The general secretory, or Sec, system is a primary protein export pathway from the cytosol of Escherichia coli and all eubacteria. Integral membrane protein complex SecDF is a translocation factor ...that enhances polypeptide secretion, which is driven by the Sec translocase, consisting of translocon SecYEG and ATPase SecA. SecDF is thought to utilize a proton gradient to effectively pull precursor proteins from the cytoplasm into the periplasm. Working models have been developed to describe the structure and function of SecDF, but important mechanistic questions remain unanswered. Atomic force microscopy (AFM) is a powerful technique for studying the dynamics of single-molecule systems including membrane proteins in near-native conditions. The sharp tip of the AFM provides direct access to membrane-external protein conformations. Here, we acquired AFM images and kymographs (∼100 ms resolution) to visualize SecDF protrusions in near-native supported lipid bilayers and compared the experimental data to simulated AFM images based on static structures. When studied in isolation, SecDF exhibited a stable and compact conformation close to the lipid bilayer surface, indicative of a resting state. Interestingly, upon SecYEG introduction, we observed changes in both SecDF conformation and conformational dynamics. The population of periplasmic protrusions corresponding to an intermediate form of SecDF, which is thought to be active in precursor protein handling, increased more than ninefold. In conjunction, our dynamics measurements revealed an enhancement in the transition rate between distinct SecDF conformations when the translocon was present. Together, this work provides a novel vista of basal-level SecDF conformational dynamics in near-native conditions.
There is limited evidence linking airway inflammation and lung function impairment in older non-smoking asthmatics with fixed airflow obstruction (FAO), which can develop despite treatment with ...inhaled corticosteroids (ICS). We assessed lung function (spirometry, forced oscillation technique (FOT)), lung elastic recoil and airway inflammation using bronchoalveolar lavage (BAL) in non-smoking adult asthmatics with FAO, following 2 months treatment with high-dose ICS/long-acting beta-agonist. Subjects demonstrated moderate FAO, abnormal FOT indices and loss of lung elastic recoil. This cross-sectional study showed a lack of a relationship between BAL neutrophils, eosinophils, inflammatory cytokines and lung function impairment. Other inflammatory pathways or the effect of inflammation on lung function over time may explain FAO development.
Typical responses of cortical neurons to identical sensory stimuli appear highly variable. It has thus been proposed that the cortex primarily uses a rate code. However, other studies have argued for ...spike-time coding under certain conditions. The potential role of spike-time coding is directly limited by the internally generated variability of cortical circuits, which remains largely unexplored. Here, we quantify this internally generated variability using a biophysical model of rat neocortical microcircuitry with biologically realistic noise sources. We find that stochastic neurotransmitter release is a critical component of internally generated variability, causing rapidly diverging, chaotic recurrent network dynamics. Surprisingly, the same nonlinear recurrent network dynamics can transiently overcome the chaos in response to weak feed-forward thalamocortical inputs, and support reliable spike times with millisecond precision. Our model shows that the noisy and chaotic network dynamics of recurrent cortical microcircuitry are compatible with stimulus-evoked, millisecond spike-time reliability, resolving a long-standing debate.
There is a need for psychometrically sound measures of children’s participation in recreation and leisure activities, for both clinical and research purposes. This paper provides information about ...the construct validity of the Children’s Assessment of Participation and Enjoyment (CAPE) and its companion measure, Preferences for Activities of Children (PAC). These measures are appropriate for children and youth with and without disabilities between the ages of 6 and 21 years. They provide information about six dimensions of participation (i.e. diversity, intensity, where, with whom, enjoyment and preference) and two categories of recreation and leisure activities: (i) formal and informal activities; and (ii) five types of activities (recreational, active physical, social, skill‐based and self‐improvement). This paper presents information about the performance of the CAPE and PAC activity type scores using data from a study involving 427 children with physical disabilities between the ages of 6 and 15 years. Intensity, enjoyment and preference scores were significantly correlated with environmental, family and child variables, in expected ways. Predictions also were supported with respect to differences in mean scores for boys vs. girls, and children in various age groups. The information substantiates the construct validity of the measures. The clinical and research utility of the measures are discussed.
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Asthma and COPD make up the majority of obstructive airways diseases (OADs), which affects ∼11 % of the population. The main drugs used to treat OADs have not changed in the past five ...decades, with advancements mainly comprising variations on existing treatments. The recent biologics are beneficial to only specific subsets of patients. Part of this may lie in our inability to adequately characterise the tremendous heterogeneity in every aspect of OAD. The field is currently moving towards the concept of personalised medicine, based on a focus on treatable traits that are objective, measurable and modifiable. We propose extending this concept via the use of emerging clinical tools for comprehensive physiological phenotyping. We describe, based on published data, the evidence for the use of functional imaging, gas washout techniques and oscillometry, as well as potential future applications, to more comprehensively assess and predict treatment response in OADs. In this way, we hope to demonstrate how physiological phenotyping tools will improve the way in which drugs are prescribed, but most importantly, will facilitate development of new drugs for OADs.
Although most diffusion research focuses on firms adopting new practices to maintain their legitimacy, this paper examines a setting in which firms adopted a controversial practice to defend ...themselves against challenges relating to corporate deviance. We argue that understanding defensive adoption requires attending to both the dynamics of organizational stigma and impression management, and test our theoretical claims by analysing the diffusion of an accounting practice, stock option expensing (SOPEX), following the Enron scandal. We first provide evidence that the media and shareholder activists transformed the practice into a defensive device by theorizing it as a solution to problems relating to corporate fraud and corporate governance. Using event history analysis, we then show that corporations that became targets of stigma‐inducing threats were more likely to adopt SOPEX and that the media were a key force channelling these threats.
We present first results from RoboPol, a novel-design optical polarimeter operating at the Skinakas Observatory in Crete. The data, taken during the 2013 May–June commissioning of the instrument, ...constitute a single-epoch linear polarization survey of a sample of gamma-ray-loud blazars, defined according to unbiased and objective selection criteria, easily reproducible in simulations, as well as a comparison sample of, otherwise similar, gamma-ray-quiet blazars. As such, the results of this survey are appropriate for both phenomenological population studies and for tests of theoretical population models. We have measured polarization fractions as low as 0.015 down to R-mag of 17 and as low as 0.035 down to 18 mag. The hypothesis that the polarization fractions of gamma-ray-loud and gamma-ray-quiet blazars are drawn from the same distribution is rejected at the 3σ level. We therefore conclude that gamma-ray-loud and gamma-ray-quiet sources have different optical polarization properties. This is the first time this statistical difference is demonstrated in optical wavelengths. The polarization fraction distributions of both samples are well described by exponential distributions with averages of
$\langle p \rangle =6.4 ^{+0.9}_{-0.8}\times 10^{-2}$
for gamma-ray-loud blazars, and
$\langle p \rangle =3.2 ^{+2.0}_{-1.1}\times 10^{-2}$
for gamma-ray-quiet blazars. The most probable value for the difference of the means is
$3.4^{+1.5}_{-2.0}\times 10^{-2}$
. The distribution of polarization angles is statistically consistent with being uniform.
We present first results on polarization swings in optical emission of blazars obtained by RoboPol, a monitoring programme of an unbiased sample of gamma-ray bright blazars specially designed for ...effective detection of such events. A possible connection of polarization swing events with periods of high activity in gamma-rays is investigated using the data set obtained during the first season of operation. It was found that the brightest gamma-ray flares tend to be located closer in time to rotation events, which may be an indication of two separate mechanisms responsible for the rotations. Blazars with detected rotations during non-rotating periods have significantly larger amplitude and faster variations of polarization angle than blazars without rotations. Our simulations show that the full set of observed rotations is not a likely outcome (probability ≤1.5 × 10−2) of a random walk of the polarization vector simulated by a multicell model. Furthermore, it is highly unlikely (∼5 × 10−5) that none of our rotations is physically connected with an increase in gamma-ray activity.
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