-horizontal plane, but also uses gravity to remain anchored to the allocentric bearings in the earth-horizontal plane. Collectively, these results demonstrate that a three-dimensional, gravity-based, neural compass is likely a ubiquitous property of mammalian species, including ground-dwelling animals.Seed size is a key agronomic trait that greatly determines plant yield. Elucidating the molecular mechanism underlying seed size regulation is also an important question in developmental biology. Here, we show that the KIX-PPD-MYC-GIF1 pathway plays a crucial role in seed size control in Arabidopsis thaliana. Disruption of KIX8/9 and PPD1/2 causes large seeds due to increased cell proliferation and cell elongation in the integuments. KIX8/9 and PPD1/2 interact with transcription factors MYC3/4 to form the KIX-PPD-MYC complex in Arabidopsis. The KIX-PPD-MYC complex associates with the typical G-box sequence in the promoter of GRF-INTERACTING FACTOR 1 (GIF1), which promotes seed growth, and represses its expression. Genetic analyses support that KIX8/9, PPD1/2, MYC3/4, and GIF1 function in a common pathway to control seed size. Thus, our results reveal a genetic and molecular mechanism by which the transcription factors MYC3/4 recruit KIX8/9 and PPD1/2 to the promoter of GIF1 and repress its expression, thereby determining seed size in Arabidopsis.