7,630 research outputs found
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 . This
quantity can be estimated directly from the characteristic length of the
exponential filament size distribution 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 () and depolymerization () rates, where again it
is possible to disentangle non-ideal and confinement effects.Comment: 24 pages, 7 figure
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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.
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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”
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