Based on scientific facts and the analysis of literature, and the experience of the author, Chlamydiae and Chlamydial Infections attempts to shed light on the cited problems, in terms of modern ...microbiology, cell biology and molecular biology.
Functional effectiveness of erythrocytes depends on their high deformability that allows them to pass through narrow tissue capillaries. The erythrocytes can deform easily due to discoid shape ...provided by the stabilization of an optimal cell volume at a given cell surface area. We used mathematical simulation to study the role of transport Na/K-ATPase and transmembrane Na+ and K+ gradients in human erythrocyte volume stabilization at non-selective increase in cell membrane permeability to cations. The model included Na/K-ATPase activated by intracellular Na+, Na+ and K+ transmembrane gradients, and took into account contribution of glycolytic metabolites and adenine nucleotides to cytoplasm osmotic pressure. We found that this model provides the best stabilization of the erythrocyte volume at non-selective increase in the permeability of the cell membrane, which can be caused by an oxidation of the membrane components or mechanical stress during circulation. The volume of the erythrocyte deviates from the optimal value by no more than 10% with a change in the non-selective permeability of the cell membrane to cations from 50 to 200% of the normal value. If only one transmembrane ion gradient is present (Na+), the cell loses the ability to stabilize volume and even small changes in membrane permeability cause dramatic changes in the cell volume. Our results reveal that the presence of two oppositely directed transmembrane ion gradients is fundamentally important for robust stabilization of cellular volume in human erythrocytes.
While performance management (PM) is pervasive across contemporary workplaces, extant research into how performance management affects workers is often indirect or scattered across disciplinary ...silos. This paper reviews and synthesizes this research, identifies key gaps and explores ‘recognition theory’ as a nascent framework that can further develop this important body of knowledge. The paper develops in three main stages. The first stage reviews ‘mainstream’ human resource management (HRM) research. While this research analyses workers’ reactions to performance management in some depth, its focus on serving organizational goals marginalizes extra‐organizational impacts. The second stage reviews more critical HRM research, which interprets performance management as a disciplinary, coercive or inequitable management device. While this literature adds an important focus on organizational power, there is scope to analyse further how PM affects workers’ well‐being. To develop this strand of PM research, the third stage turns to the emerging field of recognition theory independently developed by Axel Honneth and Christophe Dejours. The authors focus especially on recognition theory's exploration of how (in)adequate acknowledgement of workers’ contributions can significantly affect their well‐being at the level of self‐conception. Although recognition theory is inherently critical, the paper argues that it can advance both mainstream and critical performance management research, and also inform broader inquiry into recognition and identity at work.
•Mast cells are increasingly associated with pathophysiology of pain disorders.•Mast cell-focused pre-clinical rodent models of pain can reveal relevant mechanisms.•Mast cell-neuron synapses in the ...tissue modulate nociceptive signal cascades.•Mast cell contributions to central and peripheral pain will inform new therapeutics.
Mast cells are important first responders in protective pain responses that provoke withdrawal from intense, noxious environmental stimuli, in part because of their sentinel location in tissue–environment interfaces. In chronic pain disorders, the proximity of mast cells to nerves potentiates critical molecular cross-talk between these two cell types that results in their synergistic contribution to the initiation and propagation of long-term changes in pain responses via intricate signal networks of neurotransmitters, cytokines and adhesion molecules. Both in rodent models of inflammatory pain and chronic pain disorders, as well as in increasing evidence from the clinic, it is abundantly clear that understanding the mast cell-mediated mechanisms underlying protective and maladaptive pain cascades will lead to improved understanding of mast cell biology as well as the development of novel, targeted therapies for the treatment and management of debilitating pain conditions.
Purpose
To introduce the heterogeneous multiscale (HetMS) model for Monte Carlo simulations of gold nanoparticle dose‐enhanced radiation therapy (GNPT), a model characterized by its varying levels of ...detail on different length scales within a single phantom; to apply the HetMS model in two different scenarios relevant for GNPT and to compare computed results with others published.
Methods
The HetMS model is implemented using an extended version of the EGSnrc user‐code egs_chamber; the extended code is tested and verified via comparisons with recently published data from independent GNP simulations. Two distinct scenarios for the HetMS model are then considered: (a) monoenergetic photon beams (20 keV to 1 MeV) incident on a cylinder (1 cm radius, 3 cm length); (b) isotropic point source (brachytherapy source spectra) at the center of a 2.5 cm radius sphere with gold nanoparticles (GNPs) diffusing outwards from the center. Dose enhancement factors (DEFs) are compared for different source energies, depths in phantom, gold concentrations, GNP sizes, and modeling assumptions, as well as with independently published values. Simulation efficiencies are investigated.
Results
The HetMS MC simulations account for the competing effects of photon fluence perturbation (due to gold in the scatter media) coupled with enhanced local energy deposition (due to modeling discrete GNPs within subvolumes). DEFs are most sensitive to these effects for the lower source energies, varying with distance from the source; DEFs below unity (i.e., dose decreases, not enhancements) can occur at energies relevant for brachytherapy. For example, in the cylinder scenario, the 20 keV photon source has a DEF of 3.1 near the phantom's surface, decreasing to less than unity by 0.7 cm depth (for 20 mg/g). Compared to discrete modeling of GNPs throughout the gold‐containing (treatment) volume, efficiencies are enhanced by up to a factor of 122 with the HetMS approach. For the spherical phantom, DEFs vary with time for diffusion, radionuclide, and radius; DEFs differ considerably from those computed using a widely applied analytic approach.
Conclusions
By combining geometric models of varying complexity on different length scales within a single simulation, the HetMS model can effectively account for both macroscopic and microscopic effects which must both be considered for accurate computation of energy deposition and DEFs for GNPT. Efficiency gains with the HetMS approach enable diverse calculations which would otherwise be prohibitively long. The HetMS model may be extended to diverse scenarios relevant for GNPT, providing further avenues for research and development.
Sulfide oxidation is expected to play an important role in cellular switching between low steady-state intracellular hydrogen sulfide levels and the higher concentrations where the physiological ...effects are elicited. Yet despite its significance, fundamental questions regarding how the sulfide oxidation pathway is wired remain unanswered, and competing proposals exist that diverge at the very first step catalyzed by sulfide quinone oxidoreductase (SQR). We demonstrate that, in addition to sulfite, glutathione functions as a persulfide acceptor for human SQR and that rhodanese preferentially synthesizes rather than utilizes thiosulfate. The kinetic behavior of these enzymes provides compelling evidence for the flow of sulfide via SQR to glutathione persulfide, which is then partitioned to thiosulfate or sulfite. Kinetic simulations at physiologically relevant metabolite concentrations provide additional support for the organizational logic of the sulfide oxidation pathway in which glutathione persulfide is the first intermediate formed.
Gold NanoParticle (GNP) dose-enhanced radiation therapy (GNPT) requires consideration of physics across macro- to microscopic length scales, however, this presents computational challenges that have ...limited previous investigations.
To develop and apply multiscale Monte Carlo (MC) simulations to assess variations in nucleus and cytoplasm dose enhancement factors (n,cDEFs) over tumor-scale volumes.
The intrinsic variation of n,cDEFs (due to fluctuations in local gold concentration and cell/nucleus size variation) are estimated via MC modeling of varied cellular GNP uptake and cell/nucleus sizes. Then, the Heterogeneous MultiScale (HetMS) model is implemented in MC simulations by combining detailed models of populations of cells containing GNPs within simplified macroscopic tissue models to evaluate n,cDEFs. Simulations of tumors with spatially uniform gold concentrations (5, 10, or 20 mg
/g
) and spatially varying gold concentrations eluted from a point are performed to determine n,cDEFs as a function of distance from the source for 10 to 370 keV photons. All simulations are performed for three different intracellular GNP configurations: GNPs distributed on the surface of the nucleus (perinuclear) and GNPs packed into one or four endosome(s).
Intrinsic variations in n,cDEFs can be substantial, for example, if GNP uptake and cell/nucleus radii are varied by 20%, variations of up to 52% in nDEF and 25% in cDEF are observed compared to the nominal values for uniform cell/nucleus size and GNP concentration. In HetMS models of macroscopic tumors, subunity n,cDEFs (i.e., dose decreases) can occur for low energies and high gold concentrations due to attenuation of primary photons through the gold-filled volumes, for example, n,cDEF<1 is observed 3 mm from a 20 keV source for the four endosome configuration. In HetMS simulations of tumors with spatially uniform gold concentrations, n,cDEFs decrease with depth into the tumor as photons are attenuated, with relative differences between GNP models remaining approximately constant with depth in the tumor. Similar initial n,cDEF decreases with radius are seen in the tumors with spatially varying gold concentrations, but the n,cDEFs for all of the GNP configurations converge to a single value for each energy as gold concentration reaches zero.
The HetMS framework has been implemented for multiscale MC simulations of GNPT to compute n,cDEFs over tumor-scale volumes, with results demonstrating that cellular doses are highly sensitive to cell/nucleus size, GNP intracellular distribution, gold concentration, and cell position in tumor. This work demonstrates the importance of proper choice of computational model when simulating GNPT scenarios and the need to account for intrinsic variations in n,cDEFs due to variations in cell/nucleus size and gold concentration.
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