Gap Junctions Suppress Electrical but Not [Ca2+] Heterogeneity in Resistance Arteries

Despite stochastic variation in the molecular composition and morphology of individual smooth muscle and endothelial cells, the membrane potential along intact microvessels is remarkably uniform. This is crucial for coordinated vasomotor responses. To investigate how this electrical homogeneity arises, a virtual arteriole was developed that introduces variation in the activities of ion-transport proteins between cells. By varying the level of heterogeneity and subpopulations of gap junctions (GJs), the resulting simulations shows that GJs suppress electrical variation but can only reduce cytosolic [Ca²⁺] variation. The process of electrical smoothing, however, introduces an energetic cost due to permanent currents, one which is proportional to the level of heterogeneity. This cost is particularly large when electrochemically different endothelial-cell and smooth-muscle-cell layers are coupled. Collectively, we show that homocellular GJs in a passively open state are crucial for electrical uniformity within the given cell layer, but homogenization may be limited by biophysical or energetic constraints. Owing to the ubiquitous presence of ion transport-proteins and cell-cell heterogeneity in biological tissues, these findings generalize across most biological fields.     

Anticancer potency of small linear and cyclic tetrapeptides and pharmacokinetic investigations of peptide binding to human serum albumin

We have in the present study explored the anticancer activity against human Burkitt's lymphoma cells (Ramos) of a series of small linear and cyclic tetrapeptides containing a β^2,2‐amino acid with either two 2‐naphthyl‐methylene or two para‐CF₃‐benzyl side chains, along with their interaction with the main plasma protein human serum albumin (HSA). The cyclic and more amphipathic tetrapeptides revealed a notably higher anticancer potency against Ramos cells [50% inhibitory concentration (IC₅₀) 11–70 μM] compared to the linear tetrapeptide counterparts (IC₅₀ 18.7 to >413 μM). The most potent cyclic tetrapeptide c3 had a 16.5‐fold preference for Ramos cells compared to human red blood cells, whereas the cyclic tetrapeptide c1 both showed low hemolytic activity and displayed the overall highest (2.9‐fold) preference for Ramos cells (IC₅₀ 23 μM) compared to healthy human lung fibroblast cells (MRC‐5). Investigating the interaction of selected tetrapeptides and recently reported hexapeptides with HSA revealed that the peptides bind to drug site II of HSA in the 22–28 μM range, disregarding size and overall structure. NMR and in silico molecular docking experiments identified the lipophilic residues as responsible for the interaction, but in vitro studies showed that the anticancer potency of the peptides varied in the presence of HSA and that c3 remained the most potent peptide. Based on our findings, we call for implementing serum albumin binding in development of anticancer peptides, as it may have implications for future administration and systemic distribution of peptide‐based cancer drugs. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.     

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A cerebellar-thalamocortical pathway drives behavioral context-dependent movement initiation

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13C-n.m.r. studies of monomeric composition and sequence in alginate

High-resolution, ¹³C-n.m.r. spectra of slightly depolymerised alginates have been interpreted. The sequence of monomer units, l-guluronate (G) and d-mannuronate (M), markedly influenced the chemical shifts. At 50 MHz, some of the individual carbon resonances of both units were resolved into four lines, in evident dependence upon the identities of the units immediately preceding and following them in the chains. The relative intensifies of the signals permitted rapid computation of (1) monomeric composition (M/G ratio), (2) monomeric sequence in terms of a complete set of four diad and eight triad frequencies, and (3) the composition (M/G ratio) of end units and of the units adjacent to M-residues at the non-reducing end. The diad frequencies indicated that alginate was a block co-polymer containing number-average, co-monomer block-lengths of ～2?8. The triad frequencies indicated average lengths of ～4?8 for blocks containing two or more units, these being somewhat longer for G- than for M-blocks. Regions of the chains having a strictly alternating sequence of M- and G-residues were short. The relative occurrence of G-centred triads deviated significantly from those predicted by first-order Markovian statistics.     

Hans Kappert zum 60. Geburtstag

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