481 research outputs found
Real-time propagator eigenstates
Obtaining a numerical solution of the time-dependent Schrödinger equation requires an initial state for the time evolution. If the system Hamiltonian can be split into a time-independent part and a time-dependent perturbation, the initial state is typically chosen as an eigenstate of the former. For propagation using approximate methods such as operator splitting, we show that both imaginary-time evolution and diagonalization of the time-independent Hamiltonian produce states that are not exactly stationary in absence of the perturbation. In order to avoid artifacts from these non-stationary initial states, we propose an iterative method for calculating eigenstates of the real-time propagator. We compare the performance of different initial states by simulating ionization of a model atom in a short laser pulse and we demonstrate that much lower noise levels can be achieved with the real-time propagator eigenstates
Electron Microscopy Of Wood Of Callixylon And Cordaites
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141638/1/ajb210693.pd
Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension
AIMS: Renal inflammation, leading to fibrosis and impaired function is a major contributor to the development of hypertension. The NLRP3 inflammasome mediates inflammation in several chronic diseases by processing the cytokines pro-interleukin (IL)-1beta and pro-IL-18. In this study, we investigated whether MCC950, a recently-identified inhibitor of NLRP3 activity, reduces blood pressure (BP), renal inflammation, fibrosis and dysfunction in mice with established hypertension.
METHODS AND RESULTS: C57BL6/J mice were made hypertensive by uninephrectomy and treatment with deoxycorticosterone acetate (2.4 mg/day, s.c.) and 0.9% NaCl in the drinking water (1K/DOCA/salt). Normotensive controls were uninephrectomized and received normal drinking water. Ten days later, mice were treated with MCC950 (10 mg/kg/day, s.c.) or vehicle (saline, s.c.) for up to 25 days. BP was monitored by tail-cuff or radiotelemetry; renal function by biochemical analysis of 24-h urine collections; and kidney inflammation/pathology was assessed by real-time PCR for inflammatory gene expression, flow cytometry for leucocyte influx, and Picrosirius red histology for collagen. Over the 10 days post-surgery, 1K/DOCA/salt-treated mice became hypertensive, developed impaired renal function, and displayed elevated renal levels of inflammatory markers, collagen and immune cells. MCC950 treatment from day 10 attenuated 1K/DOCA/salt-induced increases in renal expression of inflammasome subunits (NLRP3, ASC, pro-caspase-1) and inflammatory/injury markers (pro-IL-18, pro-IL-1beta, IL-17A, TNF-alpha, osteopontin, ICAM-1, VCAM-1, CCL2, vimentin), each by 25-40%. MCC950 reduced interstitial collagen and accumulation of certain leucocyte subsets in kidneys of 1K/DOCA/salt-treated mice, including CD206+ (M2-like) macrophages and interferon-gamma-producing T cells. Finally, MCC950 partially reversed 1K/DOCA/salt-induced elevations in BP, urine output, osmolality, [Na+], and albuminuria (each by 20-25%). None of the above parameters were altered by MCC950 in normotensive mice.
CONCLUSION: MCC950 was effective at reducing BP and limiting renal inflammation, fibrosis and dysfunction in mice with established hypertension. This study provides proof-of-concept that pharmacological inhibition of the NLRP3 inflammasome is a viable anti-hypertensive strategy
New Insights into Mechanisms Controlling the NLRP3 Inflammasome and Its Role in Lung Disease
Inflammasomes are large macromolecular signaling complexes that control the proteolytic activation of two highly proinflammatory IL-1 family cytokines, IL-1β and IL-18. The NLRP3 inflammasome is of special interest because it can assemble in response to a diverse array of stimuli and because the inflammation it triggers has been implicated in a wide variety of disease pathologies. To avoid aberrant activation, the NLRP3 inflammasome is modulated on multiple levels, ranging from transcriptional control to post-translational protein modifications. Emerging genetic and pharmacological evidence suggests that NLRP3 inflammasome activation may also be involved in acute lung inflammation after viral infection and during progression of several chronic pulmonary diseases, including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma. Here, we review the most recent contributions to our understanding of the regulatory mechanisms controlling activation of the NLRP3 inflammasome and discuss the contribution of the NLRP3 inflammasome to the pathology of lung diseases
Current Distribution in the Three-Dimensional Random Resistor Network at the Percolation Threshold
We study the multifractal properties of the current distribution of the
three-dimensional random resistor network at the percolation threshold. For
lattices ranging in size from to we measure the second, fourth and
sixth moments of the current distribution, finding {\it e.g.\/} that
where is the conductivity exponent and is the
correlation length exponent.Comment: 10 pages, latex, 8 figures in separate uuencoded fil
Depth profile analyses of films grown at different temperatures
Cu(In,Ga)Se2films are used as absorber layers in chalcopyrite thin filmsolar
cells. As the gallium concentration in the absorber can be used to control the
band gap, there have been many efforts to vary the gallium concentration in
depth to gain an optimum balance of light absorption, carrier collection, and
recombination at different depths of the absorber film, leading to improved
quantum efficiency. In this study, we investigate the effect of the maximum
substrate temperature during film growth on the depth dependent gallium
concentration. For the in-depth gallium concentration analyses, we use two
techniques, covering complementary depth ranges. Angle dependent soft x-ray
emission spectroscopy provides access to information depths between 20 and 470
nm, which covers the depth range of the space charge region, where most of the
photoexcited carriers are generated. Therefore, this depth range is of
particular interest. To complement this investigation we use secondary neutral
mass spectrometry, which destructively probes the whole thickness of the
absorber (≈2 μm). The two methods show increasingly pronounced gallium and
indium gradients with decreasing maximum substrate temperature. The probing of
the complementary depth ranges of the absorbers gives a consistent picture of
the in-depth gallium distribution, which provides a solid basis for a
comprehensive discussion about the effect of a reduced substrate temperature
on the formation of gallium gradients in Cu(In,Ga)Se2 and the device
performance of the corresponding reference solar cells
Resolution of Racemic Guaifenesin Applying a Coupled Preferential Crystallization-Selective Dissolution Process: Rational Process Development
Preferential
crystallization is a cost efficient method to provide
pure enantiomers from a racemic mixture of a conglomerate forming
system. Exploiting small amounts of pure crystals of both enantiomers,
several batch or continuous processes were developed, capable of providing
both species. However, an intermediate production step has to be used
when pure enantiomers are not available. In such cases, partially
selective synthesis, chromatography, or crystallization processes
utilizing chiral auxiliaries have to be used to provide the initial
seed material. Recently, it was shown that a coupled Preferential
Crystallization-selective Dissolution process (CPCD) in two coupled
crystallizers can be applied if at least one pure enantiomer is available
to produce both antipodes within one batch. The corresponding process
is carried out in one reactor (crystallization tank) by seeding a
racemic supersaturated solution with the available enantiomer at a
certain temperature. The second reactor (dissolution tank) contains
a saturated racemic suspension at a higher temperature. Both reactors
are coupled via the fluid phase, allowing for a selective dissolution
of the preferentially crystallizing enantiomer from the solid racemic
feed provided in the dissolution vessel. The dissolution and crystallization
processes continue until the solid racemic material is completely
resolved and becomes enantiopure. At this point, both enantiomers
can be harvested in their pure crystalline form. For a specific pharmaceutically
relevant case study, a rational process design and the applied empirical
optimization procedure will be described. The achieved productivities
after optimization show the great potential of this approach also
for industrial applications. Also, a strategy to control this process
based on inline turbidity measurement will be presented
LPS-TLR4 Signaling to IRF-3/7 and NF-κB Involves the Toll Adapters TRAM and TRIF
Toll–IL-1–resistance (TIR) domain–containing adaptor-inducing IFN-β (TRIF)–related adaptor molecule (TRAM) is the fourth TIR domain–containing adaptor protein to be described that participates in Toll receptor signaling. Like TRIF, TRAM activates interferon regulatory factor (IRF)-3, IRF-7, and NF-κB-dependent signaling pathways. Toll-like receptor (TLR)3 and 4 activate these pathways to induce IFN-α/β, regulated on activation, normal T cell expressed and secreted (RANTES), and γ interferon–inducible protein 10 (IP-10) expression independently of the adaptor protein myeloid differentiation factor 88 (MyD88). Dominant negative and siRNA studies performed here demonstrate that TRIF functions downstream of both the TLR3 (dsRNA) and TLR4 (LPS) signaling pathways, whereas the function of TRAM is restricted to the TLR4 pathway. TRAM interacts with TRIF, MyD88 adaptor–like protein (Mal)/TIRAP, and TLR4 but not with TLR3. These studies suggest that TRIF and TRAM both function in LPS-TLR4 signaling to regulate the MyD88-independent pathway during the innate immune response to LPS
Interaction of TLR4 and TLR8 in the Innate Immune Response against Mycobacterium Tuberculosis
The interaction and crosstalk of Toll-like receptors (TLRs) is an established pathway in which the innate immune system recognises and fights pathogens. In a single nucleotide polymorphisms (SNP) analysis of an Indian cohort, we found evidence for both TLR4-399T and TRL8-1A conveying increased susceptibility towards tuberculosis (TB) in an interdependent manner, even though there is no established TLR4 ligand present in Mycobacterium tuberculosis (Mtb), which is the causative pathogen of TB. Docking studies revealed that TLR4 and TLR8 can build a heterodimer, allowing interaction with TLR8 ligands. The conformational change of TLR4-399T might impair this interaction. With immunoprecipitation and mass spectrometry, we precipitated TLR4 with TLR8-targeted antibodies, indicating heterodimerisation. Confocal microscopy confirmed a high co-localisation frequency of TLR4 and TLR8 that further increased upon TLR8 stimulation. The heterodimerisation of TLR4 and TLR8 led to an induction of IL12p40, NF-κB, and IRF3. TLR4-399T in interaction with TLR8 induced an increased NF-κB response as compared to TLR4-399C, which was potentially caused by an alteration of subsequent immunological pathways involving type I IFNs. In summary, we present evidence that the heterodimerisation of TLR4 and TLR8 at the endosome is involved in Mtb recognition via TLR8 ligands, such as microbial RNA, which induces a Th1 response. These findings may lead to novel targets for therapeutic interventions and vaccine development regarding TB
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