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Chemical exchange saturation transfer (CEST) imaging of amine protons exchanging at intermediate rates and whose chemical shift is around 2 ppm may provide a means of mapping creatine. However, the quantification of this effect may be compromised by the influence of overlapping CEST signals from fast-exchanging amines and hydroxyls. We aimed to investigate the exchange rate filtering effect of a variation of CEST, named chemical exchange rotation transfer (CERT), as a means of isolating creatine contributions at around 2 ppm from other overlapping signals. Simulations were performed to study the filtering effects of CERT for the selection of transfer effects from protons of specific exchange rates. Control samples containing the main metabolites in brain, bovine serum albumin (BSA) and egg white albumen (EWA) at their physiological concentrations and pH were used to study the ability of CERT to isolate molecules with amines at 2 ppm that exchange at intermediate rates, and corresponding methods were used for in vivo rat brain imaging. Simulations showed that exchange rate filtering can be combined with conventional filtering based on chemical shift. Studies on samples showed that signal contributions from creatine can be separated from those of other metabolites using this combined filter, but contributions from protein amines may still be significant. This exchange filtering can also be used for in vivo imaging. CERT provides more specific quantification of amines at 2 ppm that exchange at intermediate rates compared with conventional CEST imaging.
Copyright © 2017 John Wiley & Sons, Ltd.
PURPOSE - A method is described for characterizing magnetically inhomogeneous media and the spatial scales of intrinsic susceptibility variations within samples. The rate of spin-lattice relaxation in the rotating frame, R1ρ , is affected by diffusion effects to a degree that depends on the magnitude of an applied spin-locking field. Appropriate analysis of the dispersion of R1ρ with locking field may be used to characterize susceptibility variations in inhomogeneous tissues.
THEORY AND METHODS - The contribution of diffusion to R1ρ is quantified by an analytic expression derived by analyzing of the effects of diffusion through periodic variations of magnetic susceptibility and is used to predict the effects of inhomogeneities in simple phantoms. The theory is further applied to imaging to derive parametric images that portray the dimensions of susceptibility inhomogeneities independent of their magnitude.
RESULTS - Significant dispersion of R1ρ with locking field was predicted and measured experimentally for suspensions of microspheres ranging from 1 to 90 μm in diameter. For scales of practical interest, these dispersion effects occur at much lower locking fields than the range in which chemical exchange effects cause similar dispersion.
CONCLUSION - There is good agreement between theory and experiment, and the method has potential for quantitative tissue characterization and functional imaging.
Copyright © 2013 Wiley Periodicals, Inc.
The topology of most experimentally determined protein domains is defined by the relative arrangement of secondary structure elements, i.e. α-helices and β-strands, which make up 50-70% of the sequence. Pairing of β-strands defines the topology of β-sheets. The packing of side chains between α-helices and β-sheets defines the majority of the protein core. Often, limited experimental datasets restrain the position of secondary structure elements while lacking detail with respect to loop or side chain conformation. At the same time the regular structure and reduced flexibility of secondary structure elements make these interactions more predictable when compared to flexible loops and side chains. To determine the topology of the protein in such settings, we introduce a tailored knowledge-based energy function that evaluates arrangement of secondary structure elements only. Based on the amino acid C(β) atom coordinates within secondary structure elements, potentials for amino acid pair distance, amino acid environment, secondary structure element packing, β-strand pairing, loop length, radius of gyration, contact order and secondary structure prediction agreement are defined. Separate penalty functions exclude conformations with clashes between amino acids or secondary structure elements and loops that cannot be closed. Each individual term discriminates for native-like protein structures. The composite potential significantly enriches for native-like models in three different databases of 10,000-12,000 protein models in 80-94% of the cases. The corresponding application, "BCL::ScoreProtein," is available at www.meilerlab.org.
Left ventricular (LV) rotation occurs due to contraction of obliquely oriented myocardial fibres. Left ventricular twist (LVT) results from rotation of the apex and base in opposite directions. Although LVT is altered in various cardiac diseases, physiological factors that affect LVT remain incompletely understood. Isometric handgrip testing (IHGT), a well-established laboratory-based technique to increase LV afterload, was performed for 3 min at 40% maximum force generation in healthy human subjects (n = 18, mean age 29.7 ± 2.7 years). Speckle-tracking echocardiography was used to measure LV volumes, LV apical and basal rotation, peak systolic LVT and peak early diastolic untwisting rate (UTR) at rest and at peak IHGT. IHGT led to significant increase in systemic blood pressure (systolic, 120.6 ± 9.7 vs. 155.6 ± 14.5 mmHg, P < 0.001; diastolic, 67.5 ± 6.4 vs. 94.1 ± 21.1 mmHg, P < 0.001) and LV end-systolic volume (44.2 ± 7.8 vs. 50.5 ± 10.8 ml, P = 0.005), as well as a significant increase in heart rate (62.8 ± 11.7 vs. 84.7 ± 13.8 beats min−1; P < 0.001). IHGT produced a significant acute reduction in LV stroke volume (63.9 ± 12.0 vs. 49.4 ± 7.8 ml, P < 0.001). In this setting, there was a significant decrease in peak systolic apical rotation (11.9 ± 3.0 vs. 8.6 ± 2.2 deg, P < 0.001) and a resultant 25% decrease in peak systolic LVT (16.6 ± 2.8 vs. 12.5 ± 2.8 deg, P < 0.001). The magnitude of peak early diastolic UTR did not change (−114.5 ± 26.4 vs. −110.6 ± 39.8 deg s−1, P = 0.71). Peak systolic apical rotation and LVT decrease during IHGT in healthy humans. This impairment of LV twist mechanics may in part underlie the LV dysfunction that can occur in the clinical context of acute increase in afterload.
The Thatcher Illusion or Thatcher Effect (TE--Thompson 1980, Perception 9 483-484) reflects the difficulty in perceiving the local inversion of parts when the whole object, generally a face, is globally inverted. We tested the generality of the TE with a range of faces and nonface objects, and observed the TE with many non-face categories including cars, buildings, bikes, and letter strings. In terms of magnitude, the face TE is not exceptionally large compared to other object categories, and the magnitude of the TE can be predicted by performance on this task for upright stimuli, regardless of whether the object is a face or not. We did not observe evidence for a unique mechanism contributing to the TE for faces. We discuss factors that influence the magnitude of the TE, some common across domains and others more specific to a particular category.
BACKGROUND - The ability to identify pitchers at risk for injury could be valuable to a professional baseball organization. To our knowledge, there have been no prior studies examining the predictive value of preseason strength measurements.
HYPOTHESIS - Preseason weakness of shoulder external rotators is associated with increased risk of in-season throwing-related injury in professional baseball pitchers.
STUDY DESIGN - Cohort study (prognosis); Level of evidence, 2.
METHODS - Preseason shoulder strength was measured for all pitchers in a professional baseball organization over a 5-year period (2001-2005). Prone internal rotation (IR), prone external rotation (PER), seated external rotation (SER), and supraspinatus (SS) strength were tested during spring training before each season. The players were then prospectively followed throughout the season for incidence of throwing-related injury. Injuries were categorized on an ordinal scale, with no injury, injury treated conservatively, and injury resulting in surgery delineated 0, 1, and 2, respectively. Subset analyses of shoulder injuries and of players with prior surgery were also performed. The association between strength measurements and injury was analyzed using Spearman rank correlation.
RESULTS - A statistically significant association was observed for PER strength (P = .003), SER strength (P = .048), and SS strength (P = .006) with throwing-related injury requiring surgical intervention. Supraspinatus strength was also significantly associated with incidence of any shoulder injury (P = .031). There was an association between the ratio of PER/IR strength and incidence of shoulder injury (P = .037) and some evidence for an association with overall incidence of throwing-related injury (P = .051). No associations were noted in the subgroup of players with prior surgery.
CONCLUSION - Preseason weakness of external rotation and SS strength is associated with in-season throwing-related injury resulting in surgical intervention in professional baseball pitchers. Thus, preseason strength data may help identify players at risk for injury and formulate strengthening plans for prevention.
Parkinson's disease is caused primarily by degeneration of brain dopaminergic neurons in the substantia nigra and the consequent deficit of dopamine in the striatum. Dopamine replacement therapy with the dopamine precursor l-dopa is the mainstay of current treatment. After several years, however, the patients develop l-dopa-induced dyskinesia, or abnormal involuntary movements, thought to be due to excessive signaling via dopamine receptors. G protein-coupled receptor kinases (GRKs) control desensitization of dopamine receptors. We found that dyskinesia is attenuated by lentivirus-mediated overexpression of GRK6 in the striatum in rodent and primate models of Parkinson's disease. Conversely, reduction of GRK6 concentration by microRNA delivered with lentiviral vector exacerbated dyskinesia in parkinsonian rats. GRK6 suppressed dyskinesia in monkeys without compromising the antiparkinsonian effects of l-dopa and even prolonged the antiparkinsonian effect of a lower dose of l-dopa. Our finding that increased availability of GRK6 ameliorates dyskinesia and increases duration of the antiparkinsonian action of l-dopa suggests a promising approach for controlling both dyskinesia and motor fluctuations in Parkinson's disease.
We describe a simple and reliable fabrication method for producing multiple, manually activated microfluidic control valves in polydimethylsiloxane (PDMS) devices. These screwdriver-actuated valves reside directly on the microfluidic chip and can provide both simple on/off operation as well as graded control of fluid flow. The fabrication procedure can be easily implemented in any soft lithography lab and requires only two specialized tools-a hot-glue gun and a machined brass mold. To facilitate use in multi-valve fluidic systems, the mold is designed to produce a linear tape that contains a series of plastic rotary nodes with small stainless steel machine screws that form individual valves which can be easily separated for applications when only single valves are required. The tape and its valves are placed on the surface of a partially cured thin PDMS microchannel device while the PDMS is still on the soft-lithographic master, with the master providing alignment marks for the tape. The tape is permanently affixed to the microchannel device by pouring an over-layer of PDMS, to form a full-thickness device with the tape as an enclosed underlayment. The advantages of these Tape Underlayment Rotary-Node (TURN) valves include parallel fabrication of multiple valves, low risk of damaging a microfluidic device during valve installation, high torque, elimination of stripped threads, the capabilities of TURN hydraulic actuators, and facile customization of TURN molds. We have utilized these valves to control microfluidic flow, to control the onset of molecular diffusion, and to manipulate channel connectivity. Practical applications of TURN valves include control of loading and chemokine release in chemotaxis assay devices, flow in microfluidic bioreactors, and channel connectivity in microfluidic devices intended to study competition and predator/prey relationships among microbes.
The mechanical properties of biomaterial scaffolds are crucial for their efficacy in tissue engineering and regenerative medicine. At the microscopic scale, the scaffold must be sufficiently rigid to support cell adhesion, spreading, and normal extracellular matrix deposition. Concurrently, at the macroscopic scale the scaffold must have mechanical properties that closely match those of the target tissue. The achievement of both goals may be possible by careful control of the scaffold architecture. Recently, electrospinning has emerged as an attractive means to form fused fibre scaffolds for tissue engineering. The diameter and relative orientation of fibres affect cell behaviour, but their impact on the tensile properties of the scaffolds has not been rigorously characterized. To examine the structure-property relationship, electrospun meshes were made from a polyurethane elastomer with different fibre diameters and orientations and mechanically tested to determine the dependence of the elastic modulus on the mesh architecture. Concurrently, a multiscale modelling strategy developed for type I collagen networks was employed to predict the mechanical behaviour of the polyurethane meshes. Experimentally, the measured elastic modulus of the meshes varied from 0.56 to 3.0 MPa depending on fibre diameter and the degree of fibre alignment. Model predictions for tensile loading parallel to fibre orientation agreed well with experimental measurements for a wide range of conditions when a fitted fibre modulus of 18 MPa was used. Although the model predictions were less accurate in transverse loading of anisotropic samples, these results indicate that computational modelling can assist in design of electrospun artificial tissue scaffolds.