Substantial Attenuation Research Articles

DNMT and HDAC inhibitors together abrogate endotoxemia mediated macrophage death by STAT3-JMJD3 signaling.

Acute lung injury (ALI) is a common complication of sepsis that often leads to fatal lung disease without effective therapies. It is known that bone marrow derived macrophages are important in resolving the inflammation and maintaining tissue homeostasis. Here, we hypothesize that treatment in combination of DNA methyl transferase inhibitor (DNMTi) 5-Aza 2-deoxycytidine (Aza) and histone deacetylase inhibitor (HDACi) Trichostatin A (TSA) mitigates the inflammation induced pyroptosis and apoptosis during endotoxemia induced ALI. To test this hypothesis, the mice challenged with a sublethal dose of LPS followed by one-hour post-treatment with a single dose of Aza and TSA intraperitoneally showed a substantial attenuation of apoptosis and inflammation. Importantly, we observed significant changes in the mitochondrial membrane structure, and lower levels of DNA fragmentation, reduced expression of apoptotic and pyroptotic genes both transcriptionally and translationally in LPS induced BMDMs treated by a combination of Aza and TSA than in LPS-induced BMDMs treated with either drug alone. The protection was mediated by an inhibition of JNK-ERK and STAT3-JMJD3 activated pathways. Thus, targeting these important signaling pathways with the combination of Aza and TSA would be a good treatment modality for ALI.

Violent flows in aqueous foams III: physical multi-phase model comparison with aqueous foam shock tube experiments

Mitigation of blast waves in aqueous foams is a problem that has a strong dependence on multi-phase effects. Here, a simplified model is developed from the previous articles treating violent flows (D’Alesio et al. in Eur J Mech B Fluids 54:105–124, 2015; Faure and Ghidaglia in Eur J Mech B Fluids 30:341–359, 2011) to capture the essential phenomena. The key is to have two fluids with separate velocities to represent the liquid and gas phases. This allows for the interaction between the two phases, which may include terms for drag, heat transfer, mass transfer due to phase change, added mass effects, to be included explicitly in the model. A good test for the proposed model is provided by two experimental data sets that use a specially designed shock tube. The first experiment has a test section filled with spray droplets, and the second has a range of aqueous foams in the test section. A substantial attenuation of the shock wave is seen in both cases, but a large difference is observed in the sound speeds. The droplets cause no observable change from the air sound speed, while the foams have a reduced sound speed of approximately 50–75 $$\hbox {m}/\hbox {s}$$ . In the model given here, an added mass term is introduced in the governing equations to capture the low sound speed. The match between simulation and experiment is found to be satisfactory for both droplets and the foam. This is especially good when considering the complexity of the physics and the effects that are unaccounted for, such as three-dimensionality and droplet atomisation. The resulting statistics illuminate the processes occurring in such flows.

On the origin of gamma-rays in Fermi blazars: beyondthe broad-line region

The gamma-ray emission in broad-line blazars is generally explained as inverse Compton (IC) radiation of relativistic electrons in the jet scattering optical-UV photons from the Broad Line Region (BLR), the so-called BLR External Compton scenario. We test this scenario on the Fermi gamma-ray spectra of 106 broad-line blazars detected with the highest significance or largest BLR, by looking for cut-off signatures at high energies compatible with gamma-gamma interactions with BLR photons. We do not find evidence for the expected BLR absorption. For 2/3 of the sources, we can exclude any significant absorption ($\tau_{max}<1$), while for the remaining 1/3 the possible absorption is constrained to be 1.5-2 orders of magnitude lower than expected. This result holds also dividing the spectra in high and low-flux states, and for powerful blazars with large BLR. Only 1 object out of 10 seems compatible with substantial attenuation ($\tau_{max}>5$). We conclude that for 9 out of 10 objects, the jet does not interact with BLR photons. Gamma-rays seem either produced outside the BLR most of the time, or the BLR is ~100x larger than given by reverberation mapping. This means that i) External Compton on BLR photons is disfavoured as the main gamma-ray mechanism, vs IC on IR photons from the torus or synchrotron self-Compton; ii) the Fermi gamma-ray spectrum is mostly intrinsic, determined by the interaction of the particle distribution with the seed-photons spectrum; iii) without suppression by the BLR, broad-line blazars can become copious emitters above 100 GeV, as demonstrated by 3C454.3. We expect the CTA sky to be much richer of broad-line blazars than previously thought.

Childhood Risk Factors for Heavy Episodic Alcohol Use and Alcohol Problems in Late Adolescence: A Marginal Structural Model Analysis.

This study seeks to clarify the nature of the association between five well-studied late childhood predictors and alcohol-related behaviors in adolescence. We examined, in 7,168 subjects from the Avon Longitudinal Study of Parents and Children (ALSPAC), using linear probability and marginal structural models, the association between parental alcohol problems, peer group deviance, antisocial behavior, and low parental monitoring, and sensation seeking assessed at multiple times from ages 12.5 to 18 years and heavy episodic drinking and alcohol problems at ages 16.5, 17.5, and 20 years. Based on the pattern of the attenuation in the association with heavy episodic drinking and alcohol problems from the linear probability to marginal structural models, our five factors were divisible into three groups. For parental alcohol problems, no substantial attenuation was seen. For peer group deviance and antisocial behavior, the associations in the marginal structural models were modestly attenuated (10%-20%). By contrast, for low parental monitoring and sensation seeking, moderate attenuations of 41% and 35%, respectively, were observed. Our results are consistent with the hypothesis that all or nearly all of the association between parental alcohol problems and heavy episodic drinking and alcohol problems in mid to late adolescence is causal. For peer group deviance and antisocial behavior, the large majority of the associations appear to be causal, but confounding influences are also present. However, for low parental monitoring and sensation seeking, our findings suggest that a substantial proportion of the observed association with alcohol outcomes reflects confounding rather than causal influences.

Dendritic spikes in hippocampal granule cells are necessary for long-term potentiation at the perforant path synapse.

Long-term potentiation (LTP) of synaptic responses is essential for hippocampal memory function. Perforant-path (PP) synapses on hippocampal granule cells (GCs) contribute to the formation of associative memories, which are considered the cellular correlates of memory engrams. However, the mechanisms of LTP at these synapses are not well understood. Due to sparse firing activity and the voltage attenuation in their dendrites, it remains unclear how associative LTP at distal synapses occurs. Here, we show that NMDA receptor-dependent LTP can be induced at PP-GC synapses without backpropagating action potentials (bAPs) in acute rat brain slices. Dendritic recordings reveal substantial attenuation of bAPs as well as local dendritic Na+ spike generation during PP-GC input. Inhibition of dendritic Na+ spikes impairs LTP induction at PP-GC synapse. These data suggest that dendritic spikes may constitute a key cellular mechanism for memory formation in the dentate gyrus.

Across-ear integration of acoustic-phonetic information under competitive conditions: Effects of attenuation increase in the presence of an extraneous formant

Previous research using consonant-vowel syllables where one ear receives the first formant (F1) and the other receives the second and third has shown that dichotic release from masking allows F2 + F3 to remain effective speech cues even after substantial attenuation. This study used three-formant analogues of natural sentences and extended the approach to include competitive conditions. Target formants were presented dichotically (F1 + F3; F2), either alone or accompanied by an extraneous competitor for F2 (i.e., F1±F2C + F3; F2) that listeners must reject to optimize recognition. In experiment 1, F2C was absent and F2 was attenuated in 6-dB steps (range: -6-48 dB). Intelligibility was unaffected until attenuation &amp;gt;30 dB; F2 still provided useful information at 48-dB attenuation. In experiment 2, F2 was attenuated in 12-dB steps (range: 0-36 dB). F2C was created by inverting the F2 frequency contour and using the F2 amplitude contour without attenuation. When F2C was present, 12-dB attenuation was sufficient to cause some loss of intelligibility; the effect was large when attenuation ≥24 dB. This interaction suggests that some mandatory across-ear spectral integration occurs, such that informational masking arising from F2C rapidly swamps the acoustic-phonetic information carried by F2 as its relative level is attenuated. [Work supported by ESRC.]

Modification of particle laden near-wall turbulence in a vertical channel bounded by rough walls

The paper deals with the mutual interactions between micro-particles and turbulence in vertical channel bounded by rough walls. Particles are momentum coupled with the fluid and are treated as pointwise spheres subject to Stokes drag, buoyancy and gravity forces. Two-way coupling is investigated using direct numerical simulation (DNS) of fluid flow with lagrangian particle tracking (LPT) and point-force approximation for small, heavy particles with a diameter smaller than the Kolmogorov length scale of the fluid. The particle back-reaction on the fluid flow is modelled by means of a modified version of the Particle-Source-In-Cell (PSIC) model. The friction Reynolds number of the unladen flow is Reτ=180, based on the friction velocity, uτ, of the free particle flow and the half wall distance, δ. The Stokes number, based on the wall units considered in the study, is St+=20 while the average mass and volume fractions ψm=0.141 and ϕv=1.7×10−4, respectively. The interest is focused on the effects of particles on the near-wall coherent structures. The issue has been widely analysed in turbulent flow bounded by smooth walls, whereas the effect of the roughness on momentum coupled two-phase flows has been much less investigated. The study of turbulence modulation is coupled to the analysis of slip velocity distribution, since both drag and particles back-reaction are closely linked to differences in fluid velocity seen by each particle and its own velocity. The effect of the roughness of the wall is investigated taking into account elastic rebounds of particles onto the wavy wall, instead of introducing a virtual rebound model. Results show that the main features of turbulence are generally maintained but the streamwise turbulence intensity increases whereas the velocity fluctuations in the wall-normal directions are damped, along with substantial attenuation of the Reynolds shear stress.

Intravenously injected human multilineage-differentiating stress-enduring cells selectively engraft into mouse aortic aneurysms and attenuate dilatation by differentiating into multiple cell types

ObjectivesAortic aneurysms result from the degradation of multiple components represented by endothelial cells, vascular smooth muscle cells, and elastic fibers. Cells that can replenish these components are desirable for cell-based therapy. Intravenously injected multilineage-differentiating stress-enduring (Muse) cells, endogenous nontumorigenic pluripotent-like stem cells, reportedly integrate into the damaged site and repair the tissue through spontaneous differentiation into tissue-compatible cells. We evaluated the therapeutic efficacy of Muse cells in a murine aortic aneurysm model. MethodsHuman bone marrow Muse cells, isolated as stage-specific embryonic antigen-3+ from bone marrow mesenchymal stem cells, or non-Muse cells (stage-specific embryonic antigen-3- cells in mesenchymal stem cells), bone marrow mesenchymal stem cells, or vehicle was intravenously injected at day 0, day 7, and 2 weeks (20,000 cells/injection) after inducing aortic aneurysms by periaortic incubation of CaCl2 and elastase in severe combined immunodeficient mice. ResultsAt 8 weeks, infusion of human Muse cells attenuated aneurysm dilation, and the aneurysmal size in the Muse group corresponded to approximately 62.5%, 55.6%, and 45.6% in the non-Muse, mesenchymal stem cell, and vehicle groups, respectively. Multiphoton laser confocal microscopy revealed that infused Muse cells migrated into aneurysmal tissue from the adventitial side and penetrated toward the luminal side. Histologic analysis demonstrated robust preservation of elastic fibers and spontaneous differentiation into endothelial cells and vascular smooth muscle cells. ConclusionsAfter intravenous injection, Muse cells homed and expanded to the aneurysm from the adventitial side. Subsequently, Muse cells differentiated spontaneously into vascular smooth muscle cells and endothelial cells, and elastic fibers were preserved. These Muse cell features together led to substantial attenuation of aneurysmal dilation.

Predicting new-onset HF in patients undergoing coronary or peripheral angiography: results from the Catheter Sampled Blood Archive in Cardiovascular Diseases (CASABLANCA) study.

AimsMethods to identify patients at risk for incident HF would be welcome as such patients might benefit from earlier interventions.Methods and resultsFrom a registry of 1251 patients referred for coronary and/or peripheral angiography, we sought to identify independent predictors of incident HF during follow‐up and develop a clinical and biomarker strategy to predict this outcome. There were 991 patients free of prevalent HF at baseline. Cox proportional hazard models were developed to predict adjudicated diagnosis of incident HF. Model discrimination and reclassification were evaluated. At follow‐up, 177 (18%) developed new‐onset HF. Independent predictors of new‐onset HF included five clinical variables (age, male sex, heart rate, history of atrial fibrillation/flutter, and history of hypertension) and two biomarkers (amino‐terminal pro‐B type natriuretic peptide and ST2). The c‐statistic for the model without biomarkers was 0.69; including biomarkers increased the c‐statistic to 0.76 (P < 0.001). A score was developed from the model. Patients in the highest score quintile had shortest time to incident HF compared with lower quintiles (log‐rank P < 0.001). Following 100 bootstrap iterations, internal validation was confirmed with Harrell's c‐statistic of 0.77. Use of angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, and beta‐blockers at enrollment was associated with substantial attenuation of predictive value of the risk score.ConclusionsPatients undergoing coronary/peripheral angiographic procedures are a population at high risk for incident HF. We describe an accurate clinical and biomarker strategy for predicting incident HF and possibly intervening in such patients (NCT00842868).

An investigation of the near-wake flow structure of a cylinder with guiding plates

In this study, the flow behind a circular cylinder with a pair of outer identical guiding plates was investigated using particle image velocimetry (PIV) for various angular positions of the plates (i.e. α=±70°, ±100°, and ±130°). The gaps between these plates and cylinder are equal and are 0.3D. Experiments were carried out at a subcritical Reynolds (Re=ρ·U∞·D/μ) number of 7500, based on the cylinder diameter (D) and the flow velocity (U∞). The features of the near-wake with and without the guiding plates were interpreted in terms of patterns of time-averaged vorticity and streamlines, time-averaged and fluctuating velocity components. The spectral analysis was also carried out to determine the time-dependent variation of the transverse velocity at given locations in the near-wake. Two-dimensional computations of flow around circular cylinders with and without guiding plates have also been performed to predict the timeaveraged and root-mean-square of force coefficients of the various models. It was seen that the guiding plates at an appropriate angular position can lead to substantial attenuation, or retardation, of the process of large-scale vortex formation in the near-wake, thus can lead to vortex-induced vibration (VIV) suppression without any increase in drag.

Methionine Ameliorates Polymyxin-Induced Nephrotoxicity by Attenuating Cellular Oxidative Stress.

Polymyxins are a last line of defense against multidrug-resistant Gram-negative pathogens. Recent pharmacological data show that intravenous polymyxins can cause nephrotoxicity in up to 60% of patients, and the plasma concentrations of polymyxins achieved with the currently recommended dosage regimens are suboptimal in a large proportion of patients. Simply increasing the daily dose of polymyxins is not possible due to nephrotoxicity. This study aimed to examine the protective effect of methionine against polymyxin-induced nephrotoxicity. Methionine (400 mg/kg of body weight), polymyxin B (35 mg/kg), a combination of methionine (100 or 400 mg/kg) and polymyxin B, and saline were administered to mice twice daily over 3.5 days. Kidneys were collected immediately at the end of the experiment for histological examination. The effect of methionine on the pharmacokinetics of polymyxin B was investigated in rats. The attenuation of polymyxin B (0.75 mM)-induced mitochondrial superoxide production by methionine (10.0 mM) was examined in rat kidney (NRK-52E) cells. Histological results revealed that the polymyxin-induced nephrotoxicity in mice was ameliorated by methionine in a dose-dependent manner. The methionine doses were well tolerated in the mice and rats, and the pharmacokinetics of polymyxin B in rats were not affected by methionine. In the group receiving polymyxin B-methionine, the total body clearance of polymyxin B was very similar to that in the group receiving polymyxin B alone (3.71 ± 0.57 versus 3.12 ± 1.66 ml/min/kg, P > 0.05). A substantial attenuation of polymyxin-induced mitochondrial superoxide production in NRK-52E cells was observed following pretreatment with methionine. Our results demonstrate that coadministration of methionine significantly ameliorated polymyxin-induced nephrotoxicity and decreased mitochondrial superoxide production in renal tubular cells.

Negative inotropic effects of diadenosine tetraphosphate are mediated by protein kinase C and phosphodiesterases stimulation in the rat heart

Extracellular diadenosine polyphosphates (ApnA) are recently considered as an endogenous signaling compounds with transmitter-like activity which present in numerous tissues, including heart. It has been demonstrated previously that extracellular ApnA cause alteration of the heart functioning via purine receptors in different mammalian species. Nevertheless, principal intracellular pathways which underlie ApnA action in the heart remain unknown. In the present study the role of the P2Y-associated intracellular regulatory pathway in the mediation of diadenosine tetraphosphate (Ap4A) effects in the rat heart has been investigated for the first time.Extracellular Ap4A caused significant decreasing of the ventricular inotropy. Ap4A evoked reduction of the left ventricle contractility in the isolated Langendorff-perfused rat hearts, decreasing of the Ca2+ transients in the enzymatically isolated ventricular cardiomyocytes and induced shortening of action potentials in the ventricle multicellular preparations. The inhibitory effects of Ap4A in the rat heart were significantly attenuated by protein kinase C (PKC) inhibitor chelerythrine but these effects were not affected by NO-synthase inhibitor L-NAME and guanylyl cyclase (sGC) inhibitor ODQ. In addition, substantial attenuation of Ap4A-caused negative inotropy in the left ventricle was produced by nonselective phsophodiesterase (PDE) inhibitor IBMX, while PDE type 2 inhibitor EHNA was ineffective.In conclusion, our results allow suggesting that Ap4A-induced inhibitory effects in the rat heart are mediated by PKC, but not by NO/sGC/PKG-related signaling pathway. In addition, PDE stimulation may contribute to Ap4A-caused inhibition of the rat heart contractility.

Modelling stunting in LiST: the effect of applying smoothing to linear growth data

BackgroundThe Lives Saved Tool (LiST) is a widely used resource for evidence-based decision-making regarding health program scale-up in low- and middle-income countries. LiST estimates the impact of specified changes in intervention coverage on mortality and stunting among children under 5 years of age. We aimed to improve the estimates of the parameters in LiST that determine the rate at which the effects of interventions to prevent stunting attenuate as children get older.MethodsWe identified datasets with serial measurements of children’s lengths or heights and used random effects models and restricted cubic splines to model the growth trajectories of children with at least six serial length/height measurements. We applied WHO growth standards to both measured and modelled (smoothed) lengths/heights to determine children’s stunting status at multiple ages (1, 6, 12, 24 months). We then calculated the odds ratios for the association of stunting at one age point with stunting at the next (“stunting-to-stunting ORs”) using both measured and smoothed data points. We ran analyses in LiST to compare the impact on intervention effect attenuation of using smoothed rather than measured stunting-to-stunting ORs.ResultsA total of 21,786 children with 178,786 length/height measurements between them contributed to our analysis. The odds of stunting at a given age were strongly related to whether a child is stunted at an earlier age, using both measured and smoothed lengths/heights, although the relationship was stronger for smoothed than measured lengths/heights. Using smoothed lengths/heights, we estimated that children stunted at 1 month have 45 times the odds of being stunted at 6 months, with corresponding odds ratios of 362 for the period 6 to 12 months and 175 for the period 12 to 24 months. Using the odds ratios derived from the smoothed data in LiST resulted in a somewhat slower attenuation of intervention effects over time, but substantial attenuation was still observed in the LiST outputs. For example, in Mali the effect of effectively eliminating SGA births reduced prevalence of stunting at age 59 months from 44.4% to 43.7% when using odds ratios derived from measured lengths/heights and from 44.4% to 41.9% when using odds ratios derived from smoothed lengths/heights.ConclusionsSmoothing of children’s measured lengths/heights increased the strength of the association between stunting at a given age and stunting at an earlier age. Using odds ratios based on smoothed lengths/heights in LiST resulted in a small reduction in the attenuation of intervention effects with age and thus some increase in the estimated benefits, and may better reflect the true benefits of early nutritional interventions.

Calcium (Ti,Zr) hexaorthophosphate bioceramics for electrically stimulated biomedical implant devices: A position paper

Osseointegration of biomedical implants as well as healing of broken bones are supported by novel bioceramic materials that, owing to their engineered ionic conductivity, in the presence of an electric field provide accumulation of negative electrical charges close to the interface between an implant and living bone tissue, thus stimulating the rate of bone growth. In this position paper, the structure as well as the chemical, electrical, and biomedical properties of Ca (Ti,Zr) hexaorthophosphates are reviewed. In addition, based on evaluation of the material’s properties, a conceptual configuration of a capacity-coupled bone growth stimulator will be presented. The advantage of the proposed novel device over already existing bone-growth stimulators is its provision of the intimate contact of a capacity-coupled electric field with the growing bone tissue as opposed to an externally applied inductively coupled electromagnetic field, which suffers substantial attenuation when transmitted through soft tissue covering the locus of bone growth. To achieve higher ionic conductivity in Ca (Ti,Zr) hexaorthophosphates, aliovalent doping with highly mobile Na or Li ions intercalated into the only partially occupied M1 sites appears to be a suitable route.

Specificity of surface EMG recordings for gastrocnemius during upright standing

The relatively large pick-up volume of surface electrodes has for long motivated the concern that muscles other than that of interest may contribute to surface electromyograms (EMGs). Recent findings suggest however the pick-up volume of surface electrodes may be smaller than previously appreciated, possibly leading to the detection of surface EMGs insensitive to muscle activity. Here we combined surface and intramuscular recordings to investigate how comparably action potentials from gastrocnemius and soleus are represented in surface EMGs detected with different inter-electrode distances. We computed the firing instants of motor units identified from intramuscular EMGs detected from gastrocnemius and soleus while five participants stood upright. We used these instants to trigger and average surface EMGs detected from multiple skin regions along gastrocnemius. Results from 66 motor units (whereof 31 from gastrocnemius) revealed the surface-recorded amplitude of soleus action potentials was 6% of that of gastrocnemius and did not decrease for inter-electrode distances smaller than 4 cm. Gastrocnemius action potentials were more likely detected for greater inter-electrode distances and their amplitude increased steeply up to 5 cm inter-electrode distance. These results suggest that reducing inter-electrode distance excessively may result in the detection of surface EMGs insensitive to gastrocnemius activity without substantial attenuation of soleus crosstalk.

Controlled release of insulin-like growth factor 1 enhances urethral sphincter function and histological structure in the treatment of female stress urinary incontinence in a rat model.

To determine the effects of controlled release of insulin-like growth factor 1 (IGF-1) from alginate-poly-L-ornithine-gelatine (A-PLO-G) microbeads on external urethral sphincter (EUS) tissue regeneration in a rat model of stress urinary incontinence (SUI), as SUI diminishes the quality of life of millions, particularly women who have delivered vaginally, which can injure the urethral sphincter. Despite several well-established treatments for SUI, growth factor therapy might provide an alternative to promote urethral sphincter repair. In all, 44 female Sprague-Dawley rats were randomised into four groups: vaginal distension (VD) followed by periurethral injection of IGF-1-A-PLO-G microbeads (VD + IGF-1 microbeads; 1 × 104 microbeads/1 mL normal saline); VD + empty microbeads; VD + saline; or sham-VD + saline (sham). Urethral function (leak-point pressure, LPP) was significantly lesser 1 week after VD + saline [mean (sem) 23.9 (1.3) cmH2 O] or VD + empty microbeads [mean (sem) 21.7 (0.8) cmH2 O) compared to the sham group [mean (sem) 44.4 (3.4) cmH2 O; P < 0.05), indicating that the microbeads themselves do not create a bulking or obstructive effect in the urethra. The LPP was significantly higher 1 week after VD + IGF-1 microbeads [mean (sem) 28.4 (1.2) cmH2 O] compared to VD + empty microbeads (P < 0.05), and was not significantly different from the LPP in sham rats, demonstrating an initiation of a reparative effect even at 1 week after VD. Histological analysis showed well-organised skeletal muscle fibres and vascular development in the EUS at 1 week after VD + IGF-1 microbeads, compared to substantial muscle fibre attenuation and disorganisation, and less vascular formation at 1 week after VD + saline or VD + empty microbeads. Periurethral administration of IGF-1-A-PLO-G microbeads facilitates recovery from SUI by promoting skeletal myogenesis and revascularisation. This therapy is promising, but detailed and longer term studies in animal models and humans are needed.

Mutations Driving Airborne Transmission of A/H5N1 Virus in Mammals Cause Substantial Attenuation in Chickens only when combined

A/H5N1 influenza viruses pose a threat to human and animal health. A fully avian A/H5N1 influenza virus was previously shown to acquire airborne transmissibility between ferrets upon accumulation of five or six substitutions that affected three traits: polymerase activity, hemagglutinin stability and receptor binding. Here, the impact of these traits on A/H5N1 virus replication, tissue tropism, pathogenesis and transmission was investigated in chickens. The virus containing all substitutions associated with transmission in mammals was highly attenuated in chickens. However, single substitutions that affect polymerase activity, hemagglutinin stability and receptor binding generally had a small or negligible impact on virus replication, morbidity and mortality. A virus carrying two substitutions in the receptor-binding site was attenuated, although its tissue tropism in chickens was not affected. This data indicate that an A/H5N1 virus that is airborne-transmissible between mammals is unlikely to emerge in chickens, although individual mammalian adaptive substitutions have limited impact on viral fitness in chickens.

Hepatoprotective Effect of Aqueous Extract from the Seeds of Orychophragmus violaceus against Liver Injury in Mice and HepG2 Cells.

Orychophragmus violaceus (O. violaceus) is a kind of edible wild herb in north China and its seeds have medical potential, however, the effect of O. violaceus seeds on liver injury and the mechanism of action remains poorly understood. Thus, the purpose of the present study is to investigate the effect of O. violaceus seeds on liver injury and further explore the molecular mechanism of the beneficial effects using aqueous extract from the seeds of O. violaceus (AEOV). Mice were orally administrated with saline, AEOV, and biphenyldicarboxylate for 4 days, and were then injected subcutaneously with 0.1% carbon tetrachloride (CCl4) dissolved in corn oil. Sixteen hours later, mice were sacrificed and blood samples were collected. Then, the serum was separated and used for biochemical assay. Livers were excised and were routinely processed for histological examinations. Enzyme activities and protein levels in liver homogenates were detected using commercial kits or by western blot analysis. Additionally, the hepatoprotective effect of AEOV in vitro was evaluated using epigoitrin, the major alkaloid compound isolated from AEOV. We found that AEOV attenuated liver injury induced by CCl4 as evidenced by decreased levels of alanine aminotransferase (ALT) and aminotransferase (AST) in serum, improvement of liver histopathological changes, and substantial attenuation of oxidative stress and inflammation via regulation of nuclear factor-erythroid 2-related factor-2 (Nrf2) and nuclear factor κB (NFκB) pathways. These effects of AEOV were comparable to that of biphenyldicarboxylate which was commonly used as a hepatoprotective reference. Moreover, pretreatment of HepG2 cells with epigoitrin improved cell viability, decreased lactate dehydrogenase (LDH) and malondialdehyde (MDA) levels, increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity, attenuated the NFκB pathway, and elevated the Nrf2 pathway after exposure to H2O2. These results suggest that AEOV could effectively prevent CCl4-induced liver injury in mice via regulating the Nrf2 and NFκB pathways, and reveal the cytoprotective effects of epigoitrin against H2O2-induced oxidative stress in HepG2 cells.

Variable Action Potential Backpropagation during Tonic Firing and Low-Threshold Spike Bursts in Thalamocortical But Not Thalamic Reticular Nucleus Neurons

Backpropagating action potentials (bAPs) are indispensable in dendritic signaling. Conflicting Ca2+-imaging data and an absence of dendritic recording data means that the extent of backpropagation in thalamocortical (TC) and thalamic reticular nucleus (TRN) neurons remains unknown. Because TRN neurons signal electrically through dendrodendritic gap junctions and possibly via chemical dendritic GABAergic synapses, as well as classical axonal GABA release, this lack of knowledge is problematic. To address this issue, we made two-photon targeted patch-clamp recordings from rat TC and TRN neuron dendrites to measure bAPs directly. These recordings reveal that “tonic”' and low-threshold-spike (LTS) “burst” APs in both cell types are always recorded first at the soma before backpropagating into the dendrites while undergoing substantial distance-dependent dendritic amplitude attenuation. In TC neurons, bAP attenuation strength varies according to firing mode. During LTS bursts, somatic AP half-width increases progressively with increasing spike number, allowing late-burst spikes to propagate more efficiently into the dendritic tree compared with spikes occurring at burst onset. Tonic spikes have similar somatic half-widths to late burst spikes and undergo similar dendritic attenuation. In contrast, in TRN neurons, AP properties are unchanged between LTS bursts and tonic firing and, as a result, distance-dependent dendritic attenuation remains consistent across different firing modes. Therefore, unlike LTS-associated global electrical and calcium signals, the spatial influence of bAP signaling in TC and TRN neurons is more restricted, with potentially important behavioral-state-dependent consequences for synaptic integration and plasticity in thalamic neurons.SIGNIFICANCE STATEMENT In most neurons, action potentials (APs) initiate in the axosomatic region and propagate into the dendritic tree to provide a retrograde signal that conveys information about the level of cellular output to the locations that receive most input: the dendrites. In thalamocortical and thalamic reticular nucleus neurons, the site of AP generation and the true extent of backpropagation remain unknown. Using patch-clamp recordings, this study measures dendritic propagation of APs directly in these neurons. In either cell type, high-frequency low-threshold spike burst or lower-frequency tonic APs undergo substantial voltage attenuation as they spread into the dendritic tree. Therefore, backpropagating spikes in these cells can only influence signaling in the proximal part of the dendritic tree.

Transmission Characteristics of Hybrid Modes in Corrugated Waveguides Above the Bragg Frequency

We studied the transmission characteristics of hybrid modes in a corrugated circular waveguide above the Bragg frequency to develop a broad-band transmission line for millimeter waves. Millimeter waves at 294 GHz were transmitted into a straight waveguide. From observed power profiles in waveguide cross-sections, a high attenuation rate of 0.13 dB/m was obtained. To match a theoretical attenuation constant with the experimental one, we introduced an ad hoc coefficient of conventional surface reactance in the waveguide wall. This was necessary because the wall began to look like the surface with a decreasing anisotropic reactance owing to the frequency above the Bragg frequency. Using nonlinear optimization for mode content analysis, the observed power profiles in the waveguide cross-section were matched with theoretical profiles. There was good agreement between the calculated and observed centers of power profiles and attenuation rate along the waveguide. The theoretical analysis showed that the magnetic field at the waveguide wall increases and the substantial attenuation takes place. Above the Bragg frequency coupling to backwards propagating modes is a point of consideration. A combination of the backwards propagating EH1,26 and the forward propagating HE11 modes satisfied the Bragg condition at 294.7 GHz which was the nearest frequency of operating frequency. A strong attenuation of the incoming HE11 mode by Bragg resonance was not expected due to large difference of 0.7 GHz. It becomes clear that the observed high transmission loss outside of the Bragg resonance can be explained by a decrease in anisotropic surface reactance at the wall.