Standardization and validation of a novel and simple method to assess lumbar dural sac size

AimTo develop and validate a simple, reproducible method to assess dural sac size using standard imaging technology.Materials and methodsThis study was institutional review board-approved. Two readers, blinded to the diagnoses, measured anterior–posterior (AP) and transverse (TR) dural sac diameter (DSD), and AP vertebral body diameter (VBD) of the lumbar vertebrae using MRI images from 53 control patients with pre-existing MRI examinations, 19 prospectively MRI-imaged healthy controls, and 24 patients with Marfan syndrome with prior MRI or CT lumbar spine imaging. Statistical analysis utilized linear and logistic regression, Pearson correlation, and receiver operating characteristic (ROC) curves.ResultsAP-DSD and TR-DSD measurements were reproducible between two readers (r = 0.91 and 0.87, respectively). DSD (L1–L5) was not different between male and female controls in the AP or TR plane (p = 0.43; p = 0.40, respectively), and did not vary by age (p = 0.62; p = 0.25) or height (p = 0.64; p = 0.32). AP-VBD was greater in males versus females (p = 1.5 × 10−8), resulting in a smaller dural sac ratio (DSR) (DSD/VBD) in males (p = 5.8 × 10−6). Marfan patients had larger AP-DSDs and TR-DSDs than controls (p = 5.9 × 10−9; p = 6.5 × 10−9, respectively). Compared to DSR, AP-DSD and TR-DSD better discriminate Marfan from control subjects based on area under the curve (AUC) values from unadjusted ROCs (AP-DSD p < 0.01; TR-DSD p = 0.04).ConclusionIndividual vertebrae and L1–L5 (average) AP-DSD and TR-DSD measurements are simple, reliable, and reproducible for quantitating dural sac size without needing to control for gender, age, or height

Distribution modelling and statistical phylogeography: an integrative framework for generating and testing alternative biogeographical hypotheses

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73644/1/j.1365-2699.2007.01814.x.pd

Modelling mucociliary clearance

Mathematical modelling of the fluid mechanics of mucociliary clearance (MCC) is reviewed and future challenges for researchers are discussed. The morphology of the bronchial and tracheal airway surface liquid (ASL) and ciliated epithelium are briefly introduced. The cilia beat cycle, beat frequency and metachronal coordination are described, along with the rheology of the mucous layer. Theoretical modelling of MCC from the late 1960s onwards is reviewed, and distinctions between ‘phenomenological’, ‘slender body theory’ and recent ‘fluid–structure interaction’ models are explained.\ud \ud The ASL consists of two layers, an overlying mucous layer and underlying watery periciliary layer (PCL) which bathes the cilia. Previous models have predicted very little transport of fluid in the PCL compared with the mucous layer. Fluorescent tracer transport experiments on human airway cultures conducted by Matsui et al. [Matsui, H., Randell, S.H., Peretti, S.W., Davis, C.W., Boucher, R.C., 1998. Coordinated clearance of periciliary liquid and mucus from airway surfaces. J. Clin. Invest. 102 (6), 1125–1131] apparently showed equal transport in both the PCL and mucous layer. Recent attempts to resolve this discrepancy by the present authors are reviewed, along with associated modelling findings. These findings have suggested new insights into the interaction of cilia with mucus due to pressure gradients associated with the flat PCL/mucus interface. This phenomenon complements previously known mechanisms for ciliary propulsion. Modelling results are related to clinical findings, in particular the increased MCC observed in patients with pseudohypoaldosteronism. Recent important advances by several groups in modelling the fluid–structure interaction by which the cilia movement and fluid transport emerge from specification of internal mechanics, viscous and elastic forces are reviewed. Finally, we discuss the limitations of existing work, and the challenges for the next generation of models, which may provide further insight into this complex and vital system

Using Co-solvability to Model and Exploit Synergetic Effects in Evolution

We introduce, analyze, and experimentally verify the concept of co-solvability, meant as the ability of a solution maintained by an evolutionary run to solve (correctly process) a pair of fitness cases (tests). The method based on this concept can be considered as a second-order implicit fitness sharing, where solutions compete for the rewards granted for solving pairs of tests, rather than single tests. We prove that co-solvability fitness function is by definition synergistic and imposes selection pressure which is qualitatively different from that induced by standard fitness function or implicit fitness sharing. The results of experimental verification on eight genetic programming tasks demonstrate that evolutionary runs driven by the proposed fitness function usually converge faster to global optima than other methods

Trodusquemine displaces protein misfolded oligomers from cell membranes and abrogates their cytotoxicity through a generic mechanism

The onset and progression of numerous protein misfolding diseases are associated with the presence of oligomers formed during the aberrant aggregation of several different proteins, including amyloid-ß (Aß) in Alzheimer’s disease and a-synuclein (aS) in Parkinson’s disease. These small, soluble aggregates are currently major targets for drug discovery. In this study, we show that trodusquemine, a naturally-occurring aminosterol, markedly reduces the cytotoxicity of aS, Aß and HypF-N oligomers to human neuroblastoma cells by displacing the oligomers from cell membranes in the absence of any substantial morphological and structural changes to the oligomers. These results indicate that the reduced toxicity results from a mechanism that is common to oligomers from different proteins, shed light on the origin of the toxicity of the most deleterious species associated with protein aggregation and suggest that aminosterols have the therapeutically-relevant potential to protect cells from the oligomer-induced cytotoxicity associated with numerous protein misfolding diseases

Trodusquemine displaces protein misfolded oligomers from cell membranes and abrogates their cytotoxicity through a generic mechanism

10 pags., 5 figs.The onset and progression of numerous protein misfolding diseases are associated with the presence of oligomers formed during the aberrant aggregation of several different proteins, including amyloid-β (Aβ) in Alzheimer’s disease and α-synuclein (αS) in Parkinson’s disease. These small, soluble aggregates are currently major targets for drug discovery. In this study, we show that trodusquemine, a naturally-occurring aminosterol, markedly reduces the cytotoxicity of αS, Aβ and HypF-N oligomers to human neuroblastoma cells by displacing the oligomers from cell membranes in the absence of any substantial morphological and structural changes to the oligomers. These results indicate that the reduced toxicity results from a mechanism that is common to oligomers from different proteins, shed light on the origin of the toxicity of the most deleterious species associated with protein aggregation and suggest that aminosterols have the therapeutically-relevant potential to protect cells from the oligomer-induced cytotoxicity associated with numerous protein misfolding diseases.This work was supported by the Cambridge Centre for Misfolding Diseases (R.L., B.M., F.S.R., C.K.X., M.P., S.C., S.W.C., J.H., T.K., J.R.K., T.P.J.K., M.V., and C.M.D.), the UK Biotechnology and Biochemical Sciences Research Council (M.V. and C.M.D.), the Wellcome Trust (203249/Z/16/Z to T.P.J.K and M.V.), the Frances and Augustus Newman Foundation (T.P.J.K.), the Regione Toscana – FAS Salute, project SUPREMAL (R.C., A.B., C.C., and F.C.), the Gates Cambridge Trust and St. John’s College Cambridge (R.L.), Darwin College Cambridge (F.S.R.), the Herchel Smith Fund (C.K.X.), a Faculty Development Research Fund grant from the United States Military Academy, West Point (R.L.) and a DTRA Service Academy Research Initiative grant (HDTRA1033862 to R.L.)

Aerosolized Amiloride for the Treatment of Lung Disease in Cystic Fibrosis

To the Editor: The April 26 issue of the Journal presented encouraging results by Knowles et al. regarding the beneficial effects of aerosolized amiloride in the treatment of cystic fibrosis.1 The introduction and discussion sections of this article described the function of amiloride as an inhibitor of sodium transport in the airway epithelium, and the authors suggested that the beneficial effects observed were exerted “at least in part by increasing the clearance of secretions.” Although the results of this investigation were promising in terms of the improvement in the decline of forced vital capacity in patients with cystic fibrosis, this

Novel variation at chr11p13 associated with cystic fibrosis lung disease severity

Published genome-wide association studies (GWASs) identified an intergenic region with regulatory features on chr11p13 associated with cystic fibrosis (CF) lung disease severity. Targeted resequencing in n=377, followed by imputation to n=6,365 CF subjects, was used to identify unrecognized genetic variants (including indels and microsatellite repeats) associated with phenotype. Highly significant associations were in strong linkage disequilibrium and were seen only in Phe508del homozygous CF subjects, indicating a CFTR genotype-specific mechanism

Multistep Inhibition of α-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine

12 pags, 3 figs. -- The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acschembio.8b00466.The aggregation of α-synuclein, an intrinsically disordered protein that is highly abundant in neurons, is closely associated with the onset and progression of Parkinson's disease. We have shown previously that the aminosterol squalamine can inhibit the lipid induced initiation process in the aggregation of α-synuclein, and we report here that the related compound trodusquemine is capable of inhibiting not only this process but also the fibril-dependent secondary pathways in the aggregation reaction. We further demonstrate that trodusquemine can effectively suppress the toxicity of α-synuclein oligomers in neuronal cells, and that its administration, even after the initial growth phase, leads to a dramatic reduction in the number of α-synuclein inclusions in a Caenorhabditis elegans model of Parkinson's disease, eliminates the related muscle paralysis, and increases lifespan. On the basis of these findings, we show that trodusquemine is able to inhibit multiple events in the aggregation process of α-synuclein and hence to provide important information about the link between such events and neurodegeneration, as it is initiated and progresses. Particularly in the light of the previously reported ability of trodusquemine to cross the blood-brain barrier and to promote tissue regeneration, the present results suggest that this compound has the potential to be an important therapeutic candidate for Parkinson's disease and related disorders.This work was supported by the Boehringer Ingelheim Fonds (P.F.), the Studienstiftung des Deutschen Volkes (P.F.), Gates Cambridge Scholarships (R.L. and G.T.H) and a St. John’s College Benefactors’ Scholarship (R.L.), the UK Biotechnology and Biochemical Sciences Research Council (M.V. and C.M.D.), a Senior Research Fellowship award from the Alzheimer’s Society, UK, grant number (317, AS-SF-16-003) (F.A.A.), the Wellcome Trust (C.M.D., M.V., and T.P.J.K.), the Frances and Augustus Newman Foundation (T.P.J.K.), the Regione Toscana—FAS Salute—Supremal project (R.C., C.C., and F.C.), a Marie Skłodowska-Curie Actions—Individual Fellowship (C.G.), Sidney Sussex College Cambridge (G.M.), the Spanish Government—MINECO (N.C.), and by the Cambridge Centre for Misfolding Diseases (M.P., P.F., R.L., F.A.A., C.G., G.T.H., S.W.C., J.R.K., T.P.J.K., M.V., and C.M.D)

GMRT 610 MHz observations of galaxy clusters in the ACT equatorial sample

Large scale structure and cosmolog