Monoamine oxidase (MAO) is rapidly gaining appreciation for its pathophysiologic role in cardiac injury and failure. Oxidative deamination of norepinephrine by MAO generates H2O2 and the ...catecholaldehyde 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), the latter of which is a highly potent and reactive electrophile that has been linked to cardiotoxicity. However, many questions remain as to whether catecholaldehydes regulate basic physiological processes in the myocardium and the pathways involved. Here, we examined the role of MAO-derived oxidative metabolites in mediating the activation of cardiac fibroblasts in response to norepinephrine. In neonatal murine cardiac fibroblasts, norepinephrine increased reactive oxygen species (ROS), accumulation of catechol-modified protein adducts, expression and secretion of collagens I/III, and other markers of profibrotic activation including STAT3 phosphorylation. These effects were attenuated with MAO inhibitors, the aldehyde-scavenging dipeptide l-carnosine, and FPS-ZM1, an antagonist for the receptor for advanced glycation endproducts (RAGE). Interestingly, treatment of cardiac fibroblasts with a low dose (1 μM) of DOPEGAL-modified albumin phenocopied many of the effects of norepinephrine and also induced an increase in RAGE expression. Higher doses (>10 μM) of DOPEGAL-modified albumin were determined to be toxic to cardiac fibroblasts in a RAGE-dependent manner, which was mitigated by l-carnosine. Collectively, these findings suggest that norepinephrine may influence extracellular matrix remodeling via an adrenergic-independent redox pathway in cardiac fibroblasts involving the MAO-mediated generation of ROS, catecholaldehydes, and RAGE. Furthermore, since elevations in the catecholaminergic tone and oxidative stress in heart disease are linked with cardiac fibrosis, this study illustrates novel drug targets that could potentially mitigate this serious disorder.
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The maximum velocity of dewetting encodes sufficient information on the hydrodynamics of the wetting process to enable the local dynamic contact angle at the molecular scale, θ, to be ...determined from the apparent contact angle measured experimentally at much larger scales, θapp.
Effective models of wetting dynamics need to account for differing channels of dissipation. One such model was recently verified by large-scale molecular dynamics (MD). It combines the 2-parameter molecular-kinetic theory of dynamic wetting (MKT), which attributes the velocity-dependence of θ to dissipation at the contact line, with the Cox-Voinov hydrodynamic (HD) model. The latter attributes the difference between θ and θapp to viscous bending of the interface and contains an additional, non-predictable, logarithmic parameter. Crucially, the MD simulations indicated that viscous bending may play a minor role during wetting, but dominates dewetting. This observation suggested that by applying the MKT to the advancing contact angle only and combining the results with the maximum velocity of dewetting, it might be possible to extract the value of the logarithmic parameter and so determine θ and, hence, the relative significance of the two channels of dissipation. A simple iterative procedure has been developed to achieve this.
Data available to test the procedure are sparce, but comparisons with the MD results and those from three experimental studies are encouraging. Near perfect agreement is achieved with the simulations, where both θ and θapp are known, and plausible results are obtained for the experimental systems. Moreover, the procedure appears to be more effective than simply fitting θapp to the 3-parameter model.
A structural characterization of the interaction between αβ TCRs and cognate peptide-MHC (pMHC) is central to understanding adaptive T cell-mediated immunity. X-ray crystallography, although the ...source of much structural data, traditionally provides only a static snapshot of the protein. Given the emerging evidence for the important role of conformational dynamics in protein function, we interrogated 309 crystallographic structures of pMHC complexes using ensemble refinement, a technique that can extract dynamic information from the x-ray data. Focusing on a subset of human pMHC class I systems, we found that in many cases, ensemble methods were able to uncover previously hidden evidence of significant conformational plasticity, thereby revealing additional information that can build upon and significantly enhance functional interpretations that are based on a single static structure. Notable examples include the interpretation of differences in the disease association of HLA subtypes, the relationship between peptide prominence and TCR recognition, the role of conformational flexibility in vaccine design, and the discrimination between induced fit and conformational selection models of TCR binding. We show that the currently widespread practice of analyzing pMHC interactions via the study of a single crystallographic structure does not make use of pertinent and easily accessible information from x-ray data concerning alternative protein conformations. This new analysis therefore not only highlights the capacity for ensemble methods to significantly enrich the interpretation of decades of structural data but also provides previously missing information concerning the dynamics of existing characterized TCR-pMHC interactions.
Mucosal immune activation, in the context of sexual transmission of HIV-1 infection, is crucial, as the increased presence of activated T cells enhance susceptibility to infection. In this regard, it ...has been proposed that immunomodulatory compounds capable of modulating immune activation, such as Vitamin D (VitD) may reduce HIV-1 transmission and might be used as a safe and cost-effective strategy for prevention. Considering this, we examined the in vitro effect of the treatment of peripheral blood mononuclear cells (PBMCs) with the active form of VitD, calcitriol, on cellular activation, function and susceptibility of CD4+ T cells to HIV-1 infection.
We treated PBMCs from healthy HIV unexposed individuals (Co-HC) and frequently exposed, HIV-1 seronegative individuals (HESNs) from Colombia and from healthy non-exposed individuals from Canada (Ca-HC) with calcitriol and performed in vitro HIV-1 infection assays using X4- and R5-tropic HIV-1 strains respectively. In addition, we evaluated the activation and function of T cells and the expression of viral co-receptors, and select antiviral genes following calcitriol treatment.
Calcitriol reduced the frequency of infected CD4+ T cells and the number of viral particles per cell, for both, X4- and R5-tropic viruses tested in the Co-HC and the Ca-HC, respectively, but not in HESNs. Furthermore, in the Co-HC, calcitriol reduced the frequency of polyclonally activated T cells expressing the activation markers HLA-DR and CD38, and those HLA-DR+CD38-, whereas increased the subpopulation HLA-DR-CD38+. Calcitriol treatment also decreased production of granzyme, IL-2 and MIP-1β by T cells and increased the transcriptional expression of the inhibitor of NF-kB and the antiviral genes cathelicidin (CAMP) and APOBEC3G in PBMCs from Co-HC.
Our in vitro findings suggest that VitD treatment could reduce HIV-1 transmission through a specific modulation of the activation levels and function of T cells, and the production of antiviral factors. In conclusion, VitD remains as an interesting potential strategy to prevent HIV-1 transmission that should be further explored.
The development of metalated covalent organic frameworks (COFs) is useful for generating recyclable catalytic systems for practical applications. Herein, we report the synthesis, characterization, ...and catalytic properties of an azine-linked two-dimensional (2D) COF containing nickel-doped dehydrobenzoannulene (DBA) units. We demonstrate that Ni-DBA-2D-COF can be used to reductively cleave the aryl C–S bonds of several organosulfur compounds utilizing dimethylethylsilane as the reducing agent. The Ni-DBA-2D-COF catalytic system displays excellent recyclability and good yields. This work highlights a rare example of utilizing metalated DBA complexes to perform catalytic transformations.
Weak decays of the vector
D
∗
0
and
B
(
s
)
∗
0
mesons to the
μ
+
μ
-
final state provide novel potential to test the Standard Model of particle physics. Such processes have extremely small branching ...fractions as the vector mesons are able to decay through electromagnetic and (for the
D
∗
0
meson) strong interactions. Nonetheless, the production of copious quantities of these particles in LHC collisions, and the ability to exploit experimental techniques that can suppress background to low levels, provides good potential to reach interesting sensitivity. The possibility to reconstruct these processes as part of the decay chain of
B
-
or
B
c
+
mesons appears particularly attractive due to the clean experimental signature of the displaced vertex. Indeed, published LHCb data on
B
-
→
π
-
μ
+
μ
-
decays already implies a stringent limit on the branching fraction of
D
∗
0
→
μ
+
μ
-
. Estimates are made on the achievable sensitivity to
D
∗
0
→
μ
+
μ
-
and
B
(
s
)
∗
0
→
μ
+
μ
-
decays with the LHCb experiment.
We report an experimental study of the dynamics of spontaneous spreading of aqueous glycerol drops on glass. For a range of glycerol concentrations, we follow the evolution of the radius and contact ...angle over several decades of time and investigate the influence of solution viscosity. The application of the molecular kinetic theory to the resulting data allows us to extract the coefficient of contact-line friction ζ, the molecular jump frequency κ0, and the jump length λ for each solution. Our results show that the modified theory, which explicitly accounts for the effect of viscosity, can successfully be applied to droplet spreading. The viscosity affects the jump frequency but not the jump length. In combining these data, we confirm that the contact-line friction of the solution/air interface against the glass is proportional to the viscosity and exponentially dependent on the work of adhesion.
The agouti viable yellow (A
) allele is an insertional mutation in the mouse genome caused by a variably methylated intracisternal A particle (VM-IAP) retrotransposon. A
expressivity is sensitive to ...a range of early-life chemical exposures and nutritional interventions, suggesting that environmental perturbations can have long-lasting effects on the methylome. However, the extent to which VM-IAP elements are environmentally labile with phenotypic implications is unknown. Using a recently identified repertoire of VM-IAPs, we assessed the epigenetic effects of different environmental contexts. A longitudinal aging analysis indicated that VM-IAPs are stable across the murine lifespan, with only small increases in DNA methylation detected for a subset of loci. No significant effects were observed after maternal exposure to the endocrine disruptor bisphenol A, an obesogenic diet or methyl donor supplementation. A genetic mouse model of abnormal folate metabolism exhibited shifted VM-IAP methylation levels and altered VM-IAP-associated gene expression, yet these effects are likely largely driven by differential targeting by polymorphic KRAB zinc finger proteins. We conclude that epigenetic variability at retrotransposons is not predictive of environmental susceptibility.
EOS: a software for flavor physics phenomenology van Dyk, D.; Beaujean, F.; Blake, T. ...
The European physical journal. C, Particles and fields,
06/2022, Letnik:
82, Številka:
6
Journal Article
Recenzirano
Odprti dostop
EOS is an open-source software for a variety of computational tasks in flavor physics. Its use cases include theory predictions within and beyond the Standard Model of particle physics, Bayesian ...inference of theory parameters from experimental and theoretical likelihoods, and simulation of pseudo events for a number of signal processes. EOS ensures high-performance computations through a C++ back-end and ease of usability through a Python front-end. To achieve this flexibility, EOS enables the user to select from a variety of implementations of the relevant decay processes and hadronic matrix elements at run time. In this article, we describe the general structure of the software framework and provide basic examples. Further details and in-depth interactive examples are provided as part of the EOS online documentation.
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The thermal fluctuations of the three-phase contact line formed between a liquid and a solid at equilibrium can be used to determine key parameters that control dynamic wetting.
We ...use large-scale molecular dynamics simulations and Lennard-Jones potentials to model a liquid bridge between two molecularly smooth solid surfaces and study the positional fluctuations of the contact lines so formed as a function of the solid–liquid interaction.
We show that the fluctuations have a Gaussian distribution and may be modelled as an overdamped one-dimensional Langevin oscillator. Our analysis allows us to extract the coefficients of friction per unit length of the contact lines ζ, which arise from the collective interaction of the contact-line’s constituent liquid atoms with each other and the solid surface. We then compare these coefficients with those obtained by measuring the dynamic contact angle as a function of contact-line speed in independent simulations and applying the molecular-kinetic theory of dynamic wetting. We find excellent agreement between the two, with the same dependence on solid–liquid interaction and, therefore, the equilibrium contact angle θ0. As well as providing further evidence for the underlying validity of the molecular-kinetic model, our results suggest that it should be possible to predict the dynamics of wetting and, in particular, the velocity-dependence of the local, microscopic dynamic contact angle, by experimentally measuring the fluctuations of the contact line of a capillary system at equilibrium. This would circumvent the need to measure the microscopic dynamic contact angle directly.
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