Tibio-femoral joint constraints for bone pose estimation during movement using multi-body optimization

The financial support of the Universita'Italo-Francese (Call Vinci) and of the Department of Human Movement and Sport Sciences of the University of Rome ''Foro Italico'' is gratefully acknowledged. The authors wish to acknowledge Dr. Sophie Lacoste for her technical support and John McCamley for his contribution to the refinement of the manuscriptWhen using skin markers and stereophotogrammetry for movement analysis, bone pose estimation may be performed using multi-body optimization with the intent of reducing the effect of soft tissue artefacts. When the joint of interest is the knee, improvement of this approach requires defining subject-specific relevant kinematic constraints. The aim of this work was to provide these constraints in the form of plausible values for the distances between origin and insertion of the main ligaments (ligament lengths), during loaded healthy knee flexion, taking into account the indeterminacies associated with landmark identification during anatomical calibration. Ligament attachment sites were identified through virtual palpation on digital bone templates. Attachments sites were estimated for six knee specimens by matching the femur and tibia templates to low-dose stereoradiography images. Movement data were obtained using stereophotogrammetry and pin markers. Relevant ligament lengths for the anterior and posterior cruciate, lateral collateral, and deep and superficial bundles of the medial collateral ligaments (ACL, PCL, LCL, MCLdeep, MCLsup) were calculated. The effect of landmark identification variability was evaluated performing a Monte Carlo simulation on the coordinates of the origin-insertion centroids. The ACL and LCL lengths were found to decrease, and the MCLdeep length to increase significantly during flexion, while variations in PCL and MCLsup length was concealed by the experimental indeterminacy. An analytical model is given that provides subject-specific plausible ligament length variations as functions of the knee flexion angle and that can be incorporated in a multi-body optimization procedure

Increasing phylogenetic stochasticity at high elevations on summits across a remote North American wilderness

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150529/1/ajb21328-sup-0002-AppendixS2.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150529/2/ajb21328-sup-0003-AppendixS3.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150529/3/ajb21328-sup-0004-AppendixS4.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150529/4/ajb21328.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150529/5/ajb21328-sup-0009-AppendixS9.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150529/6/ajb21328-sup-0005-AppendixS5.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150529/7/ajb21328-sup-0007-AppendixS7.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150529/8/ajb21328-sup-0006-AppendixS6.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150529/9/ajb21328-sup-0008-AppendixS8.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150529/10/ajb21328_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150529/11/ajb21328-sup-0001-AppendixS1.pd

Dynamic Energy Landscapes of Riboswitches Help Interpret Conformational Rearrangements and Function

Riboswitches are RNAs that modulate gene expression by ligand-induced conformational changes. However, the way in which sequence dictates alternative folding pathways of gene regulation remains unclear. In this study, we compute energy landscapes, which describe the accessible secondary structures for a range of sequence lengths, to analyze the transcriptional process as a given sequence elongates to full length. In line with experimental evidence, we find that most riboswitch landscapes can be characterized by three broad classes as a function of sequence length in terms of the distribution and barrier type of the conformational clusters: low-barrier landscape with an ensemble of different conformations in equilibrium before encountering a substrate; barrier-free landscape in which a direct, dominant “downhill” pathway to the minimum free energy structure is apparent; and a barrier-dominated landscape with two isolated conformational states, each associated with a different biological function. Sharing concepts with the “new view” of protein folding energy landscapes, we term the three sequence ranges above as the sensing, downhill folding, and functional windows, respectively. We find that these energy landscape patterns are conserved in various riboswitch classes, though the order of the windows may vary. In fact, the order of the three windows suggests either kinetic or thermodynamic control of ligand binding. These findings help understand riboswitch structure/function relationships and open new avenues to riboswitch design

Inhibition of Src kinase activity attenuates amyloid associated microgliosis in a murine model of Alzheimer’s disease

<p>Abstract</p> <p>Background</p> <p>Microglial activation is an important histologic characteristic of the pathology of Alzheimer’s disease (AD). One hypothesis is that amyloid beta (Aβ) peptide serves as a specific stimulus for tyrosine kinase-based microglial activation leading to pro-inflammatory changes that contribute to disease. Therefore, inhibiting Aβ stimulation of microglia may prove to be an important therapeutic strategy for AD.</p> <p>Methods</p> <p>Primary murine microglia cultures and the murine microglia cell line, BV2, were used for stimulation with fibrillar Aβ1-42. The non-receptor tyrosine kinase inhibitor, dasatinib, was used to treat the cells to determine whether Src family kinase activity was required for the Aβ stimulated signaling response and subsequent increase in TNFα secretion using Western blot analysis and enzyme-linked immunosorbent assay (ELISA), respectively. A histologic longitudinal analysis was performed using an AD transgenic mouse model, APP/PS1, to determine an age at which microglial protein tyrosine kinase levels increased in order to administer dasatinib via mini osmotic pump diffusion. Effects of dasatinib administration on microglial and astroglial activation, protein phosphotyrosine levels, active Src kinase levels, Aβ plaque deposition, and spatial working memory were assessed via immunohistochemistry, Western blot, and T maze analysis.</p> <p>Results</p> <p>Aβ fibrils stimulated primary murine microglia via a tyrosine kinase pathway involving Src kinase that was attenuated by dasatinib. Dasatinib administration to APP/PS1 mice decreased protein phosphotyrosine, active Src, reactive microglia, and TNFα levels in the hippocampus and temporal cortex. The drug had no effect on GFAP levels, Aβ plaque load, or the related tyrosine kinase, Lyn. These anti-inflammatory changes correlated with improved performance on the T maze test in dasatinib infused animals compared to control animals.</p> <p>Conclusions</p> <p>These data suggest that amyloid dependent microgliosis may be Src kinase dependent <it>in vitro</it> and <it>in vivo.</it> This study defines a role for Src kinase in the microgliosis characteristic of diseased brains and suggests that particular tyrosine kinase inhibition may be a valid anti-inflammatory approach to disease. Dasatinib is an FDA-approved drug for treating chronic myeloid leukemia cancer with a reported ability to cross the blood-brain barrier. Therefore, this suggests a novel use for this drug as well as similar acting molecules.</p

Experiments directed to the compound-specific determination of the stable carbon isotope ratios of the Toxaphene congener B8-1413 in two technical mixtures and Antarctic Weddell seal

The carbon stable isotope ratio (delta C-13 value) of an environmentally-relevant Toxaphene congener in technical products and a biological sample from a remote region was in the focus of this work. For this reason, the major octachlorobornane residue of the multicomponent pesticide Toxaphene in biological samples, 2-endo,3-exo,5-endo,6-exo,8,8,10,10-octachlorobornane (B8-1413 or P26), was quantitatively enriched from two technical Toxaphene mixtures (Toxaphene and Melipax) in duplicates as well as from an Antarctic Weddell seal sample. Normal phase followed by reversed-phase high-performance liquid chromatography (HPLC) with three columns, respectively, coupled in series was used for this purpose. Four of the five fractionated samples fulfilled the requirement of an interference-free GC-elution for subsequent determination of the delta C-13 value by gas chromatography interfaced to an isotope ratio mass spectrometer (GC-IRMS). B8-1413 in Toxaphene (n = 1) was more depleted in C-12 than in Melipax (n = 2), which agrees with previous results obtained for the entire mixtures. The B8-1413 isolate from a Weddell seal sample from the Antarctic showed a 8 degrees C value between the two technical products. Although a source appointment to the one or the other product was not possible, this example indicates that long range transport to the Antarctic and by uptake and food-chain bioaccumulation of B8-1413 in seals did not change the delta C-13 value significantly. The observed differences in one duplicate sample indicate that statistic evaluation of samples used for isotope ratio MS measurements is an important issue. (c) 2006 Elsevier B.V. All rights reserved. [References: 24