A protein interaction map for cell polarity development

Many genes required for cell polarity development in budding yeast have been identified and arranged into a functional hierarchy. Core elements of the hierarchy are widely conserved, underlying cell polarity development in diverse eukaryotes. To enumerate more fully the protein–protein interactions that mediate cell polarity development, and to uncover novel mechanisms that coordinate the numerous events involved, we carried out a large-scale two-hybrid experiment. 68 Gal4 DNA binding domain fusions of yeast proteins associated with the actin cytoskeleton, septins, the secretory apparatus, and Rho-type GTPases were used to screen an array of yeast transformants that express ∼90% of the predicted Saccharomyces cerevisiae open reading frames as Gal4 activation domain fusions. 191 protein–protein interactions were detected, of which 128 had not been described previously. 44 interactions implicated 20 previously uncharacterized proteins in cell polarity development. Further insights into possible roles of 13 of these proteins were revealed by their multiple two-hybrid interactions and by subcellular localization. Included in the interaction network were associations of Cdc42 and Rho1 pathways with proteins involved in exocytosis, septin organization, actin assembly, microtubule organization, autophagy, cytokinesis, and cell wall synthesis. Other interactions suggested direct connections between Rho1- and Cdc42-regulated pathways; the secretory apparatus and regulators of polarity establishment; actin assembly and the morphogenesis checkpoint; and the exocytic and endocytic machinery. In total, a network of interactions that provide an integrated response of signaling proteins, the cytoskeleton, and organelles to the spatial cues that direct polarity development was revealed

Host Immune Transcriptional Profiles Reflect the Variability in Clinical Disease Manifestations in Patients with Staphylococcus aureus Infections

Staphylococcus aureus infections are associated with diverse clinical manifestations leading to significant morbidity and mortality. To define the role of the host response in the clinical manifestations of the disease, we characterized whole blood transcriptional profiles of children hospitalized with community-acquired S. aureus infection and phenotyped the bacterial strains isolated. The overall transcriptional response to S. aureus infection was characterized by over-expression of innate immunity and hematopoiesis related genes and under-expression of genes related to adaptive immunity. We assessed individual profiles using modular fingerprints combined with the molecular distance to health (MDTH), a numerical score of transcriptional perturbation as compared to healthy controls. We observed significant heterogeneity in the host signatures and MDTH, as they were influenced by the type of clinical presentation, the extent of bacterial dissemination, and time of blood sampling in the course of the infection, but not by the bacterial isolate. System analysis approaches provide a new understanding of disease pathogenesis and the relation/interaction between host response and clinical disease manifestations

Performance and characterization of the SPT-3G digital frequency-domain multiplexed readout system using an improved noise and crosstalk model

The third-generation South Pole Telescope camera (SPT-3G) improves upon its predecessor (SPTpol) by an order of magnitude increase in detectors on the focal plane. The technology used to read out and control these detectors, digital frequency-domain multiplexing (DfMUX), is conceptually the same as used for SPTpol, but extended to accommodate more detectors. A nearly 5× expansion in the readout operating bandwidth has enabled the use of this large focal plane, and SPT-3G performance meets the forecasting targets relevant to its science objectives. However, the electrical dynamics of the higher-bandwidth readout differ from predictions based on models of the SPTpol system due to the higher frequencies used and parasitic impedances associated with new cryogenic electronic architecture. To address this, we present an updated derivation for electrical crosstalk in higher-bandwidth DfMUX systems and identify two previously uncharacterized contributions to readout noise, which become dominant at high bias frequency. The updated crosstalk and noise models successfully describe the measured crosstalk and readout noise performance of SPT-3G. These results also suggest specific changes to warm electronics component values, wire-harness properties, and SQUID parameters, to improve the readout system for future experiments using DfMUX, such as the LiteBIRD space telescope

The Prevalence of Social and Behavioral Topics and Related Educational Opportunities During Attending Rounds

PurposeTo quantify the prevalence of social and behavioral sciences (SBS) topics during patient care and to rate team response to these topics once introduced.MethodThis cross-sectional study used five independent raters to observe 80 inpatient ward teams on internal medicine and pediatric services during attending rounds at two academic hospitals over a five-month period. Patient-level primary outcomes-prevalence of SBS topic discussions and rate of positive responses to discussions-were captured using an observational tool and summarized at the team level using hierarchical models. Teams were scored on patient- and learner-centered behaviors.ResultsObservations were made of 80 attendings, 83 residents, 75 interns, 78 medical students, and 113 allied health providers. Teams saw a median of 8.0 patients per round (collectively, 622 patients), and 97.1% had at least one SBS topic arise (mean = 5.3 topics per patient). Common topics were pain (62%), nutrition (53%), social support (52%), and resources (39%). After adjusting for team characteristics, the number of discussion topics raised varied significantly among the four services and was associated with greater patient-centeredness. When topics were raised, 38% of teams' responses were positive. Services varied with respect to learner- and patient-centeredness, with most services above average for learner-centered, and below average for patient-centered behaviors.ConclusionsOf 30 SBS topics tracked, some were addressed commonly and others rarely. Multivariable analyses suggest that medium-sized teams can address SBS concerns by increasing time per patient and consistently adopting patient-centered behaviors

Influenza Neuraminidase Inhibitors: Structure-Based Design of a Novel Inhibitor Series

Combinatorial and structure-based medicinal chemistry strategies were used together to advance a lead compound with an activity of Ki = 58 μM via a potency enhancement of < 70 000-fold to an analogue with an activity of Ki = 0.8 nM against influenza neu

Effect of Swell on Wind Stress for Light to Moderate Winds

AbstractBuoy observations from a 1999 Gulf of Mexico field program (GOM99) are used to investigate the relationships among friction velocityu*, wind speedU, and amount of swell present. AU–u*seaparameterization is developed for the case of pure wind sea (denoted byu*sea), which is linear inUover the range of available winds (2–16 m s−1). The curve shows no sign of an inflection point near 7–8 m s−1as suggested in a 2012 paper by Andreas et al. on the basis of a transition from smooth to rough flow. When observations containing more than minimal swell energy are included, a differentU–u*equation forU< 8 m s−1is found, which would intersect the pure wind-sea curve about 7–8 m s−1. These two relationships yield a bilinear curve similar to Andreas et al. with an apparent inflection near 7–8 m s−1. The absence of the inflection in the GOM99 experiment pure wind-sea curve and the similarity of the GOM99 swell-dominated low wind speed to Andreas et al.’s low wind speed relationship suggest that the inflection may be due to the effect of swell and not a flow transition. Swell heights in the range of only 25–50 cm may be sufficient to impact stress at low wind speeds

Novel Kunitz-like Peptides Discovered in the Zoanthid <i>Palythoa caribaeorum</i> through Transcriptome Sequencing

<i>Palythoa caribaeorum</i> (class Anthozoa) is a zoanthid that together jellyfishes, hydra, and sea anemones, which are venomous and predatory, belongs to the Phyllum Cnidaria. The distinguished feature in these marine animals is the cnidocytes in the body tissues, responsible for toxin production and injection that are used majorly for prey capture and defense. With exception for other anthozoans, the toxin cocktails of zoanthids have been scarcely studied and are poorly known. Here, on the basis of the analysis of <i>P. caribaeorum</i> transcriptome, numerous predicted venom-featured polypeptides were identified including allergens, neurotoxins, membrane-active, and Kunitz-like peptides (PcKuz). The three predicted PcKuz isotoxins (1–3) were selected for functional studies. Through computational processing comprising structural phylogenetic analysis, molecular docking, and dynamics simulation, PcKuz3 was shown to be a potential voltage gated potassium-channel inhibitor. PcKuz3 fitted well as new functional Kunitz-type toxins with strong antilocomotor activity as <i>in vivo</i> assessed in zebrafish larvae, with weak inhibitory effect toward proteases, as evaluated <i>in vitro</i>. Notably, PcKuz3 can suppress, at low concentration, the 6-OHDA-induced neurotoxicity on the locomotive behavior of zebrafish, which indicated PcKuz3 may have a neuroprotective effect. Taken together, PcKuz3 figures as a novel neurotoxin structure, which differs from known homologous peptides expressed in sea anemone. Moreover, the novel PcKuz3 provides an insightful hint for biodrug development for prospective neurodegenerative disease treatment