Journal articles: 'Ski bindings'

1

Campbell, Jeffrey R., Irving S. Scher, David Carpenter, Bruce L. Jahnke, and Randal P. Ching. "Performance of Alpine Touring Boots When Used in Alpine Ski Bindings." Journal of Applied Biomechanics 33, no. 5 (October 1, 2017): 330–38. http://dx.doi.org/10.1123/jab.2016-0256.

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Alpine touring (AT) equipment is designed for ascending mountains and snow skiing down backcountry terrain. Skiers have been observed using AT boots in alpine (not made for Alpine Touring) ski bindings. We tested the effect on the retention-release characteristics of AT boots used in alpine bindings. Ten AT ski boots and 5 alpine ski boots were tested in 8 models of alpine ski bindings using an ASTM F504-05 (2012) apparatus. Thirty-one percent of the AT boots released appropriately when used in alpine ski bindings. One alpine binding released appropriately for all alpine and AT boots tested; 2 alpine ski bindings did not release appropriately for any AT boots. Altering the visual indicator settings on the bindings (that control the release torque of an alpine system) had little or no effect on the release torque when using AT boots in alpine ski bindings. Many combinations released appropriately in ski shop tests, but did not release appropriately in the more complex loading cases that simulated forward and backward falls; the simple tests performed by ski shops could produce a “false-negative” test result. These results indicate that using AT boots with alpine ski bindings could increase the likelihood of lower leg injuries.

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Natri, Antero, Bruce D. Beynnon, Carl F. Ettlinger, Robert J. Johnson, and Jasper E. Shealy. "Alpine Ski Bindings and Injuries." Sports Medicine 28, no. 1 (1999): 35–48. http://dx.doi.org/10.2165/00007256-199928010-00004.

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3

Suderman, Bethany L., Alexander Sklar, Lenka L. Stepan, and Irving S. Scher. "Water Ski Binding Release Characteristics in Forward Lean." Proceedings 49, no. 1 (June 15, 2020): 76. http://dx.doi.org/10.3390/proceedings2020049076.

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To reduce the risk of injury, waterski bindings should secure the foot to the ski when the likelihood of lower leg injury is low (retention) and free the foot when the likelihood of injury is high (release). Unlike snow skiing, there are no standards dictating the release of waterski bindings. Testing was completed to determine release torques in forward lean of three commercially available waterski boot-binding systems. Each binding was mounted to a 66-inch waterski and the boot was fitted on a lower leg surrogate with a torque transducer. A forward-lean bending moment was applied quasi-statically about the transverse axis of the ski until the binding released the boot. For the three boot-binding systems, the range of release torques were 126 to 219, 50 Nm to 141, and 63 to 127 Nm.

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Graf, Simon, Stefan Litzenberger, and Anton Sabo. "Edging stiffness of ski touring bindings." Procedia Engineering 13 (2011): 37–43. http://dx.doi.org/10.1016/j.proeng.2011.05.048.

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5

Ettlinger, Carl F., David Dodge, Robert J. Johnson, Jasper E. Shealy, Michael Sargent, R. J. Johnson, J. Stealy, V. Senner, and S. W. Dean. "Retention Requirements for Alpine Ski Bindings." Journal of ASTM International 7, no. 6 (2010): 102978. http://dx.doi.org/10.1520/jai102978.

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6

Wunderly, Glenn S., and Maury L. Hull. "A Biomechanical Approach to Alpine Ski Binding Design." International Journal of Sport Biomechanics 5, no. 3 (August 1989): 308–23. http://dx.doi.org/10.1123/ijsb.5.3.308.

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A new approach to ski binding design is advanced. It begins with a release locus derived from injury mechanics research and knowledge of the expected loading conditions and then incorporates these into the final binding design. A mechanical ski binding designed by following the new approach is presented. This binding offers a number of performance features not found in commercially available designs. One feature is the ability to eliminate the axial force supported by the tibial shaft from affecting release in forward bending. A second feature is the binding’s ability to release according to virtually any preprogrammed locus of the combination of moments in both bending and torsion. A third feature is a release mechanism that is insensitive to the common frictional forces that affect the release consistency of conventional heel/toe bindings. In addition to these features, the binding offers a variety of operational conveniences. The presentation of the binding not only describes the design details but also evaluates the release performance (i.e., locus and consistency) based upon laboratory tests under quasistatic loading.

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7

Boldrino, Christian, Bob Goethals, and Renate Wachter-Fritz. "The actual release-values of ski safety-bindings on ski-runs in Austria." International Journal for Consumer and Product Safety 3, no. 1 (March 1996): 39–46. http://dx.doi.org/10.1080/09298349608945763.

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8

Mote, C. D. "The Forces of Skiing and Their Implication to Injury." International Journal of Sport Biomechanics 3, no. 4 (November 1987): 309–25. http://dx.doi.org/10.1123/ijsb.3.4.309.

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The forces and moments applied to the leg by the ski during skiing are compared to the forces necessary to cause injury to the tibia and ligaments at the knee and to standard recommendations for ski release binding adjustment. These forces and moments of recreational skiing are shown to be similar to, or greater than, those capable of causing injury to the knee and tibia. The adjustment of release bindings by current standards unavoidably permits forces of sufficient magnitude to cause injury to the skier. Release bindings cannot be adjusted to guarantee that the forces transmitted to the boot are below an injury threshold for a large fraction of the population. The role of muscle contraction in skiing safety requires complete recognition in the knowledge base on skiing safety.

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9

Hull, M. L., M. Swanstrom, and B. Wade. "Electromechanical Ski Release Binding With Mechanical Backup." Journal of Mechanical Design 119, no. 1 (March 1, 1997): 145–48. http://dx.doi.org/10.1115/1.2828779.

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To better protect Alpine skiers against injuries to both the lower leg and the knee, the objective of this work was to design a binding which: (1) maintained a consistent release level in twist in the presence of combined loads; (2) released the heelpiece based on the anterior/posterior (A/P) bending moment transmitted by the leg; and (3) modulated the release level in twist depending on the degree of contraction in muscles crossing the knee. To fulfill the objective, a conventional ski binding was modified. Modifications included integrating dynamometers into the toepiece, anti-friction device (AFD), and heelpiece. The toepiece sensor indicates the twisting moment while the AFD and heelpiece sensors indicate the anterior bending moment transmitted by the leg. To gain electronic control of binding release, a solenoid actuated mechanism was added which translated the heelpiece rearward along the ski to decouple the boot from the binding. Otherwise, the binding allowed normal mechanical function. Prototype testing confirmed the ability of the dynamometers to accurately measure desired loads in the presence of extraneous loads and the reliability of the solenoid actuated mechanism in releasing the hoot under loads typical of skiing. Thus, this work demonstrated the feasibility of hybrid electromechanical/mechanical releasable bindings. Such a demonstration should encourage the development of designs for commercial use.

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10

Nusser, Michaela, Aljoscha Hermann, and Veit Senner. "Artificial Knee Joint and Ski Load Simulator for the Evaluation of Knee Braces and Ski Bindings." Procedia Engineering 147 (2016): 220–27. http://dx.doi.org/10.1016/j.proeng.2016.06.217.

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11

Howell, Rick. "MITIGATION OF ACL RUPTURE IN ALPINE SKIING THROUGH SKI BINDINGS." British Journal of Sports Medicine 51, no. 4 (February 2017): 332.1–332. http://dx.doi.org/10.1136/bjsports-2016-097372.123.

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12

Posch, Markus, Martin Burtscher, Alois Schranz, Katja Tecklenburg, Kenneth Helle, and Gerhard Ruedl. "Impact of lowering ski binding settings on the outcome of the self-release test of ski bindings among female recreational skiers." Open Access Journal of Sports Medicine Volume 8 (December 2017): 267–72. http://dx.doi.org/10.2147/oajsm.s151229.

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13

Johnson, Robert J., Carl F. Ettlinger, and Jasper E. Shealy. "Myths Concerning Alpine Skiing Injuries." Sports Health: A Multidisciplinary Approach 1, no. 6 (November 2009): 486–92. http://dx.doi.org/10.1177/1941738109347964.

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There are many commonly discussed myths about ski safety that are propagated by industry, physicians, and skiers. Through a review of the literature concerning 12 such topics, this article demonstrates that the following are untrue: (1) Broken legs have been traded for blown-out knees. (2) If you know your DIN (a slang term for release indicator value), you can adjust your own bindings. (3) Toe and heel piece settings must be the same to function properly. (4) Formal ski instruction will make you safer. (5) Very short skis do not need release bindings. (6) Spending a lot of money on children’s equipment is not worth the cost. (7) Children need plenty of room in ski boots for their growing feet. (8) If you think you are going to fall, just relax. (9) Exercise can prevent skiing injuries. (10) Lower release settings can reduce the risk of anterior cruciate ligament injury. (11) Buying new ski equipment is safer than renting. (12) Skiing is among the most dangerous of activities. It is important for the skiing public, physicians, and all those interested in improving skiing safety to verify the measures they advocate. The statements analyzed here are simply untrue and have the potential to cause harm if taken as fact by those exposed to these unsupported opinions.

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14

Nusser, Michaela, Aljoscha Hermann, and Veit Senner. "Corrigendum to ‘Artificial Knee Joint and Ski Load Simulator for the Evaluation of Knee Braces and Ski Bindings’." Procedia Engineering 147 (2016): 918. http://dx.doi.org/10.1016/j.proeng.2017.07.001.

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15

Laporte, Jean-Dominique, Marc-Hervé Binet, Nicolas Fenet, Dominique Constans, Patrick Joubert, R. J. Johnson, Jasper Shealy, Mike Langran, and S. W. Dean. "Ski Bindings and Lower Leg Injuries, A Case Control Study in Flaine, 2006." Journal of ASTM International 6, no. 1 (2009): 101625. http://dx.doi.org/10.1520/jai101625.

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16

Pigman, Edwin C., Guerard P. Grice, and Gerald W. Volcheck. "Military Nordic Skiing Injury Profiles with Two Different Types of NATO Ski Bindings." Military Medicine 155, no. 8 (August 1, 1990): 354–56. http://dx.doi.org/10.1093/milmed/155.8.354.

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17

Finch, Caroline F., and Helen L. Kelsall. "The Effectiveness of Ski Bindings and Their Professional Adjustment for Preventing Alpine Skiing Injuries." Sports Medicine 25, no. 6 (1998): 407–16. http://dx.doi.org/10.2165/00007256-199825060-00004.

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18

Bolger, Conor M., Øyvind Sandbakk, Gertjan Ettema, and Peter Federolf. "How Hinge Positioning in Cross-Country Ski Bindings Affect Exercise Efficiency, Cycle Characteristics and Muscle Coordination during Submaximal Roller Skiing." PLOS ONE 11, no. 5 (May 20, 2016): e0153078. http://dx.doi.org/10.1371/journal.pone.0153078.

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19

Tuteja, Dipika, Danyan Xu, Valeriy Timofeyev, Ling Lu, Dipika Sharma, Zhao Zhang, Yanfang Xu, et al. "Differential expression of small-conductance Ca2+-activated K+ channels SK1, SK2, and SK3 in mouse atrial and ventricular myocytes." American Journal of Physiology-Heart and Circulatory Physiology 289, no. 6 (December 2005): H2714—H2723. http://dx.doi.org/10.1152/ajpheart.00534.2005.

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Small-conductance Ca2+-activated K+ channels (SK channels, KCa channels) have been reported in excitable cells, where they aid in integrating changes in intracellular Ca2+ with membrane potential. We recently reported for the first time the functional existence of SK2 (KCa2.2) channels in human and mouse cardiac myocytes. Here, we report cloning of SK1 (KCa2.1) and SK3 (KCa2.3) channels from mouse atria and ventricles using RT-PCR. Full-length transcripts and their variants were detected for both SK1 and SK3 channels. Variants of mouse SK1 channel (mSK1) differ mainly in the COOH-terminal structure, affecting a portion of the sixth transmembrane segment (S6) and the calmodulin binding domain (CaMBD). Mouse SK3 channel (mSK3) differs not only in the number of polyglutamine repeats in the NH2 terminus but also in the intervening sequences between the polyglutamine repeats. Full-length cardiac mSK1 and mSK3 show 99 and 91% nucleotide identity with those of mouse colon SK1 and SK3, respectively. Quantification of SK1, SK2, and SK3 transcripts between atria and ventricles was performed using real-time quantitative RT-PCR from single, isolated cardiomyocytes. SK1 transcript was found to be more abundant in atria compared with ventricles, similar to the previously reported finding for SK2 channel. In contrast, SK3 showed similar levels of expression in atria and ventricles. Together, our data are the first to indicate the presence of the three different isoforms of SK channels in heart and the differential expression of SK1 and SK2 in mouse atria and ventricles. Because of the marked differential expression of SK channel isoforms in heart, specific ligands for Ca2+-activated K+ currents may offer a unique therapeutic opportunity to modify atrial cells without interfering with ventricular myocytes.

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20

Werner, S., and K. Willis. "Self-Release of Ski-Binding." International Journal of Sports Medicine 23, no. 7 (October 2002): 530–35. http://dx.doi.org/10.1055/s-2002-35072.

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21

Ricci, Clara, Francesco Onida, Davide Soligo, Giorgio Lambertenghi-Deliliers, and Riccardo Ghidoni. "Sphingosine Kinase 1 Is Involved in Proliferation and Survival of Chronic Myeloid Leukemia Cells." Blood 106, no. 11 (November 16, 2005): 4878. http://dx.doi.org/10.1182/blood.v106.11.4878.4878.

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Abstract Sphingosine Kinase 1 (SK1) is a key enzyme of the sphingolipid metabolism. By phosphorylating sphingosine (Sph), SK1 induces accumulation of sphingosine 1 phosphate (S1P). As a second messenger, S1P stimulates proliferation and survival and protects cells against ceramide-induced apoptosis. Although oncogenic activity of SK1 has been demonstrated in a variety of solid tumors, its role in leukemic cells growth remains unclear. Recently, SK1 overexpression has been reported to represent an oncogenic event during erythroleukemia progression (Lescolan E. et al, Blood 2005). We focused on Chronic Myeloid Leukemia (CML), a hematopoietic disorder characterized by the presence of the Philadelphia (Ph) chromosome that leads to the expression of the chimeric protein Bcr/Abl. Through its constitutive tyrosine kinase activity, Bcr/Abl is recognized as the pathogenetic event that causes CML and thus the basis for the development of specific inhibitors. Among these, Imatinib Mesylate (IM) represents the more successful drug for CML treatment. However, most patients who are treated in advanced stages of the disease relapse after an initial response to IM. Therefore, the existence of a functional link between Bcr/Abl and SK1 would provide new strategies to overcome acquired resistance to IM in CML. To test the hypothesis that SK1 contributes to the growth and survival of leukemic cells, we first verified that the kinase transcript is expressed in a panel of CML cell lines [AR230 (p230Bcr/Abl+), K562 and RWLeu4 (both p210Bcr/Abl+)], although at different levels. Then the effect of pharmacological inhibition of SK1 was assessed by using a competitive inhibitor (SKI, SK Inhibitor, Calbiochem) of the ATP-binding site of SK1. Cells were treated with increasing doses (1 to 50 μM) of SKI for up to 72 hrs and the WST-1 assay was performed. A dose- and time-dependent anti-proliferative and cytotoxic effect was observed (IC50: 7.02 μM for AR230, 7.06 μM for K562 and 35.8 μM for RWLeu4 cells). Surprisingly, up-regulation of SK1 transcript was detected. Finally, when the Eosinophilic Leukemia cell line Eol-1 (FIP1L1-PDGFRα+) was exposed to SKI under the same experimental conditions of CML cells, an even more potent anti-proliferative and cytotoxic effect was observed, indicating a higher sensitivity of these cells to SKI (IC50: 0.43 μM). Altogether our results suggest involvement of SK1 in the control of growth and survival of myeloid leukemia cells of different origin. To address the question whether a functional link between SK1 and Bcr/Abl occurs, we are now investigating if Bcr/Abl expression and phosphorylation status are modulated following treatment with SKI and conversely if SK1 expression and activity are affected by treatment with IM.

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22

Fang, Liang, Xiaojian Wang, Meiyang Xi, Tianqi Liu, and Dali Yin. "Assessing the ligand selectivity of sphingosine kinases using molecular dynamics and MM-PBSA binding free energy calculations." Molecular BioSystems 12, no. 4 (2016): 1174–82. http://dx.doi.org/10.1039/c6mb00067c.

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23

Baldwin, Amy, Lucia Pirisi, and Kim E. Creek. "NFI-Ski Interactions Mediate Transforming Growth Factor β Modulation of Human Papillomavirus Type 16 Early Gene Expression." Journal of Virology 78, no. 8 (April 15, 2004): 3953–64. http://dx.doi.org/10.1128/jvi.78.8.3953-3964.2004.

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ABSTRACT Human papillomaviruses (HPVs) are present in virtually all cervical cancers. An important step in the development of malignant disease, including cervical cancer, involves a loss of sensitivity to transforming growth factor β (TGF-β). HPV type 16 (HPV16) early gene expression, including that of the E6 and E7 oncoprotein genes, is under the control of the upstream regulatory region (URR), and E6 and E7 expression in HPV16-immortalized human epithelial cells is inhibited at the transcriptional level by TGF-β. While the URR contains a myriad of transcription factor binding sites, including seven binding sites for nuclear factor I (NFI), the specific sequences within the URR or the transcription factors responsible for TGF-β modulation of the URR remain unknown. To identify potential transcription factors and binding sites involved in TGF-β modulation of the URR, we performed DNase I footprint analysis on the HPV16 URR using nuclear extracts from TGF-β-sensitive HPV16-immortalized human keratinocytes (HKc/HPV16) treated with and without TGF-β. Differentially protected regions were found to be located around NFI binding sites. Electrophoretic mobility shift assays, using the NFI binding sites as probes, showed decreased binding upon TGF-β treatment. This decrease in binding was not due to reduced NFI protein or NFI mRNA levels. Mutational analysis of individual and multiple NFI binding sites in the URR defined their role in TGF-β sensitivity of the promoter. Overexpression of the NFI family members in HKc/HPV16 decreased the ability of TGF-β to inhibit the URR. Since the oncoprotein Ski has been shown to interact with and increase the transcriptional activity of NFI and since cellular Ski levels are decreased by TGF-β treatment, we explored the possibility that Ski may provide a link between TGF-β signaling and NFI activity. Anti-NFI antibodies coimmunoprecipitated endogenous Ski in nuclear extracts from HKc/HPV16, confirming that NFI and Ski interact in these cells. Ski levels dramatically decreased upon TGF-β treatment of HKc/HPV16, and overexpression of Ski eliminated the ability of TGF-β to inhibit the URR. Based on these studies, we propose that TGF-β inhibition of HPV16 early gene expression is mediated by a decrease in Ski levels, which in turn dramatically reduces NFI activity.

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24

Nicol, Rebekka, and Ed Stavnezer. "Transcriptional Repression by v-Ski and c-Ski Mediated by a Specific DNA Binding Site." Journal of Biological Chemistry 273, no. 6 (February 6, 1998): 3588–97. http://dx.doi.org/10.1074/jbc.273.6.3588.

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25

Ueki, Nobuhide, Leiqing Zhang, and Michael J. Hayman. "Ski Negatively Regulates Erythroid Differentiation through Its Interaction with GATA1." Molecular and Cellular Biology 24, no. 23 (December 1, 2004): 10118–25. http://dx.doi.org/10.1128/mcb.24.23.10118-10125.2004.

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ABSTRACT The Ski oncoprotein dramatically affects cell growth, differentiation, and/or survival. Recently, Ski was shown to act in distinct signaling pathways including those involving nuclear receptors, transforming growth factor β, and tumor suppressors. These divergent roles of Ski are probably dependent on Ski's capacity to bind multiple partners with disparate functions. In particular, Ski alters the growth and differentiation program of erythroid progenitor cells, leading to malignant leukemia. However, the mechanism underlying this important effect has remained elusive. Here we show that Ski interacts with GATA1, a transcription factor essential in erythropoiesis. Using a Ski mutant deficient in GATA1 binding, we show that this Ski-GATA1 interaction is critical for Ski's ability to repress GATA1-mediated transcription and block erythroid differentiation. Furthermore, the repression of GATA1-mediated transcription involves Ski's ability to block DNA binding of GATA1. This finding is in marked contrast to those in previous reports on the mechanism of repression by Ski, which have described a model involving the recruitment of corepressors into DNA-bound transcription complexes. We propose that Ski cooperates in the process of transformation in erythroid cells by interfering with GATA1 function, thereby contributing to erythroleukemia.

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26

Takeda, Masafumi, Masafumi Mizuide, Masako Oka, Tetsuro Watabe, Hirofumi Inoue, Hiroyuki Suzuki, Toshiro Fujita, Takeshi Imamura, Kohei Miyazono, and Keiji Miyazawa. "Interaction with Smad4 Is Indispensable for Suppression of BMP Signaling by c-Ski." Molecular Biology of the Cell 15, no. 3 (March 2004): 963–72. http://dx.doi.org/10.1091/mbc.e03-07-0478.

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c-Ski is a transcriptional corepressor that interacts strongly with Smad2, Smad3, and Smad4 but only weakly with Smad1 and Smad5. Through binding to Smad proteins, c-Ski suppresses signaling of transforming growth factor-β (TGF-β) as well as bone morphogenetic proteins (BMPs). In the present study, we found that a mutant of c-Ski, termed c-Ski (ARPG) inhibited TGF-β/activin signaling but not BMP signaling. Selectivity was confirmed in luciferase reporter assays and by determination of cellular responses in mammalian cells (BMP-induced osteoblastic differentiation of C2C12 cells and TGF-β–induced epithelial-to-mesenchymal transdifferentiation of NMuMG cells) and Xenopus embryos. The ARPG mutant recruited histone deacetylases 1 (HDAC1) to the Smad3-Smad4 complex but not to the Smad1/5-Smad4 complex. c-Ski (ARPG) was unable to interact with Smad4, and the selective loss of suppression of BMP signaling by c-Ski (ARPG) was attributed to the lack of Smad4 binding. We also found that c-Ski interacted with Smad3 or Smad4 without disrupting Smad3-Smad4 heteromer formation. c-Ski (ARPG) would be useful for selectively suppressing TGF-β/activin signaling.

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27

Eseltine, Kevin, and Maury L. Hull. "An Alpine Ski Binding with Electrically Modulated Twist Release." International Journal of Sport Biomechanics 7, no. 2 (May 1991): 183–200. http://dx.doi.org/10.1123/ijsb.7.2.183.

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This article describes the design of a new binding for Alpine skiing wherein the release level of the toepiece in twist is modulated based on the level of neural stimulation of one of the vastii muscles in the quadriceps group. A conventional binding toepiece that relies on the force of a compressed spring to resist the release of the boot was modified. To modulate the release level to either a high or a low state, a special solenoid activated mechanism that alters the binding spring constant was designed. The design details of this special mechanism are described and the computations necessary to ensure reliable activation with a low force solenoid are summarized. Also described is the special circuitry that was designed to actuate the solenoid. To demonstrate the workability of both the mechanism and the circuitry, a prototype binding system was constructed and tested. The results of this testing are described as well.

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28

Grafone, Tiziana, Simona Soverini, Gianluca Tasco, Manuela Mancini, Frank Boschelli, Jennifer Golas, David Frauling, et al. "A Study of the Binding Mode and the In Vitro Activity of the Protein Tyrosine Kinase Inhibitor SKI-606 in the BCR-ABL Positive Cells." Blood 108, no. 11 (November 1, 2006): 2335. http://dx.doi.org/10.1182/blood.v108.11.2335.2335.

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Abstract Resistance to the BCR-ABL inhibitor imatinib mesylate (IM) is often caused by the selection of leukemic clones harboring mutations that destabilize the inactive conformation of BCR-ABL, to which IM preferentially binds, shifting the equilibrium toward the active kinase conformation. Hence the need for second -generation kinase inhibitors with a greater flexibility in binding to different BCR-ABL conformations. The 4-anilino-3 quinolinecarbonitrile SKI-606 is a novel Src and ABL kinase inhibitor. We report here that SKI-606 is a potent and antiproliferative agent when tested in K562 cell line and CD34+ cells from patients with chronic myeloid leukemia (CML) blast crisis. In K562 cells, SKI-606 treatment caused a dose-dependent decrease in cell viability accompanied by accumulation in subG1 phase, an effect not observed in BCR-ABL-negative HL-60 cells. Treatment of K562 with 100 nM SKI-606 for 24 hours caused a complete dephosphorylation of Lyn, Stat5 and Bcl-xl, while AKT and Bad phosphorylation was only diminished. Unexpectedly, the phosphorylation of BCR-ABL was less affected. SKI-606 treatment caused a shift to the subG1 phase also of CD34+ cells isolated from both IM-sensitive and resistant patients, the latter harboring the BCR-ABL mutations F359V, Y253H, E255V and E255K. The inhibitory concentration 50% (IC50) was 100 nM SKI-606 for Y253H, E255V, E255K and 1000nM for F359V. Cytofluorimetric analysis of cells from IM- sensitive CML patients indicated an accumulation in subG1 phase following treatment with SKI-606 alone or in combination with IM. Because the crystal structure of the BCR-ABL kinase domain in complex with SKI-606 has not yet been determined and the mode of binding of this inhibitor is unknown, we first used a molecular docking approach to determine SKI-606 binding mode to wild type (wt) form of the BCR-ABL kinase. We found that the interaction between SKI-606 and BCR-ABL was more stable when the activation loop was in the inactive conformation. Moreover, we found that SKI-606 retained the ability of efficiently binding all the above mentioned BCR-ABL variants, but not the T315I. Finally, we identified six BCR-ABL residues located around SKI-606 that, if mutated, could potentially be able to interfere with the SKI-606/BCR-ABL interaction: the charged residues K271, D381 and H361; the hydrophobic/aliphatic residues V299, A380 and M318. These data help refining the use of SKI-606 for treatment of BCR-ABL positive leukemias.

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29

Hauser, Wolfhart, and Peter Schaff. "Ski Boots: Biomechanical Issues Regarding Skiing Safety and Performance." International Journal of Sport Biomechanics 3, no. 4 (November 1987): 326–44. http://dx.doi.org/10.1123/ijsb.3.4.326.

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In a state-of-the-art paper on skiing performance and on skiing safety, aspects of ski boot design are discussed. The influence of ski boots on the skier-bootbinding-ski system is described, and suggestions are made about improving ski boots regarding better skiing performance, less inadvertent binding releases, and less lower extremity equipment related injuries. The design of the boot sole and the boot shaft with its influence on binding release values is particularly described. Furthermore, in the forward lean the shaft stiffness of modern ski boots and their pressure distribution is very important for good skiing performance and reduction of injuries of the ankle joint and the tibia. The built-in forward lean and the stiffness to the rear can be related to the acting forces in the anterior cruciate ligament, and first approximations to reduce the risk of these injuries are given.

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30

Frech, Miriam, Sabine Teichler, Christine Weber, Caroline Bouchard, Katharina Sorg, Lars Bullinger, Uta-Maria Bauer, and Andreas Neubauer. "Identification of the Oncogene SKI As a New Target Gene of the Myeloid Transcription Factor c-MYB in AML." Blood 128, no. 22 (December 2, 2016): 2719. http://dx.doi.org/10.1182/blood.v128.22.2719.2719.

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Abstract Background: Acute myeloid leukemia (AML) accounts for 80% of acute leukemias and arises through clonal expansion and arrest of differentiation of hematopoietic progenitor cells in the bone marrow. Depending on the AML subtype and age of the patient, AML patients have a 5-year survival rate of about 25%. AML is a genetically heterogenous disease, where chromosomal aberrations, point mutations in critical oncogenes as well as aberrant expression of key regulatory factors of hematopoiesis collude during transformation. c-MYB is an important hematopoietic transcription factor involved in proliferation and differentiation of progenitor cells of the myeloid and lymphoid lineages. It was first described as a viral oncogene of avian leukemia viruses and is upregulated or mutated in many leukemic subtypes as well as solid tumors. c-MYB interacts with other transcription factors or co-factors, which are essential for its transcriptional activity. In this regard, c-MYB transactivation ability is inhibited by a histone deacetylases recruiting corepressor complex containing SKI, TIF1BETA, NCOR and mSIN3A. c-SKI is a proto-oncogene and an inhibitor of TGFβ signalling. However, it acts not only as a transcriptional co-repressor but also as a transcriptional co-activator. Like c-MYB, c-SKI is upregulated in different solid tumors and leukemias. Though SKI activity is well described, transcriptional regulation of the SKI gene itself still remains unknown. Here, we deliver insight into the transcriptional regulation of the human SKI gene via the transcription factor c-MYB. Methods: In silico analyses were performed to identify potential MYB binding sites in the SKI regulatory region. Chromatin immunoprecipitation (ChIP) assays were used to validate the interaction between MYB and the potential SKI regulatory regions. Reporter gene assays were engaged to analyze MYB regulatory potential regarding SKI expression. RNAi experiments were performed to further examine transcriptional regulation of SKI by MYB. Since MYB is known to be downregulated by the histone deacetylase inhibitor (HDACi) valproic acid (VPA), MYB and SKI protein levels were analyzed in AML cell lines treated with VPA via Western Blot. Correlated protein levels of MYB and SKI were examined in the myeloid leukemia cell lines HL60, U937, THP1, NB4 and K562 as well as in primary cells of AML patients (n=27). Correlation of MYB and SKI transcript levels were performed in three different data sets of primary AML samples. The first cohort (n=7) was analyzed via RT-qPCR. Cohort 2 consists of cDNA microarray data of AML patients (n=17). Furthermore, principal component analysis (PCA) of the gene expression profile of MYB and SKI of AML patients (n=542) were performed with the leukemia gene atlas (LGA). Results: In silico analyses revealed four putative MYB binding sites (MBS1-4) in the SKI regulatory region. Direct binding of MYB to the regulatory sites MBS2-4 of the SKI gene could be confirmed via ChIP experiments. Dual luciferase reporter gene assays comprising c-MYB binding sites present in the SKI gene locus further show c-MYB-dependent transcriptional activation of the reporter. RNAi experiments depleting c-MYB in leukemic cell lines resulted in the decrease of SKI protein levels and thereby reveal that c-MYB is essential for the induction of SKI gene expression. Accordingly, treatment of the AML cell lines with the HDACi VPA led to a decrease of MYB and consequently SKI protein levels. Consistently, we observed a positive correlation of MYB and SKI protein expression in leukemic cell lines and in samples of AML patients. Moreover, a highly positive correlation of MYB and SKI transcript levels could be observed in three different cohorts of AML patients, further confirming regulation of SKI expression by the transcription factor MYB. Conclusion: Our findings provide new insights in the transcriptional regulation of the proto-oncogene c-SKI by the oncogenic transcription factor c-MYB during leukemogenesis. c-MYB and c-SKI expression and functions are highly positively correlated in human AML suggesting that c-SKI is a mediator of c-MYB oncogenic potential. So far, various therapeutic approaches targeting MYB failed to be transferred to patients. In this regard, c-MYB and c-SKI represent promising marker and target proteins for novel HDACi-based therapeutic approaches in AML. Disclosures No relevant conflicts of interest to declare.

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SUGIYAMA, Yoshitaka, and Toshiyuki SAKATA. "Design of Binding Plate Referring to Characteristic of Ski Turn." Proceedings of Conference of Tokai Branch 2004.53 (2004): 185–86. http://dx.doi.org/10.1299/jsmetokai.2004.53.185.

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Teichler, Sabine, Thomas Illmer, Josephine Roemhild, Dmitriy Ovcharenko, Thorsten Stiewe, and Andreas Neubauer. "MicroRNA29a regulates the expression of the nuclear oncogene Ski." Blood 118, no. 7 (August 18, 2011): 1899–902. http://dx.doi.org/10.1182/blood-2010-09-306258.

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Abstract MicroRNAs (miRNAs) are small, noncoding RNA molecules that regulate growth and differentiation. miRNAs are frequently located at cancer-specific fragile sites in the human genome, such as chromosome 7q. The nuclear oncogene SKI is up-regulated in acute myeloid leukemia (AML) with −7/del7q. Here we asked whether loss of miRNAs on chromosome 7q may explain this up-regulation. miR-29a expression was found to be down-regulated in AML with −7/del7q. Forced expression of miR-29a down-regulated Ski and its target gene, Nr-CAM, whereas miR-29a inhibition induced Ski expression. Luciferase assays validated a functional binding site for miR-29a in the 3′ untranslated region of SKI. Finally, in samples of AML patients, we observed an inverse correlation of Ski and miR-29a expression, respectively. In conclusion, up-regulation of Ski in AML with −7/del7q is caused by loss of miR-29a. miR-29a may therefore function as an important tumor suppressor in AML by restraining expression of the SKI oncogene.

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Stavnezer, E., D. Brodeur, and L. A. Brennan. "The v-ski oncogene encodes a truncated set of c-ski coding exons with limited sequence and structural relatedness to v-myc." Molecular and Cellular Biology 9, no. 9 (September 1989): 4038–45. http://dx.doi.org/10.1128/mcb.9.9.4038.

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The nucleotide sequence of a biologically active v-ski gene from a cloned proviral segment shows that ski is a 1,312-base sequence embedded in the p19 region of the avian leukosis virus gag gene. The v-ski sequence contains a single open translational reading frame that encodes a polypeptide with a molecular mass of 49,000 daltons. The predicted amino acid sequence includes nuclear localization motifs that have been identified in other nuclear oncoproteins. It also contains a proline-rich region and a set of cysteine and histidine residues that could constitute a metal-binding domain. Two regions of the amino acid sequences of v-ski and v-myc are related, and the two proteins exhibit similar distributions of hydrophobic and hydrophilic amino acids. Cloned segments of the chicken c-ski proto-oncogene totaling 65 kilobases have been analyzed, and regions related to v-ski have been sequenced. The results indicate that v-ski is derived from at least five coding exons of c-ski, that it is correctly spliced, and that it is missing c-ski coding sequences at both its 5' and 3' ends. The c-ski and avian leukosis virus sequences that overlap the 5' virus/v-ski junction in Sloan-Kettering virus contain an 18-of-20-base sequence match that presumably played a role in the transduction of ski by facilitating virus/c-ski recombination.

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Stavnezer, E., D. Brodeur, and L. A. Brennan. "The v-ski oncogene encodes a truncated set of c-ski coding exons with limited sequence and structural relatedness to v-myc." Molecular and Cellular Biology 9, no. 9 (September 1989): 4038–45. http://dx.doi.org/10.1128/mcb.9.9.4038-4045.1989.

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The nucleotide sequence of a biologically active v-ski gene from a cloned proviral segment shows that ski is a 1,312-base sequence embedded in the p19 region of the avian leukosis virus gag gene. The v-ski sequence contains a single open translational reading frame that encodes a polypeptide with a molecular mass of 49,000 daltons. The predicted amino acid sequence includes nuclear localization motifs that have been identified in other nuclear oncoproteins. It also contains a proline-rich region and a set of cysteine and histidine residues that could constitute a metal-binding domain. Two regions of the amino acid sequences of v-ski and v-myc are related, and the two proteins exhibit similar distributions of hydrophobic and hydrophilic amino acids. Cloned segments of the chicken c-ski proto-oncogene totaling 65 kilobases have been analyzed, and regions related to v-ski have been sequenced. The results indicate that v-ski is derived from at least five coding exons of c-ski, that it is correctly spliced, and that it is missing c-ski coding sequences at both its 5' and 3' ends. The c-ski and avian leukosis virus sequences that overlap the 5' virus/v-ski junction in Sloan-Kettering virus contain an 18-of-20-base sequence match that presumably played a role in the transduction of ski by facilitating virus/c-ski recombination.

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SUGIYAMA, Yoshitaka, Shigehiro KAWAI, and Toshiyuki SAKATA. "A study on Influences of Binding Plate on a Ski Turn." Proceedings of Conference of Tokai Branch 2003.52 (2003): 139–40. http://dx.doi.org/10.1299/jsmetokai.2003.52.139.

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MacGregor, D., and M. L. Hull. "A microcomputer controlled snow ski binding system—II. Release decision theories." Journal of Biomechanics 18, no. 4 (January 1985): 267–75. http://dx.doi.org/10.1016/0021-9290(85)90844-9.

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Cunnington, Ryan H., Baiqiu Wang, Saeid Ghavami, Krista L. Bathe, Sunil G. Rattan, and Ian M. C. Dixon. "Antifibrotic properties of c-Ski and its regulation of cardiac myofibroblast phenotype and contractility." American Journal of Physiology-Cell Physiology 300, no. 1 (January 2011): C176—C186. http://dx.doi.org/10.1152/ajpcell.00050.2010.

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Cardiac myofibroblasts are key players in chronic remodeling of the cardiac extracellular matrix, which is mediated in part by elevated transforming growth factor-β1 (TGF-β1). The c-Ski proto-oncoprotein has been shown to modify TGF-β1 post-receptor signaling through receptor-activated Smads (R-Smads); however, little is known about how c-Ski regulates fibroblast phenotype and function. We sought to elucidate the function of c-Ski in primary cardiac myofibroblasts using a c-Ski overexpression system. Cardiac myofibroblasts expressed three forms of c-Ski with the predominant band at 105 kDa, and adenoviral c-Ski treatment resulted in overexpression of 95-kDa c-Ski in cellular nuclei. Exogenous c-Ski led to significant inhibition of type I collagen secretion and myofibroblast contractility using two-dimensional semifloating gel contraction assay in both basal and with TGF-β1 (10 ng/ml for 24 h) stimulation. Overexpressed c-Ski did not inhibit nuclear translocation of phosphorylated R-Smad2, despite their binding, as demonstrated by immunoprecipitation. Acute treatment of primary myofibroblasts with TGF-β1 in vitro revealed a marked nuclear shuttling of c-Ski at 24 and 48 h following stimulation. Remarkably, overexpression of c-Ski led to a stepwise reduction of the myofibroblast marker α-smooth muscle actin with increasing multiplicity of infection, and these results indicate that 95-kDa c-Ski overexpression may effect a loss of the myofibroblastic phenotype. Furthermore, adenovirus (Ad) for hemagglutinin-tagged c-Ski infection led to a reduction in the number of myofibroblasts versus Ad-LacZ-infected and uninfected controls, due to induction of apoptosis. Finally, we observed a significant increase in 105-kDa c-Ski in the cytosolic fraction of cells of the infarct scar and adjacent remnant myocardium vs. noninfarcted controls.

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Gratschev, Dan, Christoffer Löf, Jari Heikkilä, Anders Björkbom, Pramod Sukumaran, Ari Hinkkanen, J. Peter Slotte, and Kid Törnquist. "Sphingosine Kinase as a Regulator of Calcium Entry through Autocrine Sphingosine 1-Phosphate Signaling in Thyroid FRTL-5 Cells." Endocrinology 150, no. 11 (October 1, 2009): 5125–34. http://dx.doi.org/10.1210/en.2009-0288.

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Calcium entry is one of the main regulators of intracellular signaling. Here, we have described the importance of sphingosine, sphingosine kinase 1 (SK1), and sphingosine 1-phosphate (S1P) in regulating calcium entry in thyroid FRTL-5 cells. In cells incubated with the phosphatase inhibitor calyculin A, which evokes calcium entry without mobilizing sequestered intracellular calcium, sphingosine inhibited calcium entry in a concentration-dependent manner. Furthermore, inhibiting SK1 or the ATP-binding cassette ABCC1 multidrug transporter attenuated calcium entry. The addition of exogenous S1P restored calcium entry. Neither sphingosine nor inhibition of SK1 attenuated thapsigargin-evoked calcium entry. Blocking S1P receptor 2 or phospholipase C attenuated calcium entry, whereas blocking S1P receptor 3 did not. Overexpression of wild-type SK1, but not SK2, enhanced calyculin-evoked calcium entry compared with mock-transfected cells, whereas calcium entry was decreased in cells transfected with the dominant-negative G82D SK1 mutant. Exogenous S1P restored calcium entry in G82D cells. Our results suggest that the calcium entry pathway is blocked by sphingosine and that activation of SK1 and the production of S1P, through an autocrine mechanism, facilitate calcium entry through activation of S1P receptor 2. This is a novel mechanism by which the sphingosine-S1P rheostat regulates cellular calcium homeostasis.

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Shealy, Jasper E., and David A. Miller. "Dorsiflexion of the Human Ankle as it Relates to Ski Boot Design in Downhill Skiing." Proceedings of the Human Factors Society Annual Meeting 31, no. 10 (September 1987): 1128–32. http://dx.doi.org/10.1177/154193128703101012.

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This study is part of an on-going series of studies that relate to Alpine or Downhill Ski Boot Design. In current Alpine skiing, the ski boot is an integral part of the ski boot-binding system. One of the roles of the ski boot is to protect the ankle from excessive dorsiflexion during forward falls, as the ski boot is levered out of the heel binding. A boot designer needs to know what the ranges of dorsiflexion are for human ankles so that the allowable forward flex built into the ski boot will not exceed some specified level. That specified level should be such that a large part of the population will not exceed a safe level of dorsiflexion. The stiffening of the ankle by voluntary contraction of the muscles that control the ankle joint cannot be relied upon since the reaction time to contract the muscles will be greater than the time available to the skier under many circumstances. This study looks at the maximum voluntary dorsiflexion of a group of people (n=64) similar to a skiing population. The anatomical and biomechanical posture of the subjects was intended to represent typical skiing situations, therefore the subjects were measured in a weight bearing, flexed knee, upright posture. The age, gender, height, weight and skiing experience of the subjects was recorded as independent variables. The maximum voluntary dorsiflexion of the ankle was the dependent variable. 10 subjects were measured while the knee was kept in a straight or extended posture. The analysis indicates that there is no statistically significant relationship between dorsiflexion and any of the independent variables. The mean dorsiflexion was 42.7 degrees, the 5th% value was 28.5 and the 95th% was 56.7 degrees. The straight knee posture reduces the effective dorsiflexion by 8.5 degrees. Current standards permit as much as 40 to 45 degrees dorsiflexion. The implications are that current standards are excessive, a reasonable limit would be something under 30 degrees. Such a limit, or less, is consistent with the maximum dorsiflexion found in most current ski boots.

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MacGregor, Duncan, M. L. Hull, and L. K. Dorius. "A microcomputer controlled snow ski binding system—I. Instrumentation and field evaluation." Journal of Biomechanics 18, no. 4 (January 1985): 255–65. http://dx.doi.org/10.1016/0021-9290(85)90843-7.

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Puttini, Miriam, Addolorata M. L. Coluccia, Frank Boschelli, Anna Franceschino, Lucia Tornaghi, Shaheen Ahmed, Sara Redaelli, et al. "In Vitro and In Vivo Activity of SKI-606, a Novel Abl/Src Inhibitor, Against Imatinib Resistant BCR-ABL+ Neoplastic Cells." Blood 108, no. 11 (November 1, 2006): 2176. http://dx.doi.org/10.1182/blood.v108.11.2176.2176.

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Abstract Resistance to imatinib represents an important scientific and clinical issue in CML and Ph+ ALL and is usually due to the selection of cells harbouring kinase point mutations of the BCR-ABL gene or presenting BCR-ABL gene amplification. In order to improve Bcr-Abl inhibition, several inhibitors with higher potency compared to imatinib have been identified including dasatinib and nilotinib, which show clinical activity in patients resistant to imatinib. In the present study the effects of the novel inhibitor SKI-606 on various models of resistance to imatinib were studied. SKI-606 is a selective dual Src/Abl inhibitor potently active against several CML cell lines and transfectants with IC50 values in the low nanomolar range, 2 logs lower than those obtained with imatinib. Cells expressing activated forms of c-KIT (HMC1560 and GIST882) or PDGFR (Ba/F3 Tel-PDGFRβ) were unaffected by SKI-606, in contrast to imatinib and dasatinib. SKI-606 reduced proliferation rate of cells where resistance to imatinib was caused by BCR-ABL gene amplification, such as Lama84R and of imatinib-resistant K562R and KCL22R in which no known mechanism have been identified. D276G, Y253F and E255K kinase point mutants were affected by SKI-606, resulting in inhibition of cell proliferation with IC50 values of 25, 40 and 394 nM (imatinib:1147, 1888 and 3174 nM). No activity was observed against T315I mutant. These results were confirmed in in vivo experiments, in models where resistance was not caused by mutations, as well as in cells carrying the Y253F, E255K and D276G mutations. In the first one SKI-606 was able to eradicate tumors, while significant delay in tumor growth was observed using Ba/F3 transfectants. Modelling considerations attribute the superior activity of SKI-606 to its ability to bind the intermediate (1M52) conformation of Bcr-Abl, in contrast to imatinib. Excluding the T315 residue involved in direct hydrophilic interactions with both SKI-606 and imatinib, Y253 and E255 make electrostatic interactions stabilizing the inactive conformation of Abl nucleotide binding loop, thus affecting in a more pronounced way the binding of imatinib. Similar considerations have been made for the D276 residue affecting a-Helix C inactive conformation. The extended profile of activity performed here allows us to conclude that SKI-606 is a fairly active and specific inhibitor, with a very limited number of targets outside the Abl and Src families of TK.

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Ponath, Viviane, Miriam Frech, Mathis Bittermann, Reem Al Khayer, Andreas Neubauer, Cornelia Brendel, and Elke Pogge von Strandmann. "The Oncoprotein SKI Acts as A Suppressor of NK Cell-Mediated Immunosurveillance in PDAC." Cancers 12, no. 10 (October 3, 2020): 2857. http://dx.doi.org/10.3390/cancers12102857.

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Drugs targeting epigenetic mechanisms such as histone deacetylase inhibitors (HDACi) suppress tumor growth. HDACi also induce the expression of ligands for the cytotoxicity receptor NKG2D rendering tumors more susceptible to natural killer (NK) cell-dependent killing. The major acetylases responsible for the expression of NKG2D ligands (NKG2D-L) are CBP and p300. The role of the oncogene and transcriptional repressor SKI, an essential part of an HDAC-recruiting co-repressor complex, which competes with CBP/p300 for binding to SMAD3 in TGFβ signaling, is unknown. Here we show that the siRNA-mediated downregulation of SKI in the pancreatic cancer cell lines Panc-1 and Patu8988t leads to an increased target cell killing by primary NK cells. However, the higher cytotoxicity of NK cells did not correlate with the induction of NKG2D-L. Of note, the expression of NKG2D-L and consequently NK cell-dependent killing could be induced upon LBH589 (LBH, panobinostat) or valproic acid (VPA) treatment irrespective of the SKI expression level but was significantly higher in pancreatic cancer cells upon genetic ablation of SKI. These data suggest that SKI represses the inducible expression of NKG2D-L. The combination of HDACi with NK cell-based immunotherapy is an attractive treatment option for pancreatic tumors, specifically for patients with high SKI protein levels.

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Neptune, Rick, and Maury L. Hull. "A New Electromechanical Ski Binding with Release Sensitivity to Torsion and Bending Moments Transmitted by the Leg." International Journal of Sport Biomechanics 8, no. 4 (November 1992): 331–49. http://dx.doi.org/10.1123/ijsb.8.4.331.

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This paper describes the design of a new electromechanical ski binding whereby release in both twist and forward bending is controlled electronically and the release level in twist is modulated electronically based on the neural stimulation of muscles in the quadriceps group. To provide signals for controlling release in the two modes, the binding incorporates two dynamometers. Each dynamometer measures loads that have been shown to correlate strongly (r2>0.90) to torsional and bending moments at the lower leg injury sites. Although the binding consists of both a toepiece and heelpiece, the toepiece does not permit release of the boot from the ski in the twist mode but rather serves as one of the dynamometers. Consequently the heelpiece was designed to provide the release function in both modes. Release is realized by a low-force solenoid that actuates a multilink trigger mechanism. To prove feasibility, a prototype was constructed and evaluated.

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Kasbekar, Durgadas P., James C. Nelson, and Linda M. Hall. "enhancer of seizure: A New Genetic Locus in Drosophila melanogaster Defined by Interactions With Temperature-Sensitive Paralytic Mutations." Genetics 116, no. 3 (July 1, 1987): 423–31. http://dx.doi.org/10.1093/genetics/116.3.423.

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ABSTRACT Mutations in the enhancer of seizure (e(sei)) locus have been isolated on the basis of their ability to cause temperature-induced paralysis of alleles at the seizure (sei) locus at temperatures at which these mutations ordinarily do not paralyze. This enhancer is specific to the seizure locus and is without effect on other temperature-sensitive paralytic mutants including para, nap, tip-E and shi. This suggests that the enhancer responds specifically to the mechanism of paralysis mediated by the seizure mutations. The e(sei) is a recessive mutation which maps to 39.0 on the left arm of chromosome 3. Deficiency mapping has placed it at 69A4-B5 on the salivary gland polytene chromosome map. When a new enhancer allele was isolated following P-M hybrid dysgenesis, there was a concomitant P-element insertion at 69B. In the absence of seizure mutations, the enhancer mutation causes non-temperature dependent hyperactivity when agitated and interferes with the climbing response. Electrophysiological studies examined the effects of increasing temperature on electrical activity in the adult giant fiber/flight muscle system. Neuronal hyperactivity was seen in both e(sei) and sei single mutant homozygotes, but not in wild type. The hyperactivity was more severe in the sei;e(sei) double mutants. The correlation between the physiological effects and the mutant behavior suggests that both sei and e(sei) cause membrane excitability defects. Since previous work has shown that seizure mutants affect [3H]saxitoxin binding to the voltage-sensitive sodium channel, e(sei) may code for a gene product which interacts with this channel.

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Weston, Stuart, Lauren Baracco, Chloe Keller, Krystal Matthews, Marisa E. McGrath, James Logue, Janie Liang, et al. "The SKI complex is a broad-spectrum, host-directed antiviral drug target for coronaviruses, influenza, and filoviruses." Proceedings of the National Academy of Sciences 117, no. 48 (November 12, 2020): 30687–98. http://dx.doi.org/10.1073/pnas.2012939117.

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The SARS-CoV-2 pandemic has made it clear that we have a desperate need for antivirals. We present work that the mammalian SKI complex is a broad-spectrum, host-directed, antiviral drug target. Yeast suppressor screening was utilized to find a functional genetic interaction between proteins from influenza A virus (IAV) and Middle East respiratory syndrome coronavirus (MERS-CoV) with eukaryotic proteins that may be potential host factors involved in replication. This screening identified the SKI complex as a potential host factor for both viruses. In mammalian systems siRNA-mediated knockdown of SKI genes inhibited replication of IAV and MERS-CoV. In silico modeling and database screening identified a binding pocket on the SKI complex and compounds predicted to bind. Experimental assays of those compounds identified three chemical structures that were antiviral against IAV and MERS-CoV along with the filoviruses Ebola and Marburg and two further coronaviruses, SARS-CoV and SARS-CoV-2. The mechanism of antiviral activity is through inhibition of viral RNA production. This work defines the mammalian SKI complex as a broad-spectrum antiviral drug target and identifies lead compounds for further development.

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Liu, Xia, Ping Li, Ping Liu, Renping Xiong, En Zhang, Xingyun Chen, Dayong Gu, Yan Zhao, Zhengguo Wang, and Yuanguo Zhou. "The essential role for c-Ski in mediating TGF-β1-induced bi-directional effects on skin fibroblast proliferation through a feedback loop." Biochemical Journal 409, no. 1 (December 11, 2007): 289–97. http://dx.doi.org/10.1042/bj20070545.

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The bi-directional regulation of TGF-β1 (transforming growth factor-β1) on fibroblast proliferation with stimulation at low concentration, but inhibition at high concentration, has important significance during tissue repair. The mechanism has not been defined. c-Ski is a major co-repressor of TGF-β1/Smad3 signalling; however, the exact role of c-Ski in the bi-directional regulation of fibroblast proliferation remains to be determined. In the present study, we established a dose–effect relationship of bi-directional regulation of TGF-β1-mediated proliferation in rat skin fibroblasts, and found that c-Ski overexpression promoted fibroblast proliferation by inhibiting Smad3 activity. Importantly, c-Ski expression was decreased at the high concentration of TGF-β1, but increased at the low concentration of TGF-β1. This dose-dependent change in TGF-β1 action did not affect Smad3 phosphorylation or nuclear translocation, but altered Smad3 DNA-binding activity, transcriptional activity and expression of the downstream gene p21 that both increased at the high concentration and decreased at the low concentration. Furthermore, c-Ski overexpression exerted synergistic stimulation with TGF-β1 at the low concentration, but reversed the inhibitory effect of TGF-β1 at high concentrations, while knockdown of c-Ski by RNA interference abrogated bi-directional role of TGF-β1 on fibroblast proliferation. Thus our data reveal a new mechanism for this bi-directional regulation, i.e. c-Ski expression change induced by low or high TGF-β1 concentration in turn determines the promoting or inhibiting effects of TGF-β1 on fibroblast proliferation, and suggests an important role of c-Ski that modulates the local availability of TGF-β1 within the wound repair microenvironment.

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Kjaer, T. R., L. Jensen, A. Hansen, R. Dani, J. C. Jensenius, J. Dobó, P. Gál, and S. Thiel. "Oligomerization of Mannan-binding Lectin Dictates Binding Properties and Complement Activation." Scandinavian Journal of Immunology 84, no. 1 (June 15, 2016): 12–19. http://dx.doi.org/10.1111/sji.12441.

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Soverini, S., G. Tasco, T. Grafone, S. Colarossi, A. Gnani, M. Baccarani, R. Casadio, and G. Martinelli. "Binding mode of the tyrosine kinase inhibitor bosutinib (SKI-606) to Abl kinase." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 7049. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.7049.

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7049 Background: Bosutinib (SKI-606) is a 4-anilino-3-quinolinecarbonitrile Src/Abl kinase inhibitor. The crystal structure of Abl kinase domain in complex with bosutinib has not yet been determined and the mode of binding of this inhibitor is therefore unknown. Methods: In the present study, we used a molecular docking approach to investigate the following: a) Which Abl conformation(s) bosutinib is more likely to bind? b) Which Abl residues are likely to be involved in bosutinib binding? c) Which imatinib-resistant Abl mutants bosutinib is likely to be active against? A three-dimensional model of bosutinib was generated by Chemsketch ( http://www.acdlabs.com ). Modelling of the human Abl kinase in its inactive (closed) conformation was performed with the software Modeller, v7.7 ( http://salilab.org/modeller ) adopting the highly related Mus musculus Abl homologue as a template structure (PDB entry: 1OPJ , 0.175nm resolution). Active (open) Abl conformation is available as PDB entry 1OPL . Flexible docking of bosutinib to Abl was performed with Autodock v3.0 ( http://www.scripps.edu/mb/olson ). Results: Our binding hypothesis predicts that a) similarly to IM, the interaction between bosutinib and Abl seems to be more stable when the latter is in its inactive (closed) conformation; b) 21 Abl residues (including Y253, T315, F317 and F359 among others) surround bosutinib and engage H-bonds or Van der Waals interactions; c) bosutinib is likely to retain the ability to bind and inhibit the IM-resistant Y253H, M351T, F359V, F317L and E255V Abl mutants. In contrast, bosutinib binding to E255K and T315I mutants is predicted to be less efficient. Detailed models will be presented. Conclusions: Bosutinib is a promising second-line treatment for Ph+ leukemia patients harbouring several IM-resistant Abl mutations. The T315I remains the biggest hurdle for pharmacological therapy of Ph+ leukemias. Supported by European LeukemiaNet, AIRC, AIL, COFIN and FIRB projects, and by Fondazione del Monte di Bologna e Ravenna. No significant financial relationships to disclose.

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Doležalová, Hana, and Jakub Krátký. "Běžecké lyžování vozíčkářů venku i vevnitř." Studia sportiva 7, no. 3 (December 16, 2013): 111–17. http://dx.doi.org/10.5817/sts2013-3-9.

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Wheelchair user and cross country skiing used to be a rare connection in the Czech Republic – especially because of its difficulty incombination with unsatisfactory equipment and the poor track situation. Nowadays the ski tracks are well prepared on many places in our country, also the special equipment – sledge construction with seat matches the standard ski binding and skis. Ski simulator is an inside alternative. The movement is possible due to upper limbs bimanual locomotion and residual muscles of the trunk. It is good to try activating muscles that tend to grow weaker in ordinary life and by contrast reduce the activity of overloaded muscles. The ski simulator allows complex motoric activity that increases the fitness level influencing the ADL (activity of daily living). Cross country skiing for handicapped people can be understood as another possibility how to improve fitness abilities, compensatory locomotion and one of not many activities that can be done during winter and help people to be in the nature and get to up to now inaccessible places at the same time.

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ST-ONGE, NANCY, YAN CHEVALIER, NICOLA HAGEMEISTER, MAXIME VAN DE PUTTE, and JACQUES DE GUISE. "Effect of Ski Binding Parameters on Knee Biomechanics: A Three-Dimensional Computational Study." Medicine & Science in Sports & Exercise 36, no. 7 (July 2004): 1218–25. http://dx.doi.org/10.1249/01.mss.0000132375.00721.7a.

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Journal articles on the topic 'Ski bindings'

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