Facilitation of I Kr current by some hERG channel blockers suppresses early afterdepolarizations.

Drug-induced block of the cardiac rapid delayed rectifying potassium current (I Kr), carried by the human ether-a-go-go-related gene (hERG) channel, is the most common cause of acquired long QT syndrome. Indeed, some, but not all, drugs that block hERG channels cause fatal cardiac arrhythmias. However, there is no clear method to distinguish between drugs that cause deadly arrhythmias and those that are clinically safe. Here we propose a mechanism that could explain why certain clinically used hERG blockers are less proarrhythmic than others. We demonstrate that several drugs that block hERG channels, but have favorable cardiac safety profiles, also evoke another effect; they facilitate the hERG current amplitude in response to low-voltage depolarization. To investigate how hERG facilitation impacts cardiac safety, we develop computational models of I Kr block with and without this facilitation. We constrain the models using data from voltage clamp recordings of hERG block and facilitation by nifekalant, a safe class III antiarrhythmic agent. Human ventricular action potential simulations demonstrate the ability of nifekalant to suppress ectopic excitations, with or without facilitation. Without facilitation, excessive I Kr block evokes early afterdepolarizations, which cause lethal arrhythmias. When facilitation is introduced, early afterdepolarizations are prevented at the same degree of block. Facilitation appears to prevent early afterdepolarizations by increasing I Kr during the repolarization phase of action potentials. We empirically test this prediction in isolated rabbit ventricular myocytes and find that action potential prolongation with nifekalant is less likely to induce early afterdepolarization than action potential prolongation with dofetilide, a hERG channel blocker that does not induce facilitation. Our data suggest that hERG channel blockers that induce facilitation increase the repolarization reserve of cardiac myocytes, rendering them less likely to trigger lethal ventricular arrhythmias

The influence of physiological aging and atrophy on brain viscoelastic properties in humans

Physiological aging of the brain is accompanied by ubiquitous degeneration of neurons and oligodendrocytes. An alteration of the cellular matrix of an organ impacts its macroscopic viscoelastic properties which can be detected by magnetic resonance elastography (MRE)--to date the only method for measuring brain mechanical parameters without intervention. However, the wave patterns detected by MRE are affected by atrophic changes in brain geometry occurring in an individual's life span. Moreover, regional variability in MRE-detected age effects is expected corresponding to the regional variation in atrophy. Therefore, the sensitivity of brain MRE to brain volume and aging was investigated in 66 healthy volunteers aged 18-72. A linear decline in whole-brain elasticity was observed (-0.75%/year, R-square = 0.59, p<0.001); the rate is three times that determined by volume measurements (-0.23%/year, R-square = 0.4, p<0.001). The highest decline in elasticity (-0.92%/year, R-square = 0.43, p<0.001) was observed in a region of interest placed in the frontal lobe with minimal age-related shrinkage (-0.1%, R-square = 0.06, p = 0.043). Our results suggest that cerebral MRE can measure geometry-independent viscoelastic parameters related to intrinsic tissue structure and altered by age

Simulating local deformations in the human cortex due to blood flow-induced changes in mechanical tissue properties: Impact on functional magnetic resonance imaging

Investigating human brain tissue is challenging due to the complexity and the manifold interactions between structures across different scales. Increasing evidence suggests that brain function and microstructural features including biomechanical features are related. More importantly, the relationship between tissue mechanics and its influence on brain imaging results remains poorly understood. As an important example, the study of the brain tissue response to blood flow could have important theoretical and experimental consequences for functional magnetic resonance imaging (fMRI) at high spatial resolutions. Computational simulations, using realistic mechanical models can predict and characterize the brain tissue behavior and give us insights into the consequent potential biases or limitations of in vivo, high-resolution fMRI. In this manuscript, we used a two dimensional biomechanical simulation of an exemplary human gyrus to investigate the relationship between mechanical tissue properties and the respective changes induced by focal blood flow changes. The model is based on the changes in the brain’s stiffness and volume due to the vasodilation evoked by neural activity. Modeling an exemplary gyrus from a brain atlas we assessed the influence of different potential mechanisms: (i) a local increase in tissue stiffness (at the level of a single anatomical layer), (ii) an increase in local volume, and (iii) a combination of both effects. Our simulation results showed considerable tissue displacement because of these temporary changes in mechanical properties. We found that the local volume increase causes more deformation and consequently higher displacement of the gyrus. These displacements introduced considerable artifacts in our simulated fMRI measurements. Our results underline the necessity to consider and characterize the tissue displacement which could be responsible for fMRI artifacts

Systemic shRNA mediated knock down of S100A4 in colorectal cancer xenografted mice reduces metastasis formation

The metastasis-inducing protein S100A4 was found to be a prognostic indicator for the development of metachronous metastases. S100A4 expression levels correlate with the formation of human colorectal cancer metastases and shorter patients' survival. Inhibition of S100A4 expression in patients might therefore result in decreased metastasis formation and prolonged survival. In the present study, we used shRNA expression plasmids to inhibit S100A4 expression in the colorectal cancer cell lines HCT116, SW620 and DLD-1. Cell lines with reduced S100A4 expression showed reduced cell migration and invasion in vitro. The knock-down of S100A4 expression also led to significantly diminished formation of liver metastases when intrasplenically transplanted in mice (P = 0.004). We then focused on the therapeutic potential of systemically applied shRNA expression plasmids acting on S100A4 via repeated hydrodynamics-based tail vein injection of plasmid DNA. Mice, intrasplenically transplanted with HCT116 cells and treated systemically with S100A4‑shRNA plasmids, showed a decrease of S100A4 and MMP9 expression levels, resulting in significantly reduced liver metastases (P = 0.005). In summary, we show for the first time the intratumoral knock down of S100A4 via systemic application of S100A4‑shRNA plasmid DNA, which restricts metastasis formation in a xenografted mouse model of colorectal cancer

Individual-specific changes in the human gut microbiota after challenge with enterotoxigenic Escherichia coli and subsequent ciprofloxacin treatment

Acknowledgements The authors wish to thank Mark Stares, Richard Rance, and other members of the Wellcome Trust Sanger Institute’s 454 sequencing team for generating the 16S rRNA gene data. Lili Fox Vélez provided editorial support. Funding IA, JNP, and MP were partly supported by the NIH, grants R01-AI-100947 to MP, and R21-GM-107683 to Matthias Chung, subcontract to MP. JNP was partly supported by an NSF graduate fellowship number DGE750616. IA, JNP, BRL, OCS and MP were supported in part by the Bill and Melinda Gates Foundation, award number 42917 to OCS. JP and AWW received core funding support from The Wellcome Trust (grant number 098051). AWW, and the Rowett Institute of Nutrition and Health, University of Aberdeen, receive core funding support from the Scottish Government Rural and Environmental Science and Analysis Service (RESAS).Peer reviewedPublisher PD

Magnetic resonance elastography reveals altered brain viscoelasticity in experimental autoimmune encephalomyelitis

Cerebral magnetic resonance elastography (MRE) measures the viscoelastic properties of brain tissues in vivo. It was recently shown that brain viscoelasticity is reduced in patients with multiple sclerosis (MS), highlighting the potential of cerebral MRE to detect tissue pathology during neuroinflammation. To further investigate the relationship between inflammation and brain viscoelasticity, we applied MRE to a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). EAE was induced and monitored by MRE in a 7-tesla animal MRI scanner over 4 weeks. At the peak of the disease (day 14 after immunization), we detected a significant decrease in both the storage modulus (G') and the loss modulus (G″), indicating that both the elasticity and the viscosity of the brain are reduced during acute inflammation. Interestingly, these parameters normalized at a later time point (day 28) corresponding to the clinical recovery phase. Consistent with this, we observed a clear correlation between viscoelastic tissue alteration and the magnitude of perivascular T cell infiltration at both day 14 and day 28. Hence, acute neuroinflammation is associated with reduced mechanical cohesion of brain tissues. Moreover, the reduction of brain viscoelasticity appears to be a reversible process, which is restored when inflammation resolves. For the first time, our study has demonstrated the applicability of cerebral MRE in EAE, and showed that this novel imaging technology is highly sensitive to early tissue alterations resulting from the inflammatory processes. Thus, MRE may serve to monitor early stages of perivascular immune infiltration during neuroinflammation

Synthetic Analogues of the Snail Toxin 6-Bromo-2-mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Modulation of Voltage-Gated Potassium Channels

Drugs do not act solely by canonical ligand–receptor binding interactions. Amphiphilic drugs partition into membranes, thereby perturbing bulk lipid bilayer properties and possibly altering the function of membrane proteins. Distinguishing membrane perturbation from more direct protein–ligand interactions is an ongoing challenge in chemical biology. Herein, we present one strategy for doing so, using dimeric 6-bromo-2-mercaptotryptamine (BrMT) and synthetic analogues. BrMT is a chemically unstable marine snail toxin that has unique effects on voltage-gated K+ channel proteins, making it an attractive medicinal chemistry lead. BrMT is amphiphilic and perturbs lipid bilayers, raising the question of whether its action against K+ channels is merely a manifestation of membrane perturbation. To determine whether medicinal chemistry approaches to improve BrMT might be viable, we synthesized BrMT and 11 analogues and determined their activities in parallel assays measuring K+ channel activity and lipid bilayer properties. Structure–activity relationships were determined for modulation of the Kv1.4 channel, bilayer partitioning, and bilayer perturbation. Neither membrane partitioning nor bilayer perturbation correlates with K+ channel modulation. We conclude that BrMT’s membrane interactions are not critical for its inhibition of Kv1.4 activation. Further, we found that alkyl or ether linkages can replace the chemically labile disulfide bond in the BrMT pharmacophore, and we identified additional regions of the scaffold that are amenable to chemical modification. Our work demonstrates a strategy for determining if drugs act by specific interactions or bilayer-dependent mechanisms, and chemically stable modulators of Kv1 channels are reported

Territorial Tactics: The Socio-spatial Significance of Private Policing Strategies in Cape Town

This paper analyses the policing strategies of private security companies operating in urban space. An existing literature has considered the variety of ways that territory becomes of fundamental importance in the work of public police forces. However, this paper examines territory in the context of private security companies. Drawing on empirical research in Cape Town, it examines how demarcated territories become key subjects in private policing. Private security companies are responsible for a relatively small section of the city, while in contrast the public police ultimately have to see city space as a whole. Hence, private policing strategy becomes one of displacement, especially of so-called undesirables yielding a patchworked public space associated with private enclaves of consumption. The conclusions signal the historical resonances and comparative implications of these political-legal-security dynamics. © 2013 Urban Studies Journal Limited

The Quantum Mellin transform

We uncover a new type of unitary operation for quantum mechanics on the half-line which yields a transformation to ``Hyperbolic phase space''. We show that this new unitary change of basis from the position x on the half line to the Hyperbolic momentum $p_\eta$, transforms the wavefunction via a Mellin transform on to the critial line $s=1/2-ip_\eta$. We utilise this new transform to find quantum wavefunctions whose Hyperbolic momentum representation approximate a class of higher transcendental functions, and in particular, approximate the Riemann Zeta function. We finally give possible physical realisations to perform an indirect measurement of the Hyperbolic momentum of a quantum system on the half-line.Comment: 23 pages, 6 Figure