Leukocyte trafficking in alveoli and airway passages

Many pulmonary diseases preferentially affect the large airways or the alveoli. Although the mechanisms are often particular to each disease process, site-specific differences in leukocyte trafficking and the regulation of inflammation also occur. Differences in the process of margination, sequestration, adhesion, and migration occur that can be attributed to differences in anatomy, hemodynamics, and the expression of proteins. The large airways are nourished by the bronchial circulation, whereas the pulmonary circulation feeds the distal lung parenchyma. The presence of different cell types in large airways from those in alveoli might contribute to site-specific differences in the molecular regulation of the inflammatory process

The detection of the imprint of filaments on cosmic microwave background lensing

Galaxy redshift surveys, such as 2dF, SDSS, 6df, GAMA and VIPERS, have shown that the spatial distribution of matter forms a rich web, known as the cosmic web. The majority of galaxy survey analyses measure the amplitude of galaxy clustering as a function of scale, ignoring information beyond a small number of summary statistics. Since the matter density field becomes highly non-Gaussian as structure evolves under gravity, we expect other statistical descriptions of the field to provide us with additional information. One way to study the non-Gaussianity is to study filaments, which evolve non-linearly from the initial density fluctuations produced in the primordial Universe. In our study, we report the first detection of CMB (Cosmic Microwave Background) lensing by filaments and we apply a null test to confirm our detection. Furthermore, we propose a phenomenological model to interpret the detected signal and we measure how filaments trace the matter distribution on large scales through filament bias, which we measure to be around 1.5. Our study provides a new scope to understand the environmental dependence of galaxy formation. In the future, the joint analysis of lensing and Sunyaev-Zel'dovich observations might reveal the properties of `missing baryons', the vast majority of the gas which resides in the intergalactic medium and has so far evaded most observations

Tailoring force sensitivity and selectivity by microstructure engineering of multidirectional electronic skins

Electronic skins (e-skins) with high sensitivity to multidirectional mechanical stimuli are crucial for healthcare monitoring devices, robotics, and wearable sensors. In this study, we present piezoresistive e-skins with tunable force sensitivity and selectivity to multidirectional forces through the engineered microstructure geometries (i.e., dome, pyramid, and pillar). Depending on the microstructure geometry, distinct variations in contact area and localized stress distribution are observed under different mechanical forces (i.e., normal, shear, stretching, and bending), which critically affect the force sensitivity, selectivity, response/relaxation time, and mechanical stability of e-skins. Microdome structures present the best force sensitivities for normal, tensile, and bending stresses. In particular, microdome structures exhibit extremely high pressure sensitivities over broad pressure ranges (47,062 kPa(-1) in the range of < 1 kPa, 90,657 kPa(-1) in the range of 1-10 kPa, and 30,214 kPa(-1) in the range of 10-26 kPa). On the other hand, for shear stress, micropillar structures exhibit the highest sensitivity. As proof-of-concept applications in healthcare monitoring devices, we show that our e-skins can precisely monitor acoustic waves, breathing, and human artery/carotid pulse pressures. Unveiling the relationship between the microstructure geometry of e-skins and their sensing capability would provide a platform for future development of high-performance microstructured e-skins

Augmentation index assessed by applanation tonometry is elevated in Marfan Syndrome

<p>Abstract</p> <p>Background</p> <p>To examine whether augmentation index (AIx) is increased in Marfan syndrome (MFS) and associated with increased aortic root size, and whether a peripheral-to-central generalised transfer function (GTF) can be applied usefully in MFS.</p> <p>Methods</p> <p>10 MFS patients and 10 healthy controls (matched for sex, age and height) were studied before and after 400 μg sub-lingual GTN. Arterial waveforms were recorded using applanation tonometry. AIx and pulse pressure (PP) were determined for the radial and carotid arteries. Pulse wave velocity (PWV) was measured between carotid and femoral arteries. GTFs were generated to examine the relationship between radial and carotid waveforms.</p> <p>Results</p> <p>AIx was greater in MFS compared to controls at radial (mean -31.4 (SD 14.3)% v -50.2(15.6)%, p = 0.003) and carotid (-7.6(11.2)% v -23.7(12.7)%, p = 0.004) sites. Baseline PP at all measurement sites, and PWV, did not differ between subject groups. Multivariate analysis demonstrated that PWV and carotid AIx were positively correlated with aortic root size (p < 0.001 and p = 0.012 respectively), independent of the presence of MFS. PP was not associated with aortic root size. GTN caused similar decreases in AIx in both controls and patients. Significant differences were found in GTFs between MFS and control subjects, which changed following GTN administration. However, when an independent GTF was used to derive carotid waves from radial waves, no differences were found in the degree of error between MFS and controls.</p> <p>Conclusion</p> <p>AIx is sensitive to the vascular abnormalities present in MFS, and may have a role as an adjunct to measurement of central PP and PWV. Differences between MFS and controls in the nature of the peripheral-to-central GTF are present, although have little effect on the pulse contour.</p

Analysis of SEC9 Suppression Reveals a Relationship of SNARE Function to Cell Physiology

BACKGROUND:Growth and division of Saccharomyces cerevisiae is dependent on the action of SNARE proteins that are required for membrane fusion. SNAREs are regulated, through a poorly understood mechanism, to ensure membrane fusion at the correct time and place within a cell. Although fusion of secretory vesicles with the plasma membrane is important for yeast cell growth, the relationship between exocytic SNAREs and cell physiology has not been established. METHODOLOGY/PRINCIPAL FINDINGS:Using genetic analysis, we identified several influences on the function of exocytic SNAREs. Genetic disruption of the V-ATPase, but not vacuolar proteolysis, can suppress two different temperature-sensitive mutations in SEC9. Suppression is unlikely due to increased SNARE complex formation because increasing SNARE complex formation, through overexpression of SRO7, does not result in suppression. We also observed suppression of sec9 mutations by growth on alkaline media or on a non-fermentable carbon source, conditions associated with a reduced growth rate of wild-type cells and decreased SNARE complex formation. CONCLUSIONS/SIGNIFICANCE:Three main conclusions arise from our results. First, there is a genetic interaction between SEC9 and the V-ATPase, although it is unlikely that this interaction has functional significance with respect to membrane fusion or SNAREs. Second, Sro7p acts to promote SNARE complex formation. Finally, Sec9p function and SNARE complex formation are tightly coupled to the physiological state of the cell

Did Clinical Trials in Which Erythropoietin Failed to Reduce Acute Myocardial Infarct Size Miss a Narrow Therapeutic Window?

Background: To test a hypothesis that in negative clinical trials of erythropoietin in patients with acute myocardial infarction (MI) the erythropoietin (rhEPO) could be administered outside narrow therapeutic window. Despite overwhelming evidence of cardioprotective properties of rhEPO in animal studies, the outcomes of recently concluded phase II clinical trials have failed to demonstrate the efficacy of rhEPO in patients with acute MI. However, the time between symptoms onset and rhEPO administration in negative clinical trials was much longer that in successful animal experiments. Methodology/Principal Findings: MI was induced in rats either by a permanent ligation of a descending coronary artery or by a 2-hr occlusion followed by a reperfusion. rhEPO, 3000 IU/kg, was administered intraperitoneally at the time of reperfusion, 4 hrs after beginning of reperfusion, or 6 hrs after permanent occlusion. MI size was measured histologically 24 hrs after coronary occlusion. The area of myocardium at risk was similar among groups. The MI size in untreated rats averaged,42 % of area at risk, or,24 % of left ventricle, and was reduced by more than 50 % (p,0.001) in rats treated with rhEPO at the time of reperfusion. The MI size was not affected by treatment administered 4 hrs after reperfusion or 6 hrs after permanent coronary occlusion. Therefore, our study in a rat experimental model of MI demonstrates that rhEPO administered within 2 hrs of a coronary occlusion effectively reduces MI size, but when rhEPO was administered following a delay similar to that encountered in clinical trials, it had no effect on MI size

Social Transmission of Avoidance Behavior under Situational Change in Learned and Unlearned Rats

BACKGROUND: Rats receive information from other conspecifics by observation or other types of social interaction. Such social interaction may contribute to the effective adaptation to changes of environment such as situational switching. Learning to avoid dangerous places or objects rapidly occurs with even a single conditioning session, and the conditioned memory tends to be sustained over long periods. The avoidance is important for adaptation, but the details of the conditions under which the social transmission of avoidance is formed are unknown. We demonstrate that the previous experience of avoidance learning is important for the formation of behaviors for social transmission of avoidance and that the experienced rats adapt to a change of situation determined by the presence or absence of aversive stimuli. We systematically investigated social influence on avoidance behavior using a passive avoidance test in a light/dark two-compartment apparatus. METHODOLOGY/PRINCIPAL FINDINGS: Rats were divided into two groups, one receiving foot shocks and another with no aversive experience in a dark compartment. Experienced and inexperienced rats were further divided into subjects and partners. In Experiment 1, each subject experienced (1) interaction with an experienced partner, (2) interaction with an inexperienced partner, or (3) no interaction. In Experiment 2, each subject experienced interaction with a partner that received a shock. The entering latency to a light compartment was measured. The avoidance behavior of experienced rats was inhibited by interaction with inexperienced or experienced partners in a safely-changed situation. The avoidance of experienced rats was reinstated in a dangerously-changed situation by interaction with shocked rats. In contrast, the inexperienced rats were not affected by any social circumstances. CONCLUSIONS/SIGNIFICANCE: These results suggest that transmitted information among rats can be updated under a situational change and that the previous experience is crucial for social enhancement and inhibition of avoidance behavior in rats

Strain dyssynchrony index determined by three-dimensional speckle area tracking can predict response to cardiac resynchronization therapy

<p>Abstract</p> <p><b>Background</b></p> <p>We have previously reported strain dyssynchrony index assessed by two-dimensional speckle tracking strain, and a marker of both dyssynchrony and residual myocardial contractility, can predict response to cardiac resynchronization therapy (CRT). A newly developed three-dimensional (3-D) speckle tracking system can quantify endocardial area change ratio (area strain), which coupled with the factors of both longitudinal and circumferential strain, from all 16 standard left ventricular (LV) segments using complete 3-D pyramidal datasets. Our objective was to test the hypothesis that strain dyssynchrony index using area tracking (ASDI) can quantify dyssynchrony and predict response to CRT.</p> <p><b>Methods</b></p> <p>We studied 14 heart failure patients with ejection fraction of 27 ± 7% (all≤35%) and QRS duration of 172 ± 30 ms (all≥120 ms) who underwent CRT. Echocardiography was performed before and 6-month after CRT. ASDI was calculated as the average difference between peak and end-systolic area strain of LV endocardium obtained from 3-D speckle tracking imaging using 16 segments. Conventional dyssynchrony measures were assessed by interventricular mechanical delay, Yu Index, and two-dimensional radial dyssynchrony by speckle-tracking strain. Response was defined as a ≥15% decrease in LV end-systolic volume 6-month after CRT.</p> <p>Results</p> <p>ASDI ≥ 3.8% was the best predictor of response to CRT with a sensitivity of 78%, specificity of 100% and area under the curve (AUC) of 0.93 (p < 0.001). Two-dimensional radial dyssynchrony determined by speckle-tracking strain was also predictive of response to CRT with an AUC of 0.82 (p < 0.005). Interestingly, ASDI ≥ 3.8% was associated with the highest incidence of echocardiographic improvement after CRT with a response rate of 100% (7/7), and baseline ASDI correlated with reduction of LV end-systolic volume following CRT (r = 0.80, p < 0.001).</p> <p><b>Conclusions</b></p> <p>ASDI can predict responders and LV reverse remodeling following CRT. This novel index using the 3-D speckle tracking system, which shows circumferential and longitudinal LV dyssynchrony and residual endocardial contractility, may thus have clinical significance for CRT patients.</p

Architecture of the RNA polymerase–Spt4/5 complex and basis of universal transcription processivity

Spt5 and NusG play a conserved role in stimulating RNA polymerase II transcription elongation and processivity. Here, the crystal structure of Spt4/5 bound to the RNA polymerase clamp domain reveals that the factor binds above DNA and RNA in the active centre cleft preventing premature dissociation of the polymerase

Involvement of RhoA-mediated Ca(2+ )sensitization in antigen-induced bronchial smooth muscle hyperresponsiveness in mice

BACKGROUND: It has recently been suggested that RhoA plays an important role in the enhancement of the Ca(2+ )sensitization of smooth muscle contraction. In the present study, a participation of RhoA-mediated Ca(2+ )sensitization in the augmented bronchial smooth muscle (BSM) contraction in a murine model of allergic asthma was examined. METHODS: Ovalbumin (OA)-sensitized BALB/c mice were repeatedly challenged with aerosolized OA and sacrificed 24 hours after the last antigen challenge. The contractility and RhoA protein expression of BSMs were measured by organ-bath technique and immunoblotting, respectively. RESULTS: Repeated OA challenge to sensitized mice caused a BSM hyperresponsiveness to acetylcholine (ACh), but not to high K(+)-depolarization. In α-toxin-permeabilized BSMs, ACh induced a Ca(2+ )sensitization of contraction, which is sensitive to Clostridium botulinum C3 exoenzyme, indicating that RhoA is implicated in this Ca(2+ )sensitization. Interestingly, the ACh-induced, RhoA-mediated Ca(2+ )sensitization was significantly augmented in permeabilized BSMs of OA-challenged mice. Moreover, protein expression of RhoA was significantly increased in the hyperresponsive BSMs. CONCLUSION: These findings suggest that the augmentation of Ca(2+ )sensitizing effect, probably via an up-regulation of RhoA protein, might be involved in the enhanced BSM contraction in antigen-induced airway hyperresponsiveness