Tumor necrosis factor (TNF) inhibitors (anti-TNFs) represent a cornerstone of the treatment of various immune-mediated inflammatory diseases and are among the most commercially successful therapeutic ...agents. Knowledge of TNF binding partners is critical for identification of the factors able to affect clinical efficacy of the anti-TNFs. Here, we report that among eighteen representatives of the multifunctional S100 protein family, only S100A11, S100A12 and S100A13 interact with the soluble form of TNF (sTNF) in vitro. The lowest equilibrium dissociation constants (
) for the complexes with monomeric sTNF determined using surface plasmon resonance spectroscopy range from 2 nM to 28 nM. The apparent
values for the complexes of multimeric sTNF with S100A11/A12 estimated from fluorimetric titrations are 0.1-0.3 µM. S100A12/A13 suppress the cytotoxic activity of sTNF against Huh-7 cells, as evidenced by the MTT assay. Structural modeling indicates that the sTNF-S100 interactions may interfere with the sTNF recognition by the therapeutic anti-TNFs. Bioinformatics analysis reveals dysregulation of TNF and S100A11/A12/A13 in numerous disorders. Overall, we have shown a novel potential regulatory role of the extracellular forms of specific S100 proteins that may affect the efficacy of anti-TNF treatment in various diseases.
Abstract
The ocean energy cycle is calculated using a new available potential energy (APE) decomposition, which partitions adiabatic buoyancy fluxes from diapycnal mixing, applied to results from the ...Estimating the Circulation and Climate of the Ocean, Phase II (ECCO2), eddy-permitting ocean state estimate and observed surface buoyancy fluxes from the WHOI OAFlux project. Compared with the traditional Lorenz energy cycle, this framework provides a more accurate estimate of the background potential energy (PE) of the global oceans and the surface generation and interior fluxes of APE. Calculations of the global energy budget using 16 yr of ECCO2 output suggest that the adiabatic portion of the general circulation is maintained by a balance between the mean wind-driven upwelling that increases APE (+0.27 TW) and time-fluctuating processes, including mesoscale eddies, which release APE (−0.27 TW). The APE generated by surface buoyancy fluxes (0.46 TW) is comparable to the generation by the mean winds. The global rate of irreversible mixing (0.46 TW), which balances surface APE generation, is consistent with previous estimates of the diapycnal fluxes associated with maintaining deep stratification (see Munk and Wunsch) and a global diapycnal diffusivity of
O
(1 × 10
−4
) m
2
s
−1
. However, the net contribution of diapycnal mixing to the total potential energy is negligible, which suggests that mixing, contrary to one current paradigm, does not place a global demand on kinetic energy dissipation. However, there are regions where mixing is significant, for example, between 3000 and 5000 m (in ECCO2), where mixing increases PE by 0.1 TW. The work provides a new framework for separating adiabatic–diabatic fluxes and for monitoring the global rate of diapycnal mixing rate using measurable surface properties such as SST and heat flux.
The problem of optimal initial disturbances in thermal wind shear is revisited and extended to include non-hydrostatic effects. This systematic study compares transient and modal growth rates of ...submesoscale instabilities over a large range of zonal and meridional wavenumbers, aspect ratios and different Richardson number regimes. Selection criteria were derived to remove spurious and unresolved instability modes that arise from the eigenvalue problem and we generalize the study of the hydrostatic Eady problem by Heifetz & Farrell (
J. Atmos. Sci.
, vol. 60, 2003;
J. Atmos. Sci.
, vol. 64 (12), 2007, pp. 4366–4382;
Q. J. R. Meteorol. Soc.
, vol. 134 (635), 2008, pp. 1627–1633) to thin fronts, characterized by large aspect ratios. Such fronts are commonly found at the early stages of frontogenesis, for example, in the ocean mesoscale eddies and near the eye wall of hurricanes. In particular, we show that transient energy growth rates are up to two orders of magnitude larger than modal counterparts for a wide range of Richardson number and that the effects of transient energy gain become even greater when non-hydrostatic effects become important and/or for large Richardson numbers. This study also compares the dominant energy pathways contributing to the energy growth at short and long times. For symmetric modes, we recover the inertia–gravity instability described in Xu
et al.
(
J. Atmos. Sci.
, vol. 64 (6), 2007, pp. 1764–1781). These mechanisms are shown to be the most powerful mediator of vertical transport when compared with the fastest growing baroclinic and symmetric modes. These results highlight the importance of transient processes in the ocean and the atmosphere.
Abstract A series of idealized numerical simulations is used to examine the generation of mode-one superinertial coastally trapped waves (CTW). In the first set of simulations, CTW are resonantly ...generated when freely propagating mode-one internal tides are incident on the coast such that the angle of incidence of the internal wave causes the projected wavenumber of the tide on the coast to satisfy a triad relationship with the wavenumbers of the bathymetry and the CTW. In the second set of simulations, CTW are generated by the interaction of the barotropic tide with topography that has the same scales as the CTW. Under resonant conditions superinertial coastally trapped waves are a leading order coastal process, with along-shore current magnitudes that can be larger than the barotropic or internal tides from which they are generated.
•Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an important growth factor.•Dimeric Ca-loaded forms of S100A4, S100A6, and S100P proteins binds to GM-CSF.•Calcium removal prevents ...binding to GM-CSF.•S100A4/A6 inhibit GM-CSF-induced suppression of viability of monocytic THP-1 cells.•A conserved S100A4/A6/P-binding site in the GM-CSF molecule was found by structural modelling.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic myelopoietic growth factor and proinflammatory cytokine, clinically used for multiple indications and serving as a promising target for treatment of many disorders, including cancer, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, COVID-19. We have previously shown that dimeric Ca2+-bound forms of S100A6 and S100P proteins, members of the multifunctional S100 protein family, are specific to GM-CSF. To probe selectivity of these interactions, the affinity of recombinant human GM-CSF to dimeric Ca2+-loaded forms of 18 recombinant human S100 proteins was studied by surface plasmon resonance spectroscopy. Of them, only S100A4 protein specifically binds to GM-CSF with equilibrium dissociation constant, Kd, values of 0.3–2 μM, as confirmed by intrinsic fluorescence and chemical crosslinking data. Calcium removal prevents S100A4 binding to GM-CSF, whereas monomerization of S100A4/A6/P proteins disrupts S100A4/A6 interaction with GM-CSF and induces a slight decrease in S100P affinity for GM-CSF. Structural modelling indicates the presence in the GM-CSF molecule of a conserved S100A4/A6/P-binding site, consisting of the residues from its termini, helices I and III, some of which are involved in the interaction with GM-CSF receptors. The predicted involvement of the ‘hinge’ region and F89 residue of S100P in GM-CSF recognition was confirmed by mutagenesis. Examination of S100A4/A6/P ability to affect GM-CSF signaling showed that S100A4/A6 inhibit GM-CSF-induced suppression of viability of monocytic THP-1 cells. The ability of the S100 proteins to modulate GM-CSF activity is relevant to progression of various neoplasms and other diseases, according to bioinformatics analysis. The direct regulation of GM-CSF signaling by extracellular forms of the S100 proteins should be taken into account in the clinical use of GM-CSF and development of the therapeutic interventions targeting GM-CSF or its receptors.
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Medical history, disease onset, clinical symptoms, and results of neuroimaging of 14 glossopharyngeal schwannoma patients, who were examined and treated in the Subtentorial Neurooncology Department ...of the State Institution, Romodanov Institute of Neurosurgery of the NAMS of Ukraine (8 patients) and the Neurosurgery Department No. 2 of the Municipal Enterprise, Mechnikov Dnipropetrovsk Regional Clinical Hospital of Dnipropetrovsk Regional Council (6 patients) in 2018 to 2021 have been analyzed in details. The study inclusion criteria were as follows: patient’s age over 18, presence of unilateral primary glossopharyngeal nerve schwannoma. Our study showed that most of clinical signs and symptoms of the glossopharyngeal nerve schwannoma are associated with otolaryngological disorders (such as hearing loss, tinnitus, hoarseness, or dizziness) or cerebellar disorders (such as ataxia, nystagmus, or dizziness). Neuroimaging cerebellopontine angle tumors diagnosis must include brain computed tomography (with mandatory assessment of the state of jugular foramen and internal auditory canal) and IV contrast brain magnetic resonance tomography and inclusion of high-resolution sequences, gradient echo (3D CISS, DRIVE, TRUFFI, B-FFE) with the aim of better visualization and differentiation of various cerebellopontine angle cranial nerves. The study demonstrates the complexity of a reliable preoperative diagnosis when using standard diagnostic tools. Preoperative jugular foramen and cerebellopontine angle tumors diagnosis should be based on a systematic approach and include a comparison of results of comprehensive clinical and instrumental examination and neuroimaging studies.
The possibility of using a modified composition based on slag Portland cement with the addition of stabilized finely dispersed slag in geotechnical construction and in landscape design is considered. ...The physical, mechanical and structural characteristics of samples hardening in normal conditions and under the influence of aggressive media were studied. It is established that the compressive and flexural strength of the modified samples is higher than that of the control sample. When hardening in normal conditions, on the first day, the flexural strength of modified specimens increased by 59%, at the grade age by 51%, compressive strength - 2.3 times and by 83%, respectively. When hardening in aggressive media, an increase in the strength of the modified specimens is also observed (flexural by 35–58%, compressive by 7–15%). This is explained by the fact that stabilized slag particles in a hardening system perform two functions: they are centers of directional crystallization for nucleation and growth of newgrowths, and full participants in the hydration process, binding calcium hydroxide to crystallohydrate compounds, thereby preventing the formation of ettringite when the concrete structure is exposed to aggressive media.
The data on the possibility of obtaining transition metal ferrocyanides, which are highly selective compounds with respect to cesium, in polysaccharide matrices (cellulose, chitin, chitosan) are ...systematized and generalized. Based on the electron microscopy data, it has been found that the distribution of the sorption active component (nickel ferrocyanide) in the chitosan matrix is fairly uniform. The crystallite sizes calculated from X-ray powder diffraction data are significantly higher for Zn–K chitosan/ferrocyanide sorbent as compared to Ni–K and Cu–K chitosan/ferrocyanide sorbents. A comparative analysis of the sorption properties and stabilities of the Zn–K, Zn–Ni, and Cu–K chitosan/ferrocyanide sorbents and sorbent Thermoxide-35 in the extraction of cesium from alkaline mineralized solutions and seawater has been carried out.
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