Critical Evaluation of Polarizable and Nonpolarizable Force Fields for Proteins Using Experimentally Derived Nitrile Electric Fields

Molecular dynamics (MD) simulations are frequently carried out for proteins to investigate the role of electrostatics in their biological function. The choice of force field (FF) can significantly alter the MD results, as the simulated local electrostatic interactions lack benchmarking in the absence of appropriate experimental methods. We recently reported that the transition dipole moment (TDM) of the popular nitrile vibrational probe varies linearly with the environmental electric field, overcoming well-known hydrogen bonding (H-bonding) issues for the nitrile frequency and, thus, enabling the unambiguous measurement of electric fields in proteins (J. Am. Chem. Soc. 2022, 144 (17), 7562–7567). Herein, we utilize this new strategy to enable comparisons of experimental and simulated electric fields in protein environments. Specifically, previously determined TDM electric fields exerted onto nitrile-containing o-cyanophenylalanine residues in photoactive yellow protein are compared with MD electric fields from the fixed-charge AMBER FF and the polarizable AMOEBA FF. We observe that the electric field distributions for H-bonding nitriles are substantially affected by the choice of FF. As such, AMBER underestimates electric fields for nitriles experiencing moderate field strengths; in contrast, AMOEBA robustly recapitulates the TDM electric fields. The FF dependence of the electric fields can be partly explained by the presence of additional negative charge density along the nitrile bond axis in AMOEBA, which is due to the inclusion of higher-order multipole parameters; this, in turn, begets more head-on nitrile H-bonds. We conclude by discussing the implications of the FF dependence for the simulation of nitriles and proteins in general

Flights in my hands : coherence concerns in designing Strip'TIC, a tangible space for air traffic controllers

Best Paper Honorable Mention awardInternational audienceWe reflect upon the design of a paper-based tangible interactive space to support air traffic control. We have observed, studied, prototyped and discussed with controllers a new mixed interaction system based on Anoto, video projection, and tracking. Starting from the understanding of the benefits of tangible paper strips, our goal is to study how mixed physical and virtual augmented data can support the controllers' mental work. The context of the activity led us to depart from models that are proposed in tangible interfaces research where coherence is based on how physical objects are representative of virtual objects. We propose a new account of coherence in a mixed interaction system that integrates externalization mechanisms. We found that physical objects play two roles: they act both as representation of mental objects and as tangible artifacts for interacting with augmented features. We observed that virtual objects represent physical ones, and not the reverse, and, being virtual representations of physical objects, should seamlessly converge with the cognitive role of the physical object. Finally, we show how coherence is achieved by providing a seamless interactive space

Cardiogenic shock complicating acute myocardial infarction: The use of coronary angioplasty and the integration of the new support devices into patient management

Conventional therapy for cardiogenic shock complicating acute myocardial infarction continues to be associated with a high in-hospital mortality rate. Hemodynamic support with new mechanical devices and emergency coronary revascularization may alter the long-term prognosis for patients with this complication. Between July 1985 and March 1990, 68 patients presented to the University of Michigan with acute myocardial infarction and cardiogenic shock. Interventions performed included thrombolytic therapy (46%), intraaortic balloon pump counterpulsation (70%), cardiac catheterization (86%), coronary angioplasty (73%), emergency coronary artery bypass grafting/ventricular septal defect repair (15%), Hemopump insertion (11%), percutaneous cardiopulmonary support (4%) and ventricular assist device (3%).The 30-day survival rate was significantly better in patients who had successful angioplasty of the infarct-related artery than in patients with failed angioplasty (61% vs. 7%, p = 0.002) or no attempt at angioplasty (61% vs. 14%, p = 0.003). This difference was maintained over the 1-year follow-up period. The only clinical variable that predicted survival was age <65 years.The early use of the new support devices in 10 patients was associated with death in 8 (80%), but this poor outcome may reflect a selection bias for an especially high risk population. Collectively, these recent data continue to suggest that emergency revascularization with angioplasty may reduce the mortality rate, but further study is required to define optimal utilization and integration of new support devices

Hemolysis in the Starr-Edwards aortic prostheses

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/33972/1/0000244.pd

Why 'scaffolding' is the wrong metaphor : the cognitive usefulness of mathematical representations.

The metaphor of scaffolding has become current in discussions of the cognitive help we get from artefacts, environmental affordances and each other. Consideration of mathematical tools and representations indicates that in these cases at least (and plausibly for others), scaffolding is the wrong picture, because scaffolding in good order is immobile, temporary and crude. Mathematical representations can be manipulated, are not temporary structures to aid development, and are refined. Reflection on examples from elementary algebra indicates that Menary is on the right track with his ‘enculturation’ view of mathematical cognition. Moreover, these examples allow us to elaborate his remarks on the uniqueness of mathematical representations and their role in the emergence of new thoughts.Peer reviewe

Lack of trust in maternal support is associated with negative interpretations of ambiguous maternal behavior

Attachment theory assumes that children who lack trust in maternal availability for support are more inclined to interpret maternal behavior in congruence with their expectation that mother will remain unavailable for support. To provide the first test of this assumption, early adolescents (9-13 years old) were asked to assess whether ambiguous interactions with mother should be interpreted in a positive or a negative way. In our sample (n = 322), results showed that early adolescents' lack of trust in their mother's availability for support was related to more negative interpretations of maternal behavior. The associations remained significant after controlling for depressive mood. The importance of these findings for our understanding of attachment theory, attachment stability, and clinical practice are discussed

Hemolysis in patients with the cloth-covered aortic valve prosthesis : Changing severity of hemolysis and prediction of anemia

This paper is addressed to two questions: (1) Is there evidence for Increasing hemolysis in patients with a cloth-covered aortic valve prosthesis? (2) Is it possible to predict from the hematocrit, retriculocyte count, serum hemoglobin and serum lactic dehydrogenase (LDH) levels which patients are at risk of anemia? These screening studies were performed in patients attending the postoperative clinic from 1970 to 1973. Patients were classified into anemic and nonanemic groups. LDH values for the anemic group include all yearly values for that patient including preanemia levels. The median LDH levels showed a yearly increase in the anemic group and no change in the nonanemic group (P &lt; 0.005). A subset of these patients had a mean 1 year increase of 3 LDH units for 15 nonanemic patients and 242 units in 17 anemic patients. The reticulocyte levels did not demonstrate any progressive increase in the anemic group. The LDH level was the most useful predictor of future anemia. A value of 250 units predicted anemia on the next yearly visit with 28 percent false positive and 4 percent false negative readings. The reticulocyte count of more than 2.5 percent also placed the patient at greater risk of anemia. A serum hemoglobin level in excess of 40 mg/100 ml was common in the anemic patients and was present in only 3 of 17 nonanemic patients. It is suggested that the serum LDH level should be monitored in all patients with the aortic totally cloth-covered prosthesis. Values in excess of 250 units (four times the upper limit of normal by other LDH methods) or increasing levels, or both, suggest future anemia.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22257/1/0000693.pd

Evaluation of left ventricular ejection fraction as a measure of pump performance in patients with chronic mitral regurgitation

Left ventricular (LV) ejection fraction may not adequately detect a reduction in LV systolic performance resulting from chronic mitral regurgitation (MR), due to ventricular unloading into the low-impedance left atrium. To determine whether LV ejection fraction sufficiently gauges myocardial function in MR, nine patients were studied using micromanometer-measured LV pressures and biplane cineventriculography before and 1 year after mitral valve surgery. Six control patients were also studied. LV ejection fraction was normal in MR patients, despite an increase in LV end-systolic volume index. LV end-systolic pressure-volume and stress-volume ratios in MR patients were lower than in controls ( P < 0.05 and P < 0.01), suggesting that LV systolic performance fell. One year after mitral valve surgery, LV ejection fraction decreased ( P < 0.05) even though LV end-systolic volume index ( P < 0.05), pressure-volume ( P < 0.05), and stress-volume ratios ( P < 0.01) all improved. Thus, LV ejection fraction inadequately reflected LV systolic function in MR patients before and after mitral valve surgery. Cathet. Cardiovasc. Intervent. 49:290–296, 2000. © 2000 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/35248/1/14_ftp.pd

Insight out : making creativity visible

Models of creative problem solving are predicated upon mental states to explain everything from the outcome of problem‐solving experiments to the emergence of artistic creativity. We present two converging perspectives that describe a profoundly different ontological description of creativity. Our analysis proceeds from a distinction between first‐order problem solving, where the agent interacts with a physical model of the problem and second‐order problem solving, where the agent must cogitate a solution to a problem that is presented as a verbal description of a state of the world but where the agent does not or cannot transform physical elements of a problem. We acknowledge the recent evidence that foregrounds the importance of working memory in problem solving, including insight problem solving. However, we stress that the impressive psychometric success is obtained with a methodology that only measures second‐order problem solving; we question whether first‐order problem solving is equally well predicted by measures of cognitive or dispositional capacities. We propose that if mental simulation is replaced by the opportunity to engage with a physical model of a problem then the environment can provide affordances that help the participant to solve problems. In the second part of the paper, we present the subjective experience of an artist as he monitors the microdecisions that occur during the morphogenesis of a large, clay, sculptural installation. The testimony is a vivid demonstration that creative action occurs, not in the brain, but in the movement between the hand and the clay. Insight becomes outsight