Loss-of-function analysis of EphA receptors in retinotectal mapping

Peer reviewedPublisher PD

Conscientiousness predicts greater recovery from negative emotion

Greater levels of conscientiousness have been associated with lower levels of negative affect. We focus on one mechanism through which conscientiousness may decrease negative affect: effective emotion regulation, as reflected by greater recovery from negative stimuli. In 273 adults who were 35 - 85 years old, we collected self-report measures of personality including conscientiousness and its self-control facet, followed on average 2 years later by psychophysiological measures of emotional reactivity and recovery. Among middle-aged adults (35 - 65 years old), the measures of conscientiousness and self-control predicted greater recovery from, but not reactivity to, negative emotional stimuli. The effect of conscientiousness and self-control on recovery was not driven by other personality variables or by greater task adherence on the part of high conscientiousness individuals. In addition, the effect was specific to negative emotional stimuli and did not hold for neutral or positive emotional stimuli

Approximation algorithms for hard variants of the stable marriage and hospitals/residents problems

When ties and incomplete preference lists are permitted in the Stable Marriage and Hospitals/Residents problems, stable matchings can have different sizes. The problem of finding a maximum cardinality stable matching in this context is known to be NP-hard, even under very severe restrictions on the number, size and position of ties. In this paper, we describe polynomial-time 5/3-approximation algorithms for variants of these problems in which ties are on one side only and at the end of the preference lists. The particular variant is motivated by important applications in large scale centralised matching schemes

The effect of gradual or acute arterial occlusion on skeletal muscle blood flow, arteriogenesis, and inflammation in rat hindlimb ischemia

BackgroundCurrent experimental models of critical limb ischemia are based on acute ischemia rather than on chronic ischemia. Human peripheral vascular disease is largely a result of chromic ischemia. We hypothesized that a model of chronic hindlimb ischemia would develop more collateral arteries, more blood flow, and less necrosis and inflammation than would acute hindlimb ischemia. We therefore developed a rat model of chronic hindlimb ischemia and compared the effects of chronic ischemia with those of acute ischemia on hindlimb skeletal muscle.MethodsAcute or chronic ischemia was induced in 36 male Sprague-Dawley rats. Chronic ischemia caused blood flow, as measured by laser Doppler scanning and confirmed by muscle oxygen tension measurements, to gradually decrease over 1 to 2 weeks after operation.ResultsHistologic analysis showed chronic hindlimb ischemia better preserved muscle mass and architecture and stimulated capillary angiogenesis, while lacking the muscle necrosis and inflammatory cell infiltrate seen after acute ischemia. Surprisingly, the chronic ischemia group recovered dermal blood flow more slowly and less completely than did the acute ischemia group, as measured by laser Doppler (0.66 ± 0.02 vs 0.76 ± 0.04, P < .05) and tissue oxygen tension (0.61 ± 0.06 vs 0.81 ± 0.05, P < .05) at 40 days postoperatively. Consistent with poorer blood flow recovery, chronic ischemia resulted in smaller diameter collateral arteries (average diameter of the five largest collaterals on angiogram was 0.01 ± 0.0003 mm vs 0.013 ± 0.0007 mm for acute, P < .005 at 40 days postoperatively). Acute ischemia resulted in decreased tissue concentrations of vascular endothelial growth factor (VEGF) (0.96 ± 0.23 pg/mg of muscle for acute vs 4.4 ± 0.75 and 4.8 ± 0.75 pg/mg of muscle for unoperated and chronic, respectively, P < .05 acute vs unoperated), and in increased tissue concentrations of interleukin (IL)-1β (7.3 ± 4.0 pg/mg of muscle for acute vs undetectable and 1.7 ± 1.6pg/mg of muscle for unoperated and chronic, respectively, P < 0.05 acute vs unoperated).ConclusionsWe describe here the first model of chronic hindlimb ischemia in the rat. Restoration of blood flow after induction of hindlimb ischemia is dependent on the rate of arterial occlusion. This difference in blood flow recovery correlates with distinct patterns of muscle necrosis, inflammatory cell infiltration, and cytokine induction in the ischemic muscle. Differences between models of acute and chronic hindlimb ischemia may have important consequences for future studies of mechanisms regulating arteriogenesis and for therapeutic approaches aimed at promoting arteriogenesis in humans suffering from critical limb ischemia.Clinical relevanceDespite the substantial clinical differences between acute and chronic ischemia, researchers attempting to develop molecular therapies to treat critical limb ischemia have only tested those therapies in experimental models of acute hindlimb ischemia. We present here a novel model of chronic hindlimb ischemia in the rat. We further demonstrate that when hindlimb ischemia is developed chronically, collateral artery development is poorer than when hindlimb ischemia is developed acutely. These findings suggest that further tests of molecular therapies for critical limb ischemia should be performed in chronic hindlimb ischemia models rather than in acute hindlimb ischemia models

Overexpression of endothelial nitric oxide synthase increases skeletal muscle blood flow and oxygenation in severe rat hind limb ischemia

AbstractObjectiveAlthough nitric oxide (NO) has a critical role in angiogenesis, the therapeutic potential of NO synthase overexpression in severe ischemia remains undefined. We tested the hypothesis that overexpression of endothelial NO synthase (eNOS) would improve tissue perfusion in severe hind limb ischemia.MethodsSevere hind limb ischemia was induced in 122 adult male Sprague-Dawley rats. Ten days after the induction of hind limb ischemia, vascular isolation and intraarterial delivery of an adenoviral vector encoding eNOS (AdeNOS), a control adenoviral vector (AdE1), or phosphate-buffered saline solution (PBS) was performed. Skeletal muscle blood flow, muscle oxygen tension, angiography, and immunohistochemistry for capillary counts were measured.ResultsGene transfer of AdeNOS increased eNOS protein expression and enzyme activity. Two weeks after gene transfer, skeletal muscle blood flow was fourfold higher in eNOS-transduced than in AdE1-transduced or PBS treated rats and was similar to exercise-induced maximal flow in nonischemic muscle. eNOS overexpression increased muscle oxygen tension in a titer-dependent fashion. This increase persisted 1 month after transduction, even though eNOS enzyme activity had declined to normal levels. Angiography and capillary counts showed that eNOS overexpression increased the size and number of collateral arteries, but did not significantly increase the capillary–muscle fiber ratio.ConclusionseNOS overexpression in an ischemic rat hind limb significantly increased skeletal muscle blood flow, muscle oxygen tension, and collateral arteries (arteriogenesis). Furthermore, eNOS overexpression did not result in capillary angiogenesis above control levels. These studies demonstrate the potential for eNOS overexpression as treatment for severe limb ischemia in human beings

Interactivity:the missing link between virtual reality technology and drug discovery pipelines

The potential of virtual reality (VR) to contribute to drug design and development has been recognised for many years. Hardware and software developments now mean that this potential is beginning to be realised, and VR methods are being actively used in this sphere. A recent advance is to use VR not only to visualise and interact with molecular structures, but also to interact with molecular dynamics simulations of 'on the fly' (interactive molecular dynamics in VR, IMD-VR), which is useful not only for flexible docking but also to examine binding processes and conformational changes. iMD-VR has been shown to be useful for creating complexes of ligands bound to target proteins, e.g., recently applied to peptide inhibitors of the SARS-CoV-2 main protease. In this review, we use the term 'interactive VR' to refer to software where interactivity is an inherent part of the user VR experience e.g., in making structural modifications or interacting with a physically rigorous molecular dynamics (MD) simulation, as opposed to simply using VR controllers to rotate and translate the molecule for enhanced visualisation. Here, we describe these methods and their application to problems relevant to drug discovery, highlighting the possibilities that they offer in this arena. We suggest that the ease of viewing and manipulating molecular structures and dynamics, and the ability to modify structures on the fly (e.g., adding or deleting atoms) makes modern interactive VR a valuable tool to add to the armoury of drug development methods.Comment: 19 pages, 3 figure

Measuring hadron properties at finite temperature

We estimate the numbers and mass spectra of observed lepton and kaon pairs produced from $\phi$ meson decays in the central rapidity region of an Au+Au collision at lab energy 11.6 GeV/nucleon. The following effects are considered: possible mass shifts, thermal broadening due to collisions with hadronic resonances, and superheating of the resonance gas. Changes in the dilepton mass spectrum may be seen, but changes in the dikaon spectrum are too small to be detectable.Comment: 9 pages (revtex), 3 figures (uuencoded postscript