Current status and future directions of botulinum neurotoxins for targeting pain processing.

Current evidence suggests that botulinum neurotoxins (BoNTs) A1 and B1, given locally into peripheral tissues such as skin, muscles, and joints, alter nociceptive processing otherwise initiated by inflammation or nerve injury in animal models and humans. Recent data indicate that such locally delivered BoNTs exert not only local action on sensory afferent terminals but undergo transport to central afferent cell bodies (dorsal root ganglia) and spinal dorsal horn terminals, where they cleave SNAREs and block transmitter release. Increasing evidence supports the possibility of a trans-synaptic movement to alter postsynaptic function in neuronal and possibly non-neuronal (glial) cells. The vast majority of these studies have been conducted on BoNT/A1 and BoNT/B1, the only two pharmaceutically developed variants. However, now over 40 different subtypes of botulinum neurotoxins (BoNTs) have been identified. By combining our existing and rapidly growing understanding of BoNT/A1 and /B1 in altering nociceptive processing with explorations of the specific characteristics of the various toxins from this family, we may be able to discover or design novel, effective, and long-lasting pain therapeutics. This review will focus on our current understanding of the molecular mechanisms whereby BoNTs alter pain processing, and future directions in the development of these agents as pain therapeutics

Anomalous lateral diffusion in a viscous membrane surrounded by viscoelastic media

We investigate the lateral dynamics in a purely viscous lipid membrane surrounded by viscoelastic media such as polymeric solutions. We first obtain the generalized frequency-dependent mobility tensor and focus on the case when the solvent is sandwiched by hard walls. Due to the viscoelasticity of the solvent, the mean square displacement of a disk embedded in the membrane exhibits an anomalous diffusion. An useful relation which connects the mean square displacement and the solvent modulus is provided. We also calculate the cross-correlation of the particle displacements which can be applied for two-particle tracking experiments.Comment: 6 pages, 2 figure

Compressive force generation by a bundle of living biofilaments

To study the compressional forces exerted by a bundle of living stiff filaments pressing on a surface, akin to the case of an actin bundle in filopodia structures, we have performed particulate Molecular Dynamics simulations of a grafted bundle of parallel living (self-assembling) filaments, in chemical equilibrium with a solution of their constitutive monomers. Equilibrium is established as these filaments, grafted at one end to a wall of the simulation box, grow at their chemically active free end and encounter the opposite confining wall of the simulation box. Further growth of filaments requires bending and thus energy, which automatically limit the populations of longer filaments. The resulting filament sizes distribution and the force exerted by the bundle on the obstacle are analyzed for different grafting densities and different sub- or supercritical conditions, these properties being compared with the predictions of the corresponding ideal confined bundle model. In this analysis, non-ideal effects due to interactions between filaments and confinement effects are singled out. For all state points considered at the same temperature and at the same gap width between the two surfaces, the force per filament exerted on the opposite wall appears to be a function of a rescaled free monomer density $\hat{\rho}_1^{\rm eff}$. This quantity can be estimated directly from the characteristic length of the exponential filament size distribution $P$ observed in the size domain where these grafted filaments are not in direct contact with the wall. We also analyze the dynamics of the filament contour length fluctuations in terms of effective polymerization ($U$) and depolymerization ($W$) rates, where again it is possible to disentangle non-ideal and confinement effects.Comment: 24 pages, 7 figure

Case report: targeted whole exome sequencing enables the first prenatal diagnosis of the lethal skeletal dysplasia Osteocraniostenosis.

BACKGROUND: Osteocraniostenosis (OCS) is a rare genetic disorder characterised by premature closure of cranial sutures, gracile bones and perinatal lethality. Previously, diagnosis has only been possible postnatally on clinical and radiological features. This study describes the first prenatal diagnosis of OCS. CASE PRESENTATION: In this case prenatal ultrasound images were suggestive of a serious but non-lethal skeletal dysplasia. Due to the uncertain prognosis the parents were offered Whole Exome Sequencing (WES), which identified a specific gene mutation in the FAMIIIa gene. This mutation had previously been detected in two cases and was lethal in both perinatally. This established the diagnosis, a clear prognosis and allowed informed parental choice regarding ongoing pregnancy management. CONCLUSIONS: This case report supports the use of targeted WES prenatally to confirm the underlying cause and prognosis of sonographically suspected abnormalities

Role of the fast kinetics of pyroglutamate-modified amyloid-β oligomers in membrane binding and membrane permeability.

Membrane permeability to ions and small molecules is believed to be a critical step in the pathology of Alzheimer's disease (AD). Interactions of oligomers formed by amyloid-β (Aβ) peptides with the plasma cell membrane are believed to play a fundamental role in the processes leading to membrane permeability. Among the family of Aβs, pyroglutamate (pE)-modified Aβ peptides constitute the most abundant oligomeric species in the brains of AD patients. Although membrane permeability mechanisms have been studied for full-length Aβ1-40/42 peptides, these have not been sufficiently characterized for the more abundant AβpE3-42 fragment. Here we have compared the adsorbed and membrane-inserted oligomeric species of AβpE3-42 and Aβ1-42 peptides. We find lower concentrations and larger dimensions for both species of membrane-associated AβpE3-42 oligomers. The larger dimensions are attributed to the faster self-assembly kinetics of AβpE3-42, and the lower concentrations are attributed to weaker interactions with zwitterionic lipid headgroups. While adsorbed oligomers produced little or no significant membrane structural damage, increased membrane permeabilization to ionic species is understood in terms of enlarged membrane-inserted oligomers. Membrane-inserted AβpE3-42 oligomers were also found to modify the mechanical properties of the membrane. Taken together, our results suggest that membrane-inserted oligomers are the primary species responsible for membrane permeability

The growth rate of tubercle bacilli from South Indian and British patients

CULTURES of tubercle bacilli from Indian patients have been shown to be, on average, less virulent in the guinea-pig and to have a wider range of virulence than cultures obtained from British patients (Frimodt-Moller, Mathew and Barton, 1956 ; Mitchison et al., 1960 ; Bhatia et al., 1961). In the study of Bhatia et al. (loc. cit.) about one-third of the Indian cultures were as virulent as British cultures, the remainder being less virulent. In these studies the extent of disease in the organs of the guinea-pig was scored at intervals after the intramuscular injection of the organisms. In consequence, the measure of virulence was based upon the rate of development of the lesions and, by inference, the rate of multiplication of the bacilli in the organs. It was, therefore, considered of interest to compare the growth rates in vitro of Indian and British cultures of tubercle bacilli

Hydrodynamic coupling between two fluid membranes

The coupled in-plane diffusion dynamics between point-particles embedded in stacked fluid membranes are investigated. We calculate the contributions to the coupling longitudinal and transverse diffusion coefficients due to particle motion within the different as well as the same membranes. The stacked geometry leads to a hydrodynamic coupling between the two membranes.Comment: 9 Pages, 5 figures. Accepted for publication in J. Phys.: Condens. Matte

Improving Antibiotic Resistant Infection Transmission Situational Awareness in Enclosed Facilities with a Novel Interface Design for Tactical Biosurveillance

The implementation of the Electronic Health Record to substantially improve the practice of medicine has not fully reached its projected potential partly due to many barriers to its adoption. There is growing evidence that one of the reasons for the delay in the adoption of EHR has been due to the negative impact of current EHRs on the clinician-patient interaction, clinician workflow and communications. This research studies the usability of the Electronic Health Record for clinicians involved in cardiac care by evaluating various clinician-patient interaction workflows. The aim of the study is to identify inefficiencies by examining the similarities and differences among various clinician-patient interaction workflows. This research is presented as “work in progress”