Mathematical modeling mechanisms of arrhythmias in transgenic mouse heart overexpressing TNF-α

Transgenic mice overexpressing tumor necrosis factor-α (TNF-α mice) possess many of the features of human heart failure, such as dilated cardiomyopathy, impaired Ca(2+) handling, arrhythmias, and decreased survival. Although TNF-α mice have been studied extensively with a number of experimental methods, the mechanisms of heart failure are not completely understood. We created a mathematical model that reproduced experimentally observed changes in the action potential (AP) and Ca(2+) handling of isolated TNF-α mice ventricular myocytes. To study the contribution of the differences in ion currents, AP, Ca(2+) handling, and intercellular coupling to the development of arrhythmias in TNF-α mice, we further created several multicellular model tissues with combinations of wild-type (WT)/reduced gap junction conductance, WT/prolonged AP, and WT/decreased Na(+) current (I(Na)) amplitude. All model tissues were examined for susceptibility to Ca(2+) alternans, AP propagation block, and reentry. Our modeling results demonstrated that, similar to experimental data in TNF-α mice, Ca(2+) alternans in TNF-α tissues developed at longer basic cycle lengths. The greater susceptibility to Ca(2+) alternans was attributed to the prolonged AP, resulting in larger inactivation of I(Na), and to the decreased SR Ca(2+) uptake and corresponding smaller SR Ca(2+) load. Simulations demonstrated that AP prolongation induces an increased susceptibility to AP propagation block. Programmed stimulation of the model tissues with a premature impulse showed that reduced gap junction conduction increased the vulnerable window for initiation reentry, supporting the idea that reduced intercellular coupling is the major factor for reentrant arrhythmias in TNF-α mice.     

Characterization of precipitates formed by H2S-producing, Cu-resistant Firmicute isolates of Tissierella from human gut and Desulfosporosinus from mine waste

The purpose of this study was to characterize precipitates formed in anaerobic, H₂S-producing cultures of two Tissierella isolates and Desulfosporosinus strain DB. The cultures were grown in Cu-containing media as part of a larger study of Cu resistance in anaerobic sulfidogens. The Tissierella strains produced H₂S from peptone. Desulfosporosinus formed H₂S from peptone or through dissimilatory sulfate reduction with lactate. Tissierella cultures precipitated iron phosphate, vivianite, but no crystalline phases or Cu sulfides were detected. Multiple Cu sulfides, including chalcopyrite and covellite, were detected in Desulfosporosinus cultures but vivianite was not formed. Ion microprobe spectra and electron microscopic examination showed major variation in the elemental composition and morphological differences depending on incubation conditions. Extended incubation time for at least 1–2 months increased the crystallinity of the precipitates. The results highlight biogeochemical differences in sulfide and phosphate precipitates between the two major groups of Firmicutes although they may share the same habitat including the human intestinal tract.     

Interleukin-11 binds specific EF-hand proteins via their conserved structural motifs

Interleukin-11 (IL-11) is a hematopoietic cytokine engaged in numerous biological processes and validated as a target for treatment of various cancers. IL-11 contains intrinsically disordered regions that might recognize multiple targets. Recently we found that aside from IL-11RA and gp130 receptors, IL-11 interacts with calcium sensor protein S100P. Strict calcium dependence of this interaction suggests a possibility of IL-11 interaction with other calcium sensor proteins. Here we probed specificity of IL-11 to calcium-binding proteins of various types: calcium sensors of the EF-hand family (calmodulin, S100B and neuronal calcium sensors: recoverin, NCS-1, GCAP-1, GCAP-2), calcium buffers of the EF-hand family (S100G, oncomodulin), and a non-EF-hand calcium buffer (α-lactalbumin). A specific subset of the calcium sensor proteins (calmodulin, S100B, NCS-1, GCAP-1/2) exhibits metal-dependent binding of IL-11 with dissociation constants of 1–19 μM. These proteins share several amino acid residues belonging to conservative structural motifs of the EF-hand proteins, ‘black’ and ‘gray’ clusters. Replacements of the respective S100P residues by alanine drastically decrease its affinity to IL-11, suggesting their involvement into the association process. Secondary structure and accessibility of the hinge region of the EF-hand proteins studied are predicted to control specificity and selectivity of their binding to IL-11. The IL-11 interaction with the EF-hand proteins is expected to occur under numerous pathological conditions, accompanied by disintegration of plasma membrane and efflux of cellular components into the extracellular milieu.     

Functional development of hippocampal mossy fiber synapses in rabbits

The course of functional maturation with age of mossy fiber synapses on pyramidal cells in areas CA_3,4 of the dorsal hippocampus was investigated by extracellular recording of focal potentials and single unit responses of the hippocampus to electrical stimulation of the dentate fascia in waking, unimmobilized rabbits aged from 1 to 14 days. After the 4th day of postnatal life focal potentials appeared in response to single stimulation, in the form of a biphasic short-latency wave, characteristic of responses of the mature hippocampus, accompanied by spike discharges with a latent period of 3 to 10 msec and inhibitory responses of the hippocampal neurons. During the next 10 days the amplitude of the focal potentials increased from several hundred millivolts, with the sharpest increase observed from the 4th through the 7th days. In early age periods global and unitary responses were shown to be capable of frequency potentiation and also of short-term after-potentiation.Brain Institute, Academy of Medical Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 12, No. 3, pp. 246–254, May–June, 1980.