Simulation model using standardized lineup to evaluate player offensive value

Baseball is a sport in which batting statistics are commonly used to assess the offensive value of a player. However, many traditional statistics do not accurately portray a player???s true contribution to his team since they overlook a variety of circumstances outside of the hitter???s control, in particular his position in the batting order. Using a standardized lineup, we have built a simulation based on Markov chains in which a player is evaluated by his offensive contribution in different batting positions in the lineup and then compared to other players in the league. Thus, this model is able to solely evaluate a player???s offensive skill set and distinguish which player has a greater value to his team among players with similar traditional offensive statistics. This model reveals several strategies perhaps not yet explored and can be used by major league baseball teams when making various decisions such as signing free agents, and setting offensive lineups

In Pursuit of the Epithelial Mechanosensitivity Mechanisms

Mechanosensation is critical for normal gastrointestinal (GI) function. Disruption in GI mechanosensation leads to human diseases. Mechanical forces in the GI tract are sensed by specialized mechanosensory cells, as well as non-specialized mechanosensors, like smooth muscle cells. Together, these cellular mechanosensors orchestrate physiologic responses. GI epithelium is at the interface of the body and the environment. It encounters a variety of mechanical forces that range from shear stress due to flow of luminal contents to extrinsic compression due to smooth muscle contraction. Mechanical forces applied to the GI mucosa lead to a large outflow of serotonin, and since serotonin is concentrated in a single type of an epithelial cell, called enterochromaffin cell (ECC), it was assumed that ECC is mechanosensitive. Recent studies show that a subset of ECCs is indeed mechanosensitive and that Piezo2 mechanosensitive ion channels are necessary for coupling force to serotonin release. This review aims to place this mechanism into the larger context of ECC mechanotransduction

Attachment Style as a Moderator of the Relationship Between Level of Perceived Conflict and Constructive and Psychologically Abusive Behavior in Clinic Couples

This study examined a potential moderating effect of attachment styles of members of clinical couples on the relationship between their level of perceived conflict and use of forms of psychologically abusive versus constructive conflict management behavior toward each other. Data from one hundred seventy seven couples who had sought therapy at the Family Service Center at the University of Maryland, College Park were used. Each client had completed a set of assessment questionnaires prior to beginning couple therapy at the clinic, and all data previously had been entered into a database. The subset of assessment measures utilized for this study included questionnaires assessing attachment styles, forms of psychological abuse, physical abuse, and relationship adjustment. It was hypothesized that when individuals experience conflict in their intimate relationships and their working models of attachment are activated, they will use degrees of constructive or psychologically abusive conflict management behavior based on the type of attachment style that they exhibit. It was postulated that, in general, if individuals perceive their relationship to be higher in level of conflict, they would use more psychologically abusive conflict resolution behavior than if they perceive their relationship to be lower in conflict. Results supported this hypothesis. It was also proposed that individuals perceiving their relationship to be lower in level of conflict would utilize more constructive conflict resolution behavior than individuals perceiving a higher level of conflict in their intimate relationships. Results did not support this hypothesis. In addition, individuals with secure attachment styles who perceive their relationship to be higher in conflict were expected to use more constructive conflict management skills than insecure individuals, whereas insecure individuals were expected to use more psychologically abusive behavior. The results indicated an interaction between the level of perceived conflict and the level of attachment insecurity for individuals' use of psychologically abusive conflict resolution behaviors, but not for individuals' use of constructive conflict resolution behaviors. Contrary to the hypothesis, it was found that securely attached individuals in higher conflict relationships utilized more psychologically abusive conflict resolution behavior than their insecure counterparts. However, consistent with the prediction, no significant differences were found in secure and insecure individuals' use of psychologically abusive conflict resolution behaviors in lower conflict relationships. Moreover, regarding specific types of insecure attachment, it was expected that if perceived level of conflict between the partners is relatively high: (a) individuals reporting a dismissive-avoidant attachment style would use more of the hostile withdrawal types of psychological abuse as compared with individuals reporting other forms of insecure attachment, (b) individuals with the fearful-avoidant attachment style would use more of the denigration type of psychological abuse as compared to individuals reporting other forms of insecure attachment, and (c) individuals with the preoccupied attachment style would use more of the restrictive engulfment and domination-intimidation types of psychological abuse as compared to individuals with other forms of insecure attachment. The results did not support these hypotheses. As predicted, there were no differences in the use of psychologically abusive or constructive behavior among individuals with secure attachment and the various types of insecure attachment who perceived their relationship to have a lower level of conflict. Furthermore, gender and racial (Caucasians versus African-Americans) differences in the distribution of attachment styles in members of these clinical couples were examined, and no significant results were observed. In addition, gender differences in the relationship between attachment styles and use of constructive and psychologically abusive conflict resolution behaviors in high versus low-conflict relationships were examined in an exploratory fashion. The results indicated no significant gender differences in individuals' use of constructive or psychologically abusive conflict resolution behaviors based on the level of conflict that they perceived in their relationship. Finally, the distribution of couple pairings by partners' attachment styles was explored, and the most common pairings were found to be both partners secure, both partners fearful-avoidant, and a secure male matched with a fearful female. Overall, the findings indicate that attachment styles are a variable that those who study and treat abuse within couple relationships should take into account. Implications of the study's findings for therapeutic interventions with psychologically abusive partners with various attachment patterns and suggestions for future research are discussed

A population of gut epithelial enterochromaffin cells is mechanosensitive and requires Piezo2 to convert force into serotonin release

Enterochromaffin (EC) cells constitute the largest population of intestinal epithelial enteroendocrine (EE) cells. EC cells are proposed to be specialized mechanosensory cells that release serotonin in response to epithelial forces, and thereby regulate intestinal fluid secretion. However, it is unknown whether EE and EC cells are directly mechanosensitive, and if so, what the molecular mechanism of their mechanosensitivity is. Consequently, the role of EE and EC cells in gastrointestinal mechanobiology is unclear. Piezo2 mechanosensitive ion channels are important for some specialized epithelial mechanosensors, and they are expressed in mouse and human EC cells. Here, we use EC and EE cell lineage tracing in multiple mouse models to show that Piezo2 is expressed in a subset of murine EE and EC cells, and it is distributed near serotonin vesicles by superresolution microscopy. Mechanical stimulation of a subset of isolated EE cells leads to a rapid inward ionic current, which is diminished by Piezo2 knockdown and channel inhibitors. In these mechanosensitive EE cells force leads to Piezo2-dependent intracellular Ca(2+) increase in isolated cells as well as in EE cells within intestinal organoids, and Piezo2-dependent mechanosensitive serotonin release in EC cells. Conditional knockout of intestinal epithelial Piezo2 results in a significant decrease in mechanically stimulated epithelial secretion. This study shows that a subset of primary EE and EC cells is mechanosensitive, uncovers Piezo2 as their primary mechanotransducer, defines the molecular mechanism of their mechanotransduction and mechanosensitive serotonin release, and establishes the role of epithelial Piezo2 mechanosensitive ion channels in regulation of intestinal physiology

Ranolazine-mediated attenuation of mechanoelectric feedback in atrial myocyte monolayers

[EN] Background Mechanical stretch increases Na(+)inflow into myocytes, related to mechanisms including stretch-activated channels or Na+/H(+)exchanger activation, involving Ca(2+)increase that leads to changes in electrophysiological properties favoring arrhythmia induction. Ranolazine is an antianginal drug with confirmed beneficial effects against cardiac arrhythmias associated with the augmentation ofI(NaL)current and Ca(2+)overload. Objective This study investigates the effects of mechanical stretch on activation patterns in atrial cell monolayers and its pharmacological response to ranolazine. Methods Confluent HL-1 cells were cultured in silicone membrane plates and were stretched to 110% of original length. The characteristics ofin vitrofibrillation (dominant frequency, regularity index, density of phase singularities, rotor meandering, and rotor curvature) were analyzed using optical mapping in order to study the mechanoelectric response to stretch under control conditions and ranolazine action. Results HL-1 cell stretch increased fibrillatory dominant frequency (3.65 +/- 0.69 vs. 4.35 +/- 0.74 Hz,p< 0.01) and activation complexity (1.97 +/- 0.45 vs. 2.66 +/- 0.58 PS/cm(2),p< 0.01) under control conditions. These effects were related to stretch-induced changes affecting the reentrant patterns, comprising a decrease in rotor meandering (0.72 +/- 0.12 vs. 0.62 +/- 0.12 cm/s,p< 0.001) and an increase in wavefront curvature (4.90 +/- 0.42 vs. 5.68 +/- 0.40 rad/cm,p< 0.001). Ranolazine reduced stretch-induced effects, attenuating the activation rate increment (12.8% vs. 19.7%,p< 0.01) and maintaining activation complexity-both parameters being lower during stretch than under control conditions. Moreover, under baseline conditions, ranolazine slowed and regularized the activation patterns (3.04 +/- 0.61 vs. 3.65 +/- 0.69 Hz,p< 0.01). Conclusion Ranolazine attenuates the modifications of activation patterns induced by mechanical stretch in atrial myocyte monolayers.This work was supported by the Instituto de Salud Carlos III-FEDER (Fondo Europeo de Desarrollo Regional) (Grant Nos. CB16/11/00486, CB16/11/00292, PI16/01123, PI17/01059, PI17/01106, PI18/01620, and DTS16/0160) and the Generalitat Valenciana (Grant Nos. PROMETEO/2018/078 and APOSTD/2018/181).Del-Canto, I.; Gómez-Cid, L.; Hernández-Romero, I.; Guillem Sánchez, MS.; Fernández-Santos, ME.; Atienza, F.; Such, L.... (2020). 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Calmodulin kinase II and protein kinase C mediate the effect of increased intracellular calcium to augment late sodium current in rabbit ventricular myocytes. American Journal of Physiology-Cell Physiology, 302(8), C1141-C1151. doi:10.1152/ajpcell.00374.2011Maltsev, V. A., & Undrovinas, A. (2008). Late sodium current in failing heart: Friend or foe? Progress in Biophysics and Molecular Biology, 96(1-3), 421-451. doi:10.1016/j.pbiomolbio.2007.07.010Meo, M., Pambrun, T., Derval, N., Dumas-Pomier, C., Puyo, S., Duchâteau, J., … Dubois, R. (2018). Noninvasive Assessment of Atrial Fibrillation Complexity in Relation to Ablation Characteristics and Outcome. Frontiers in Physiology, 9. doi:10.3389/fphys.2018.00929Nattel, S., & Dobrev, D. (2012). The multidimensional role of calcium in atrial fibrillation pathophysiology: mechanistic insights and therapeutic opportunities. European Heart Journal, 33(15), 1870-1877. doi:10.1093/eurheartj/ehs079Nesterenko, V. V., Zygmunt, A. C., Rajamani, S., Belardinelli, L., & Antzelevitch, C. (2011). Mechanisms of atrial-selective block of Na+ channels by ranolazine: II. Insights from a mathematical model. American Journal of Physiology-Heart and Circulatory Physiology, 301(4), H1615-H1624. doi:10.1152/ajpheart.00243.2011Neves, J. S., Leite-Moreira, A. M., Neiva-Sousa, M., Almeida-Coelho, J., Castro-Ferreira, R., & Leite-Moreira, A. F. (2016). Acute Myocardial Response to Stretch: What We (don’t) Know. Frontiers in Physiology, 6. doi:10.3389/fphys.2015.00408Pandit, S. V., Berenfeld, O., Anumonwo, J. M. B., Zaritski, R. M., Kneller, J., Nattel, S., & Jalife, J. (2005). Ionic Determinants of Functional Reentry in a 2-D Model of Human Atrial Cells During Simulated Chronic Atrial Fibrillation. Biophysical Journal, 88(6), 3806-3821. doi:10.1529/biophysj.105.060459Pandit, S. V., & Jalife, J. (2013). Rotors and the Dynamics of Cardiac Fibrillation. 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Circulation, 96(5), 1686-1695. doi:10.1161/01.cir.96.5.1686RAVELLI, F., MASÈ, M., DEL GRECO, M., MARINI, M., & DISERTORI, M. (2010). Acute Atrial Dilatation Slows Conduction and Increases AF Vulnerability in the Human Atrium. Journal of Cardiovascular Electrophysiology, 22(4), 394-401. doi:10.1111/j.1540-8167.2010.01939.xSalinet, J., Schlindwein, F. S., Stafford, P., Almeida, T. P., Li, X., Vanheusden, F. J., … Ng, G. A. (2017). Propagation of meandering rotors surrounded by areas of high dominant frequency in persistent atrial fibrillation. Heart Rhythm, 14(9), 1269-1278. doi:10.1016/j.hrthm.2017.04.031Seo, K., Inagaki, M., Hidaka, I., Fukano, H., Sugimachi, M., Hisada, T., … Sugiura, S. (2014). Relevance of cardiomyocyte mechano-electric coupling to stretch-induced arrhythmias: Optical voltage/calcium measurement in mechanically stimulated cells, tissues and organs. Progress in Biophysics and Molecular Biology, 115(2-3), 129-139. doi:10.1016/j.pbiomolbio.2014.07.008Shryock, J. C., Song, Y., Rajamani, S., Antzelevitch, C., & Belardinelli, L. (2013). The arrhythmogenic consequences of increasing late INa in the cardiomyocyte. Cardiovascular Research, 99(4), 600-611. doi:10.1093/cvr/cvt145Song, Y., Shryock, J. C., & Belardinelli, L. (2008). An increase of late sodium current induces delayed afterdepolarizations and sustained triggered activity in atrial myocytes. American Journal of Physiology-Heart and Circulatory Physiology, 294(5), H2031-H2039. doi:10.1152/ajpheart.01357.2007Sossalla, S., Kallmeyer, B., Wagner, S., Mazur, M., Maurer, U., Toischer, K., … Maier, L. S. (2010). Altered Na+Currents in Atrial Fibrillation. Journal of the American College of Cardiology, 55(21), 2330-2342. doi:10.1016/j.jacc.2009.12.055Strege, P., Beyder, A., Bernard, C., Crespo-Diaz, R., Behfar, A., Terzic, A., … Farrugia, G. (2012). Ranolazine inhibits shear sensitivity of endogenous Na+current and spontaneous action potentials in HL-1 cells. Channels, 6(6), 457-462. doi:10.4161/chan.22017Tsai, C.-T., Chiang, F.-T., Tseng, C.-D., Yu, C.-C., Wang, Y.-C., Lai, L.-P., … Lin, J.-L. (2011). Mechanical Stretch of Atrial Myocyte Monolayer Decreases Sarcoplasmic Reticulum Calcium Adenosine Triphosphatase Expression and Increases Susceptibility to Repolarization Alternans. Journal of the American College of Cardiology, 58(20), 2106-2115. doi:10.1016/j.jacc.2011.07.039White, S. M., Constantin, P. E., & Claycomb, W. C. (2004). Cardiac physiology at the cellular level: use of cultured HL-1 cardiomyocytes for studies of cardiac muscle cell structure and function. American Journal of Physiology-Heart and Circulatory Physiology, 286(3), H823-H829. doi:10.1152/ajpheart.00986.200

Loss-of-function of the Voltage-gated Sodium Channel NaV1.5 (Channelopathies) in Patients with Irritable Bowel Syndrome.

Background & Aims SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of NaV1.5. Methods We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. Results Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P <.05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted NaV1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-NaV1.5 had the greatest effect in reducing NaV1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS. Conclusions About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt Na V1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options

The core domain as the force sensor of the yeast mechanosensitive TRP channel

Stretch-activated conductances are commonly encountered in careful electric recordings. Those of known proteins (TRP, MscL, MscS, K2p, Kv, etc.) all share a core, which houses the ion pathway and the gate, but no recognizable force-sensing domain. Like animal TRPs, the yeast TRPY1 is polymodal, activated by stretch force, Ca2+, etc. To test whether its S5–S6 core senses the stretch force, we tried to uncouple it from the peripheral domains by strategic peptide insertions to block the covalent core–periphery interactions. Insertion of long unstructured peptides should distort, if not disrupt, protein structures that transmit force. Such insertions between S6 and the C-terminal tail largely removed Ca2+ activation, showing their effectiveness. However, such insertions as well as those between S5 and the N-terminal region, which includes S1–S4, did not significantly alter mechanosensitivity. Even insertions at both locations flanking the S5–S6 core did not much alter mechanosensitivity. Tryptophan scanning mutations in S5 were also constructed to perturb possible noncovalent core–periphery contacts. The testable tryptophan mutations also have little or no effects on mechanosensitivity. Boltzmann fits of the wild-type force–response curves agree with a structural homology model for a stretch-induced core expansion of ∼2 nm2 upon opening. We hypothesize that membrane tension pulls on S5–S6, expanding the core and opening the TRPY1 gate. The core being the major force sensor offers the simplest, though not the only, explanation of why so many channels of disparate designs are mechanically sensitive. Compared with the bacterial MscL, TRPY1 is much less sensitive to force, befitting a polymodal channel that relies on multiple stimuli