Pneumonia remains a global health threat, in part due to expanding categories of susceptible individuals and increasing prevalence of antibiotic resistant pathogens. However, therapeutic stimulation ...of the lungs' mucosal defenses by inhaled exposure to a synergistic combination of Toll-like receptor (TLR) agonists known as Pam2-ODN promotes mouse survival of pneumonia caused by a wide array of pathogens. This inducible resistance to pneumonia relies on intact lung epithelial TLR signaling, and inducible protection against viral pathogens has recently been shown to require increased production of epithelial reactive oxygen species (ROS) from multiple epithelial ROS generators. To determine whether similar mechanisms contribute to inducible antibacterial responses, the current work investigates the role of ROS in therapeutically-stimulated protection against Pseudomonas aerugnosa challenges. Inhaled Pam2-ODN treatment one day before infection prevented hemorrhagic lung cytotoxicity and mouse death in a manner that correlated with reduction in bacterial burden. The bacterial killing effect of Pam2-ODN was recapitulated in isolated mouse and human lung epithelial cells, and the protection correlated with inducible epithelial generation of ROS. Scavenging or targeted blockade of ROS production from either dual oxidase or mitochondrial sources resulted in near complete loss of Pam2-ODN-induced bacterial killing, whereas deficiency of induced antimicrobial peptides had little effect. These findings support a central role for multisource epithelial ROS in inducible resistance against a bacterial pathogen and provide mechanistic insights into means to protect vulnerable patients against lethal infections.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Prenyltransfer is an early-stage carbon–hydrogen bond (C–H) functionalization prevalent in the biosynthesis of a diverse array of biologically active bacterial, fungal, plant, and metazoan ...diketopiperazine (DKP) alkaloids. Toward the development of a unified strategy for biocatalytic construction of prenylated DKP indole alkaloids, we sought to identify and characterize a substrate-permissive C2 reverse prenyltransferase (PT). As the first tailoring event within the biosynthesis of cytotoxic notoamide metabolites, PT NotF catalyzes C2 reverse prenyltransfer of brevianamide F. Solving a crystal structure of NotF (in complex with native substrate and prenyl donor mimic dimethylallyl S-thiolodiphosphate (DMSPP)) revealed a large, solvent-exposed active site, intimating NotF may possess a significantly broad substrate scope. To assess the substrate selectivity of NotF, we synthesized a panel of 30 sterically and electronically differentiated tryptophanyl DKPs, the majority of which were selectively prenylated by NotF in synthetically useful conversions (2 to >99%). Quantitative representation of this substrate library and development of a descriptive statistical model provided insight into the molecular origins of NotF’s substrate promiscuity. This approach enabled the identification of key substrate descriptors (electrophilicity, size, and flexibility) that govern the rate of NotF-catalyzed prenyltransfer, and the development of an “induced fit docking (IFD)-guided” engineering strategy for improved turnover of our largest substrates. We further demonstrated the utility of NotF in tandem with oxidative cyclization using flavin monooxygenase, BvnB. This one-pot, in vitro biocatalytic cascade enabled the first chemoenzymatic synthesis of the marine fungal natural product, (−)-eurotiumin A, in three steps and 60% overall yield.
The classical picture of the force on a capacitor assumes a large density of electronic states, such that the electrochemical potential of charges added to the capacitor is given by the external ...electrostatic potential and the capacitance is determined purely by geometry1. Here we consider capacitively driven motion of a nano-mechanical resonator with a low density of states, in which these assumptions can break down25. We nd three leading-order corrections to the classical picture: the rst of which is a modulation in the static force due to variation in the internal chemical potential; the second and third are changes in the static force and dynamic spring constant due to the rate of change of chemical potential, expressed as the quantum (density of states) capacitance6,7. As a demonstration, we study capacitively driven graphene mechanical resonators, where the chemical potential is modulated independently of the gate voltage using an applied magnetic eld to manipulate the energy of electrons residing in discrete Landau levels810. In these devices, we observe large periodic frequency shifts consistent with the three corrections to the classical picture. In devices with extremely low strain and disorder, the rst correction term dominates and the resonant frequency closely follows the chemicalpotential.Thetheoreticalmodeltsthedatawithonly one adjustable parameter representing disorder-broadening of the Landau levels. The underlying electromechanical coupling mechanism is not limited by the particular choice of material, geometry, or mechanism for variation in the chemical potential, and can thus be extended to other low-dimensional systems.
Spectroscopy of discrete Landau levels (LLs) in bulk-insulating three-dimensional topological insulators (3D TIs) in perpendicular magnetic field characterizes the Dirac nature of their surface ...states. Despite a number of studies demonstrating the quantum Hall effect (QHE) of topological surface states, quantitative evaluation of the LL energies, which serve as fundamental electronic quantities for study of the quantum states, is still limited. In this work, we explore the density of states of LLs by measuring quantum capacitance (C Q) in a truly bulk insulating 3D TI via a van der Waals heterostructure configuration. By applying dual-gate voltages, we access the individual surface states’ LLs and extract their chemical potentials to quantify the LL spacings of each surface. We evaluate the LLs’ energies at two distinguished QH states, namely, dissipationless (ν = ±1) and dissipative (ν = 0) states in the 3D TI.
Mass loss from massive stars ( 8 M sub( )) can result in the formation of circumstellar wind-blown cavities surrounding the star, bordered by a thin, dense, cold shell. When the star explodes as a ...core-collapse supernova (SN), the resulting shock wave will interact with this modified medium around the star, rather than the interstellar medium. In this work we first explore the nature of the circumstellar medium around massive stars in various evolutionary stages. This is followed by a study of the evolution of SNe within these wind-blown bubbles. The evolution depends primarily on a single parameter , the ratio of the mass of the dense shell to that of the ejected material. We investigate the evolution for different values of this parameter. We also plot approximate X-ray surface brightness plots from the simulations. For very small values << 1 the effect of the shell is negligible, as one would expect. Values of 1 affect the SN evolution, but the SN "forgets" about the existence of the shell in about 10 doubling times or so. The remnant density profile changes, and consequently the X-ray emission from the remnant will also change. The initial X-ray luminosity of the remnant is quite low, but interaction of the shock wave with the dense circumstellar shell can increase the luminosity by 2-3 orders of magnitude. As the reflected shock begins to move inward, X-ray images will show the presence of a double-shelled structure. Larger values result in more SN energy being expended to the shell. The resulting reflected shock moves quickly back to the origin, and the ejecta are thermalized rapidly. The evolution of the remnant is speeded up, and the entire remnant may appear bright in X-rays. If >> 1, then a substantial amount of energy may be expended in the shell. In the extreme case the SN may go directly from the free expansion to the adiabatic stage, bypassing the Sedov stage. Our results show that in many cases the SNR spends a significant amount of time within the bubble. The low density within the bubble can delay the onset of the Sedov stage and may end up reducing the amount of time spent in the Sedov stage. The complicated density profile within the bubble makes it difficult to infer the mass-loss properties of the pre-SN star by studying the evolution of the resulting SNR.
Ferritic steels strengthened with uniformly dispersed oxides (ODS steel) have potential applications as a fuel cladding material in future nuclear reactors. In the present investigation, ODS steel ...with a nominal composition of Fe-15Cr-2W-0.3Y2O3 was synthesized from elemental powders by mechanical alloying in a high-energy Simoloyer attritor ball mill. The structural evolution occurring in the course of mechanical alloying at interrupted milling durations was investigated by XRD, SEM, TEM, and DTA. Dissolution of Cr took place at an earlier stage as compared to that of W and a complete solid solution was found to occur at 10 h of milling. Yttria was found to be stable (undissolved) and consistent till 10 h of milling though its size was refined. A strong influence of the dissolution of W in shrinking the austenite region and corresponding changes in the transformation temperatures was observed in the DTA analysis.
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•Single phase α ferrite solid solution was obtained at 10 h of milling.•During milling dissolution rate of Cr was faster than that of W.•Yttria was stable and got refined during mechanical milling.•DTA analysis indicated the role of dissolution of Cr and W in the transformations.
The lung epithelium is dynamic, capable of considerable structural and functional plasticity in response to pathogen challenges. Our laboratory has demonstrated that an inhaled combination of a ...Toll-like receptor (TLR) 2/6 agonist and a TLR9 agonist (Pam2ODN) results in robust protection against otherwise lethal pneumonias. We have previously shown that intact epithelial TLR signaling and generation of multisource epithelial reactive oxygen species (ROS) are required for inducible protection. Further investigating the mechanisms underlying this phenomenon of inducible resistance, reverse-phase protein array analysis demonstrated robust STAT3 (signal transducer and activator of transcription 3) phosphorylation following treatment of lung epithelial cells. We show here that Pam2ODN-induced STAT3 phosphorylation is IL-6-independent. We further found that therapeutic epithelial STAT3 activation is required for inducible protection against
pneumonia. Additional studies showed that inhibiting epithelial dual oxidases or scavenging ROS significantly reduced the Pam2ODN induction of STAT3 phosphorylation, suggesting a proximal role for ROS in inducible STAT3 activation. Dissecting these mechanisms, we analyzed the contributions of redox-sensitive kinases and found that Pam2ODN activated epithelial growth factor receptor in an ROS-dependent manner that is required for therapeutically inducible STAT3 activation. Taken together, we demonstrate that epithelial STAT3 is imperative for Pam2ODN's function and describe a novel redox-based mechanism for its activation. These key mechanistic insights may facilitate strategies to leverage inducible epithelial resistance to protect susceptible patients during periods of peak vulnerability.
We analyze the impact of using the penalty method on the estimation of a prescribed solution functional or ‘Quantity of Interest’ (QoI). Specifically, we consider the use of penalty methods to ...enforce Dirichlet boundary constraints, focusing our attention on boundary fluxes as QoIs. We propose an enhanced estimator of the boundary flux that includes a term involving the derivative of the flux with respect to the penalty parameter ϵ. We show that the new estimator reduces the error arising from the use of the penalty method from O(ϵ) to o(ϵ). A well-posed adjoint problem associated with the boundary flux is also proposed following an analysis of the penalty method. Errors in the enhanced flux estimator are then controlled using adjoint-based techniques. Several numerical experiments are presented to demonstrate that the enhanced estimator, in combination with adjoint error estimation, allows one to efficiently control both the discretization and penalty errors in target QoIs.
Context:
The clinical consequences of insulin resistance and hyperinsulinemia on bone remain largely unknown.
Objective:
The objective of the study was to evaluate the effect of insulin resistance on ...peripheral bone geometry, volumetric bone mineral density (vBMD), bone microarchitecture, and estimated bone strength.
Design, Setting, and Participants:
This cross-sectional study included 146 postmenopausal, nondiabetic Caucasian women (mean age 60.3 ± 2.7 y) who were participating in the Study of Women's Health Across the Nation.
Interventions:
There were no interventions.
Main Outcome Measures:
High-resolution peripheral quantitative computed tomography was used to assess bone density and microstructure at the distal radius and tibia. Fasting insulin and glucose were measured and insulin resistance was estimated using homeostasis model assessment of insulin resistance (HOMA-IR), with higher values indicating greater insulin resistance.
Results:
There was a negative association between HOMA-IR and bone size and a positive association between HOMA-IR and total vBMD, trabecular vBMD, trabecular thickness, and cortical thickness at the radius and tibia. These relationships remained, even after adjusting for body weight and other potential covariates (eg, time since menopause, cigarette smoking, physical activity, prior use of osteoporosis medications or glucocorticoids).
Conclusions:
In nondiabetic, postmenopausal women, insulin resistance was associated with smaller bone size, greater volumetric bone mineral density, and generally favorable bone microarchitecture at weight-bearing and nonweight-bearing skeletal sites. These associations were independent of body weight and other potential covariates, suggesting that hyperinsulinemia directly affects bone structure independent of obesity and may explain, in part, the higher trabecular bone density and favorable trabecular microarchitecture seen in individuals with type 2 diabetes mellitus.
The association between insulin resistance and bone microarchitecture was assessed in postmenopausal, non-diabetic women. Insulin resistance was associated with favorable bone microarchitecture at the distal radius and tibia.
Mott Insulating State in Ultraclean Carbon Nanotubes Deshpande, Vikram V; Chandra, Bhupesh; Caldwell, Robert ...
Science (American Association for the Advancement of Science),
01/2009, Letnik:
323, Številka:
5910
Journal Article
Recenzirano
Odprti dostop
The Mott insulating state is a manifestation of strong electron interactions in nominally metallic systems. Using transport spectroscopy, we showed that an energy gap exists in nominally metallic ...carbon nanotubes and occurs in addition to the band gap in small-band-gap nanotubes, indicating that carbon nanotubes are never metallic. This gap has a magnitude of ~10 to 100 milli-electron volts and a nanotube radius (r) dependence of ~1/r, which is in good agreement with predictions for a nanotube Mott insulating state. We also observed neutral excitations within the gap, as predicted for this state. Our results underscore nanotubes' exceptional capabilities for use in studying correlated electron phenomena in one dimension.
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