Myosin VI and its binding partner optineurin are involved in secretory vesicle fusion at the plasma membrane.

During constitutive secretion, proteins synthesized at the endoplasmic reticulum (ER) are transported to the Golgi complex for processing and then to the plasma membrane for incorporation or extracellular release. This study uses a unique live-cell constitutive secretion assay to establish roles for the molecular motor myosin VI and its binding partner optineurin in discrete stages of secretion. Small interfering RNA-based knockdown of myosin VI causes an ER-to-Golgi transport delay, suggesting an unexpected function for myosin VI in the early secretory pathway. Depletion of myosin VI or optineurin does not affect the number of vesicles leaving the trans-Golgi network (TGN), indicating that these proteins do not function in TGN vesicle formation. However, myosin VI and optineurin colocalize with secretory vesicles at the plasma membrane. Furthermore, live-cell total internal reflection fluorescence microscopy demonstrates that myosin VI or optineurin depletion reduces the total number of vesicle fusion events at the plasma membrane and increases both the proportion of incomplete fusion events and the number of docked vesicles in this region. These results suggest a novel role for myosin VI and optineurin in regulation of fusion pores formed between secretory vesicles and the plasma membrane during the final stages of secretion

Dynamic exchange of myosin VI on endocytic structures.

The actin-based molecular motor myosin VI functions in the endocytic uptake pathway, both during the early stages of clathrin-mediated uptake and in later transport to/from early endosomes. This study uses fluorescence recovery after photobleaching (FRAP) to examine the turnover rate of myosin VI during endocytosis. The results demonstrate that myosin VI turns over dynamically on endocytic structures with a characteristic half-life common to both the large insert isoform of myosin VI on clathrin-coated structures and the no-insert isoform on early endosomes. This half-life is shared by the myosin VI-binding partner Dab2 and is identical for full-length myosin VI and the cargo-binding tail region. The 4-fold slower half-life of an artificially dimerized construct of myosin VI on clathrin-coated structures suggests that wild type myosin VI does not function as a stable dimer, but either as a monomer or in a monomer/dimer equilibrium. Taken together, these FRAP results offer insight into both the basic turnover dynamics and the monomer/dimer nature of myosin VI

Dynamic subcanopy leaf traits drive resistance of net primary production across a disturbance severity gradient

Across the globe, the forest carbon sink is increasingly vulnerable to an expanding array of low- to moderate-severity disturbances. However, some forest ecosystems exhibit functional resistance (i.e., the capacity of ecosystems to continue functioning as usual) following disturbances such as extreme weather events and insect or fungal pathogen outbreaks. Unlike severe disturbances (e.g., stand-replacing wildfires), moderate severity disturbances do not always result in near-term declines in forest production because of the potential for compensatory growth, including enhanced subcanopy production. Community-wide shifts in subcanopy plant functional traits, prompted by disturbance-driven environmental change, may play a key mechanistic role in resisting declines in net primary production (NPP) up to thresholds of canopy loss. However, the temporal dynamics of these shifts, as well as the upper limits of disturbance for which subcanopy production can compensate, remain poorly characterized. In this study, we leverage a 4-year dataset from an experimental forest disturbance in northern Michigan to assess subcanopy community trait shifts as well as their utility in predicting ecosystem NPP resistance across a wide range of implemented disturbance severities. Through mechanical girdling of stems, we achieved a gradient of severity from 0% (i.e., control) to 45, 65, and 85% targeted gross canopy defoliation, replicated across four landscape ecosystems broadly representative of the Upper Great Lakes ecoregion. We found that three of four examined subcanopy community weighted mean (CWM) traits including leaf photosynthetic rate (p = 0.04), stomatal conductance (p = 0.07), and the red edge normalized difference vegetation index (p < 0.0001) shifted rapidly following disturbance but before widespread changes in subcanopy light environment triggered by canopy tree mortality. Surprisingly, stimulated subcanopy production fully compensated for upper canopy losses across our gradient of experimental severities, achieving complete resistance (i.e., no significant interannual differences from control) of whole ecosystem NPP even in the 85% disturbance treatment. Additionally, we identified a probable mechanistic switch from nutrient-driven to light-driven trait shifts as disturbance progressed. Our findings suggest that remotely sensed traits such as the red edge normalized difference vegetation index (reNDVI) could be particularly sensitive and robust predictors of production response to disturbance, even across compositionally diverse forests. The potential of leaf spectral indices to predict post-disturbance functional resistance is promising given the capabilities of airborne to satellite remote sensing. We conclude that dynamic functional trait shifts following disturbance can be used to predict production response across a wide range of disturbance severities

Long-term surveillance study of rituximab originator treated patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA)

Lay Summary: What does this mean for patients? Rituximab is used to treat active disease and to prevent relapses in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). Serious complications, including infections, low natural antibody levels, cancers, low white blood cell levels, heart disease and blood clots are common in AAV patients in general. Whether these complications are more or less common with rituximab is unclear. This study assessed the frequency of serious complications and compared time to first serious complications between patients, either treated with or without rituximab. Over 40% of the patients in this study experienced at least one serious complication. Overall, first serious complication occurred earlier and higher risk of serious infection was seen in rituximab patients. However, these findings should be interpreted with caution as the rituximab patients had been diagnosed with vasculitis for longer and had received a greater amount of immunosuppression in the past, compared with the patients who had not been treated with rituximab

Age, puberty and attractiveness judgments in adolescents

Previous work has suggested that judgments of the attractiveness of some facial and vocal features change during adolescence. Here, over 70 Czech adolescents aged 12–14 made forced-choice attractivenessjudgments on adolescent faces manipulated in symmetry, averageness and femininity, and on adolescent opposite-sex voices manipulated in fundamental frequency (perceived as pitch), and completed questionnaires on pubertal development. Consistent with typical adult judgments, adolescents selected the symmetric, average and feminine male and female faces as more attractive significantly more often than the asymmetric, non-average and masculine faces respectively. Moreover, preferences for symmetric faces were positively associated with adolescents’ age and stage of pubertal development. Unexpectedly, voice pitch did not significantly influence adolescents’ attractivenessjudgments. Collectively, these findings present new evidence using refined methodology that adolescent development is related to variation in attractivenessjudgments

Applying the Risk of Bias Tool in a Systematic Review of Combination Long-Acting Beta-Agonists and Inhaled Corticosteroids for Persistent Asthma

Background: The Risk of Bias (RoB) tool is used to assess internal validity of randomized controlled trials (RCTs). Our objectives were to: 1) evaluate inter-rater agreement of the RoB tool; 2) determine the time to access supplemental study information; 3) compare the RoB tool with the Jadad scale and Schulz allocation concealment (AC); and 4) examine the relationship between RoB and effect estimates. Methods: We conducted a systematic review of long-acting beta agonists (LABA) combined with inhaled corticosteroids (ICS) for adults with persistent asthma. Two reviewers independently assessed 107 trials using RoB, Jadad, and AC. One reviewer searched for study protocols. We assessed inter-rater agreement using weighted Kappa (k) and the correlation between tools using Kendall’s Tau (t). Mean differences in effect sizes for RCTs with different RoB were calculated using inverse variance method and random effects model. Results: Trials had good Jadad scores (median 4, IQR 3-4); however, 85 % had unclear AC and 87 % high RoB. The factor that most influenced RoB was the potential inappropriate influence of study sponsors (95 % industry funded). Agreement on RoB domains was fair (k = 0.40) to almost perfect (k = 0.86), and moderate for overall RoB (k = 0.41). Median time to complete RoB assessments was 21 minutes (IQR 14-27) and 12 minutes (IQR 9-16) to search for protocols. Protocols were identified for 5/42 studies (12%); in 3 cases the assessment of selective outcome reporting changed. There was low correlation between overall RoB vs. Jadad (t =0.04

Kinetic properties and small-molecule inhibition of human myosin-6.

Myosin-6 is an actin-based motor protein that moves its cargo towards the minus-end of actin filaments. Mutations in the gene encoding the myosin-6 heavy chain and changes in the cellular abundance of the protein have been linked to hypertrophic cardiomyopathy, neurodegenerative diseases, and cancer. Here, we present a detailed kinetic characterization of the human myosin-6 motor domain, describe the effect of 2,4,6-triiodophenol on the interaction of myosin-6 with F-actin and nucleotides, and show how addition of the drug reduces the number of myosin-6-dependent vesicle fusion events at the plasma membrane during constitutive secretion

V838 Monocerotis: A Geometric Distance from Hubble Space Telescope Polarimetric Imaging of its Light Echo

Following the outburst of the unusual variable star V838 Monocerotis in 2002, a spectacular light echo appeared. A light echo provides the possibility of direct geometric distance determination, because it should contain a ring of highly linearly polarized light at a linear radius of ct, where t is the time since the outburst. We present imaging polarimetry of the V838 Mon light echo, obtained in 2002 and 2005 with the Advanced Camera for Surveys onboard the Hubble Space Telescope, which confirms the presence of the highly polarized ring. Based on detailed modeling that takes into account the outburst light curve, the paraboloidal echo geometry, and the physics of dust scattering and polarization, we find a distance of 6.1+-0.6 kpc. The error is dominated by the systematic uncertainty in the scattering angle of maximum linear polarization, taken to be theta_{max}=90^o +- 5^o. The polarimetric distance agrees remarkably well with a distance of 6.2+-1.5 kpc obtained from the entirely independent method of main-sequence fitting to a sparse star cluster associated with V838 Mon. At this distance, V838 Mon at maximum light had M_V\simeq-9.8, making it temporarily one of the most luminous stars in the Local Group. Our validation of the polarimetric method offers promise for measurement of extragalactic distances using supernova light echoes.Comment: 43 pages, 17 figures, 3 tables; accepted for publication in the Astronomical Journal. Version with high-quality figures available at http://www.stsci.edu/~bond/v838monpolariz.pd

An Experimental Study of Cryptocurrency Market Dynamics

As cryptocurrencies gain popularity and credibility, marketplaces for cryptocurrencies are growing in importance. Understanding the dynamics of these markets can help to assess how viable the cryptocurrnency ecosystem is and how design choices affect market behavior. One existential threat to cryptocurrencies is dramatic fluctuations in traders' willingness to buy or sell. Using a novel experimental methodology, we conducted an online experiment to study how susceptible traders in these markets are to peer influence from trading behavior. We created bots that executed over one hundred thousand trades costing less than a penny each in 217 cryptocurrencies over the course of six months. We find that individual "buy" actions led to short-term increases in subsequent buy-side activity hundreds of times the size of our interventions. From a design perspective, we note that the design choices of the exchange we study may have promoted this and other peer influence effects, which highlights the potential social and economic impact of HCI in the design of digital institutions.Comment: CHI 201