Concerted structural rearrangements enable RNA channeling into the cytoplasmic Ski238-Ski7-exosome assembly.

The Ski2-Ski3-Ski8 (Ski238) helicase complex directs cytoplasmic mRNAs toward the nucleolytic exosome complex for degradation. In yeast, the interaction between Ski238 and exosome requires the adaptor protein Ski7. We determined different cryo-EM structures of the Ski238 complex depicting the transition from a rigid autoinhibited closed conformation to a flexible active open conformation in which the Ski2 helicase module has detached from the rest of Ski238. The open conformation favors the interaction of the Ski3 subunit with exosome-bound Ski7, leading to the recruitment of the exosome. In the Ski238-Ski7-exosome holocomplex, the Ski2 helicase module binds the exosome cap, enabling the RNA to traverse from the helicase through the internal exosome channel to the Rrp44 exoribonuclease. Our study pinpoints how conformational changes within the Ski238 complex regulate exosome recruitment for RNA degradation. We also reveal the remarkable conservation of helicase-exosome RNA channeling mechanisms throughout eukaryotic nuclear and cytoplasmic exosome complexes.

Extraction of mRNA from Stalled Ribosomes by the Ski Complex.

The evolutionarily conserved Ski2-Ski3-Ski8 (Ski) complex containing the 3'→5' RNA helicase Ski2 binds to 80S ribosomes near the mRNA entrance and facilitates 3'→5' exosomal degradation of mRNA during ribosome-associated mRNA surveillance pathways. Here, we assayed Ski's activity using an in vitro reconstituted translation system and report that this complex efficiently extracts mRNA from 80S ribosomes in the 3'→5' direction in a nucleotide-by-nucleotide manner. The process is ATP dependent and can occur on pre- and post-translocation ribosomal complexes. The Ski complex can engage productively with mRNA and extract it from 80S complexes containing as few as 19 (but not 13) 3'-terminal mRNA nucleotides starting from the P site. The mRNA-extracting activity of the Ski complex suggests that its role in mRNA quality control pathways is not limited to acceleration of exosomal degradation and could include clearance of stalled ribosomes from mRNA, poising mRNA for degradation and rendering stalled ribosomes recyclable by Pelota/Hbs1/ABCE1.

Combination of high anti-SKI and low anti-TMED5 antibody levels is preferable prognostic factor in esophageal carcinoma.

Given that esophageal cancer is highly malignant, the discovery of novel prognostic markers is eagerly awaited. We performed serological identification of antigens by recombinant cDNA expression cloning (SEREX) and identified SKI proto-oncogene protein and transmembrane p24 trafficking protein 5 (TMED5) as antigens recognized by serum IgG antibodies in patients with esophageal carcinoma. SKI and TMED5 proteins were expressed in Escherichia coli, purified by affinity chromatography, and used as antigens. The serum anti-SKI antibody (s-SKI-Ab) and anti-TMED5 antibody (s-TMED5-Ab) levels were significantly higher in 192 patients with esophageal carcinoma than in 96 healthy donors. The presence of s-SKI-Abs and s-TMED5-Abs in the patients' sera was confirmed by western blotting. Immunohistochemical staining showed that the TMED5 protein was highly expressed in the cytoplasm and nuclear compartments of the esophageal squamous cell carcinoma tissues, whereas the SKI protein was localized predominantly in the nuclei. Regarding the overall survival in 91 patients who underwent radical surgery, the s-SKI-Ab-positive and s-TMED5-Ab-negative statuses were significantly associated with a favorable prognosis. Additionally, the combination of s-SKI-Ab-positive and s-TMED5-Ab-negative cases showed an even clearer difference in overall survival as compared with that of s-SKI-Ab-negative and s-TMED5-Ab-positive cases. The s-SKI-Ab and s-TMED5-Ab biomarkers are useful for diagnosing esophageal carcinoma and distinguishing between favorable and poor prognoses.

Serum per- and polyfluoroalkyl substance (PFAS) levels and health-related biomarkers in a pilot study of skiers in New England.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS), synthetic chemicals with adverse health effects, are used extensively in consumer products. Ski waxes, applied to the base of skis, contain up to 100% PFAS by mass, but exposure and health effects are poorly characterized. OBJECTIVES: Our objectives were to quantify serum PFAS concentrations among skiers and explore associations with reported ski wax use and biomarkers of cardiometabolic, thyroid, and immune health. METHODS: We recruited 30 active adult skiers to provide non-fasting blood samples and complete questionnaires. We quantified 18 PFAS using mass spectrometry, and measured serum lipids, thyroid hormones, and immunoglobulins. We explored associations of individual and aggregate measures of serum PFAS with wax use indicators and health biomarkers using multivariable regression models, adjusted for age and gender identity. RESULTS: Nine PFAS (PFBS, PFHpS, PFHxS, Sm-PFOS, n-PFOS, PFDA, PFNA, PFUnDA, n-PFOA) were detected in 100% of participants, and MeFOSAA in 93%. Compared to NHANES, median serum concentrations (ng/ml) were similar, but higher in coaches (e.g., PFOAall: 1.1, PFOAcoaches: 2.7, PFOANHANES: 1.2; PFNAall: 0.5, PFNAcoaches: 1.7, PFNANHANES: 0.4). Factors reflecting wax exposure were positively associated with PFAS: e.g., >10 years as a snow sport athlete, compared to <10 years, was associated with 3.2 (95% CI: 0.7, 5.6) ng/ml higher aggregate PFAS, as defined by National Academies of Science, Engineering, and Medicine (NASEM). An IQR (6.3 ng/ml) increase in NASEM PFAS was associated with 32.1 (95% CI: 7.0, 57.2), 35.5 (13.5, 57.5), and 12.8 (0.6, 25.1) mg/dl higher total cholesterol, LDL-C, and sdLDL-C, respectively. DISCUSSION: Our study provides early evidence that recreational skiers, particularly coaches, are exposed to PFAS through ski wax. Several PFAS were associated with higher serum lipids among these physically active adults. Interventions to remove PFAS from fluorinated wax could decrease direct exposure to skiers and reduce PFAS release into the environment.

We know a lot about little and little about a lot: A contextualized scoping review on injury prevention in alpine ski racing.

BACKGROUND: Our goal was to summarize and contextualize the available literature on alpine ski racing injury epidemiology, injury etiology, injury prevention measures, injury prevention context, and implementation issues. MATERIALS AND METHODS: We searched four electronic databases using predetermined search terms. We included original studies that assessed injury, injury risk factors, and injury mechanisms, and assessed and reported the effect of an injury prevention measure in alpine ski racing. Two authors independently conducted title-abstract screening, and one performed the full-text review. For data synthesis and categorization, we used the Translating Research into the Injury Prevention Practice framework and a modified and adapted version of the Haddon matrix. RESULTS: Of the 157 included studies, most corresponded to injury epidemiology and etiology, whereas few studies encompassed injury prevention measure development, implementation and evaluation. Preventive interventions targeting equipment, rules and regulations, course design and snow preparation were the most prevalent in the literature. Furthermore, various contextual factors in the current literature have been found, including gender, competition level, countries and federations, and time periods within a season. CONCLUSIONS: We provided an in-depth and comprehensive overview of the current state-of-the-art in the alpine ski racing context. We know a lot about little and little about a lot across all the areas associated with injury prevention in such context. The limitations in the literature yield a road map for designing future injury prevention studies to address the key gaps identified. A more comprehensive context-driven approach throughout all stages of injury prevention would benefit the ultimate implementation of effective preventive strategies.

SKI-349, a Sphingosine Kinases 1/2 Inhibitor, Suppresses Cell Viability, Invasion, and AKT/mTOR Signaling Pathway, and Shows Synergistic Cytotoxic Effects with Sorafenib in Hepatocellular Carcinoma.

SKI-349 is a novel sphingosine kinases (SPHK) inhibitor with anti-tumor effects. This study aimed to assess the effect of SKI-349 on cell biological behaviors, downstream pathways, and its synergistic effect with sorafenib in hepatocellular carcinoma (HCC). HCC cell lines (Huh7 and Hep3B) were treated with SKI-349 at concentrations of 1, 2, 4, or 8 µM. Then, SPHK1/2 activity, cell viability, proliferation, apoptosis, invasion, and protein expressions of phosphorylated-protein kinase B (p-AKT), AKT, phosphorylated-mammalian target of rapamycin (p-mTOR) and mTOR were detected. Combination index values of SKI-349 (0, 1, 2, 4, or 8 µM) and sorafenib (0, 2.5, 5, 10, or 20 µM) were calculated. SKI-349 decreased the relative SPHK1 and SPHK2 activity compared with blank control in a dose-dependent manner in the Huh7 and Hep3B cell lines. Meanwhile, SKI-349 reduced cell viability, 5-ethynyl-2'-deoxyuridine (EdU) positive cells, and invasive cells, while it increased apoptotic cells compared to blank control in a dose-dependent manner in Huh7 and Hep3B cell lines. Based on the western blot assay, SKI-349 decreased the ratio of p-AKT to AKT and that of p-mTOR to mTOR compared with blank control in a dose-dependent manner in the Huh7 and Hep3B cell lines. Additionally, SKI-349 combined with sorafenib declined cell viability with concentration gradient effects compared to SKI-349 sole treatment, and they had synergistic cytotoxic effects in Huh7 and Hep3B cell lines. SKI-349 suppresses SPHK1 and SPHK2 activity, cell viability, invasion, and AKT/mTOR signaling pathway, as well as exhibits a synergistic cytotoxic effect with sorafenib in HCC.

Spatial and temporal assessment of China's skiing climate resources.

This study introduces an improved Ski Climate Index (SCI) designed to assess skiing suitability in China by applying fuzzy logic. Using daily meteorological data from 733 weather stations for the periods 1961-1990 and 1991-2020, the study identifies significant changes in SCI distribution over time. Additionally, a coupled analysis is performed, integrating the SCI results with the distribution and spatial vitality of 389 ski resorts in China. This analysis provides a comprehensive understanding of the interplay between actual ski resources and the ongoing evolution of the skiing industry in China and three significant results:1) The snow module has a major impact on SCI distribution, while other non-snow natural elements, such as sunshine duration, wind speed, and thermal comfort, influence the overall SCI assessment less; 2) High SCI values are concentrated in Northwestern and Northeastern China, with increased ski climate resources being observed in Shaanxi-Gansu-Ningxia, Southwest Tibet, and Sichuan due to climate change and noticeable declines in the Southern regions of Northeast China.; 3) In terms of the distribution and vitality of ski resorts, the SCI also partially reflects the development of ski resorts. This skiing suitability model uses climate resources to offer valuable insights for key decision-making in resort development and operation, thereby supporting advancement of the ice-snow economy.

Anterior cruciate ligament injuries in elite ski jumping reliably allow return to competition but severely affect future top performance.

PURPOSE: In recent years, anterior cruciate ligament (ACL) injuries have been frequently observed in ski jumping. However, available data in this discipline are very scarce. Therefore, the purpose of this study was to investigate whether an ACL injury in elite-level ski jumping limits the performance level after ACL reconstruction (ACLR). METHODS: Both male and female elite-level ski jumpers from five national A-teams who suffered an ACL injury were identified retrospectively by searching available media reports and Fédération Internationale de Ski (FIS) database. World Cup (WC) results and time-out-of-competition before ACL injury and after ACLR were compared. Only athletes who suffered the injury during or after the 2009-2010 season and who participated in at least one WC competition before the injury were included in this study. The level of athletes' performance from two full seasons before until three seasons after the injury was compared. RESULTS: Eighteen elite-level ski jumpers (11 males/seven females) were eligible for the study. All male and four female athletes returned to professional competition after ACLR. One female athlete ended her career due to prolonged recovery and two have not yet recovered due to a recent injury. The mean return-to-competition (RTC) time was 14.6 months in males and 13.5 months in females. The mean WC placement decreased after the ACL injury: two seasons before injury the mean position was 17.9 ± 11.0 (n = 12), one season before it was 22.4 ± 12.8 (n = 15). After recovery, the mean placement in seasons 1-3 was: 26.4 ± 8.9 (n = 7), 25.7 ± 10.3 (n = 13), 33.6 ± 12.2 (n = 10) (p = 0.008). Among the athletes returning to competition, only six males and three females reached their preinjury level and only one male and one female (compared to seven males and three females preinjury) reached an individual top-3 placement after ACLR, accounting for less than 10% of podiums compared to preinjury. CONCLUSION: Only 60% of the professional ski jumpers reached the preinjury level and less than 15% reached a top-3 placement after the ACL injury. These results support the fact that ACL tear during a ski jumping career may be a significant factor limiting high-level performance. In terms of clinical relevance, the findings implicate the need to analyse the reasons of these very low rates of return to elite-level performance, to analyse ACL injury and RTC rates at lower levels of performance and to develop specific prevention strategies in order to reduce the number of ACL injuries in this sport. LEVEL OF EVIDENCE: Level IV.

Distributed IMU Sensors for In-Field Dynamic Measurements on an Alpine Ski.

Modern ski design is an inherently time-consuming process that involves an iterative feedback loop comprised of design, manufacturing and in-field qualitative evaluations. Additionally consumers can only rely on qualitative evaluation for selecting the ideal ski, and due to the variation in skier styles and ability levels, consumers can find it to be an inconsistent and expensive experience. We propose supplementing the design and evaluation process with data from in-field prototype testing, using a modular sensor array that can be ported to nearly any ski. This paper discusses a new distributed Inertial Measurement Unit (IMU) suite, including details regarding the design and operation, sensor validation experiments, and outdoor in-field testing results. Data are collected from a set of spatially distributed IMUs located on the upper surface of the ski. We demonstrate that this system and associated post-processing algorithms provide accurate data at a high rate (>700 Hz), enabling the measurement of both structural and rigid ski characteristics, and are robust to repetitive testing in outdoor winter conditions.

A Smart Ski Pole for Skiing Pattern Recognition and Quantification Application.

In cross-country skiing, ski poles play a crucial role in technique, propulsion, and overall performance. The kinematic parameters of ski poles can provide valuable information about the skier's technique, which is of great significance for coaches and athletes seeking to improve their skiing performance. In this work, a new smart ski pole is proposed, which combines the uniaxial load cell and the inertial measurement unit (IMU), aiming to provide comprehensive data measurement functions more easily and to play an auxiliary role in training. The ski pole can collect data directly related to skiing technical actions, such as the skier's pole force, pole angle, inertia data, etc., and the system's design, based on wireless transmission, makes the system more convenient to provide comprehensive data acquisition functions, in order to achieve a more simple and efficient use experience. In this experiment, the characteristic data obtained from the ski poles during the Double Poling of three skiers were extracted and the sample t-test was conducted. The results showed that the three skiers had significant differences in pole force, pole angle, and pole time. Spearman correlation analysis was used to analyze the sports data of the people with good performance, and the results showed that the pole force and speed (r = 0.71) and pole support angle (r = 0.76) were significantly correlated. In addition, this study adopted the commonly used inertial sensor data for action recognition, combined with the load cell data as the input of the ski technical action recognition algorithm, and the recognition accuracy of five kinds of cross-country skiing technical actions (Diagonal Stride (DS), Double Poling (DP), Kick Double Poling (KDP), Two-stroke Glide (G2) and Five-stroke Glide (G5)) reached 99.5%, and the accuracy was significantly improved compared with similar recognition systems. Therefore, the equipment is expected to be a valuable training tool for coaches and athletes, helping them to better understand and improve their ski maneuver technique.

TDG generation in a ski-jump spillway with a fully or partial-flip bucket.

Ski-jump spillways are frequently used as discharge structures for high dams during floods with high energy heads. The selection of bucket types at the end of spillways has a pronounced effect on the hydraulics of jet characteristics, such as trajectories and entrained air features. However, there is no literature reporting how changes in the bucket types influence TDG generation. This study compares the hydraulic characteristics and TDG mass transfer properties of a hydraulic project under construction using both the traditional fully-flip bucket and the partial-flip bucket configurations. The results indicate that, the use of the partial-flip bucket at the end of the spillway significantly disperses the water flow and yields better energy dissipation effects. At low flow rates (lower than 400 m3/s for the dam in this study), there is little difference in the downstream TDG saturation between the traditional fully-flip bucket and the partial-flip bucket, the average difference is 1.6 % in three cases with a low flow rate. However, at high flow rates (higher than 400 m3/s), the partial-flip bucket generates more TDG compared to the traditional fully-flip bucket, reaching up to 6.2 % at the maximum flow rate. This phenomenon stems from significant changes in the hydrodynamics of the stilling basin at high flow rates due to variations in the flip bucket type. When strict control of TDG generation is necessary downstream of dams, the use of the partial-flip bucket should be carefully considered. This is because, at high flow rates, the partial-flip bucket might result in higher TDG saturation than the fully-flip bucket.

Negative legacy effects of past forest use on native plant diversity in semi-natural grasslands on ski slopes.

Over the past century, grassland and forest ecosystems globally have been heavily influenced by land-use changes driven by diverse socioeconomic activities. Ski resorts are a modern land-use type associated with biodiversity loss in mountain ecosystems worldwide. Below the treeline, by contrast, some ski slopes have been shown to provide suboptimal semi-natural habitats for native grassland plants and animals, depending on specific construction and management practices. We compared environmental factors and grassland vegetation between two types of ski slopes in central Japan with different land-use histories: slopes constructed on old pastures (pasture slopes) and slopes constructed by clearing secondary forests or larch plantations established on abandoned pastures during the 1940s-1990s (forest slopes). We examined the effects of land-use history and machine grading as well as other environmental factors on ski slope vegetation, including total species richness and the richness of native, endangered, and exotic plants, using a total of 108 plots of 2 m × 10 m. Compared to pasture slopes, forest slopes exhibited significantly lower richness of native grassland species, including endangered species. Forest slopes were more graded than pasture slopes, resulting in lower native and higher exotic grassland species richness. A significantly lower duration of direct sunlight on forest slopes than on pasture slopes likely decreased endangered species richness. The lower species richness on forest slopes may be also caused by seed dispersal limitations. Our findings demonstrate that ski slopes have good potential to support numerous native grassland plant species, including endangered species, but this potential is significantly and negatively affected by forest use history and concomitant environmental changes. The conservation of semi-natural conditions on pasture slopes as habitats for native grassland species can be promoted through the maintenance of annual mowing practices, avoidance of machine grading, and wider ski courses.

Fatal injury of a skier during school training - case report.

The authors present the case of a fatal accident of a 16-year-old skier who crashed into a tree during a downhill skiing lesson at school. Although the skier was wearing a protective helmet at the time of the accident and his condition did not appear to be too serious immediately after the accident, he later died in hospital as a result of a craniocerebral injury with cerebral contusion and intracranial haemorrhage. His life could not be saved even by immediate neurosurgery, during which fragments of the broken protective helmet were removed from his cranial cavity. By analysing the international literature, the authors identify head and brain injuries as the most common immediate cause of death in downhill skiing and provide insights into the possibilities of preventing these injuries by simple technical means on the part of ski area operators. These means are in particular protective covers for lift columns and protective nets placed in front of fixed, non-movable obstacles on the track.

A specialised SKI complex assists the cytoplasmic RNA exosome in the absence of direct association with ribosomes.

The Ski2-Ski3-Ski8 (SKI) complex assists the RNA exosome during the 3' to 5' degradation of cytoplasmic transcripts. Previous reports showed that the SKI complex is involved in the 3' to 5' degradation of mRNAs, including 3' untranslated regions (UTRs) and devoid of ribosomes. Paradoxically, we recently showed that the SKI complex directly interacts with ribosomes during the co-translational mRNA decay and that this interaction is necessary for its RNA degradation promoting activity. Here, we characterised a new SKI-associated factor, Ska1, that associates with a subpopulation of the SKI complex. We showed that Ska1 is specifically involved in the degradation of long 3'UTR-containing mRNAs, poorly translated mRNAs as well as other RNA regions not associated with ribosomes, such as cytoplasmic lncRNAs. We further show that the overexpression of SKA1 antagonises the SKI-ribosome association. We propose that the Ska1-SKI complex assists the cytoplasmic exosome in the absence of direct association of the SKI complex with ribosomes.

A novel selective spleen tyrosine kinase inhibitor SKI-O-703 (cevidoplenib) ameliorates lupus nephritis and serum-induced arthritis in murine models.

Spleen tyrosine kinase (Syk) plays a pivotal role in the activation of B cells and innate inflammatory cells by transducing immune receptor-triggered signals. Dysregulated activity of Syk is implicated in the development of antibody-mediated autoimmune diseases including systemic lupus erythematosus (SLE) and rheumatoid arthritis, but the effect of Syk inhibition on such diseases remains to be fully evaluated. We have developed a novel selective Syk inhibitor, SKI-O-592, and its orally bioavailable salt form, SKI-O-703 (cevidoplenib). To examine the efficacy of SKI-O-703 on the progression of SLE, New Zealand black/white mice at the autoimmunity-established phase were administrated orally with SKI-O-703 for 16 weeks. Levels of IgG autoantibody, proteinuria, and glomerulonephritis fell significantly, and this was associated with hypoactivation of follicular B cells via the germinal center. In a model of serum-transferred arthritis, SKI-O-703 significantly ameliorated synovitis, with fewer neutrophils and macrophages infiltrated into the synovial tissue. This effect was recapitulated when mice otherwise refractory to anti-TNF therapy were treated by TNF blockade combined with a suboptimal dose of SKI-O-703. These results demonstrate that the novel selective Syk inhibitor SKI-O-703 attenuates the progression of autoantibody-mediated autoimmune diseases by inhibiting both autoantibody-producing and autoantibody-sensing cells.

Luminescent reporter cells enable the identification of broad-spectrum antivirals against emerging viruses.

The emerging viruses SARS-CoV-2 and arenaviruses cause severe respiratory and hemorrhagic diseases, respectively. The production of infectious particles of both viruses and virus spread in tissues requires cleavage of surface glycoproteins (GPs) by host proprotein convertases (PCs). SARS-CoV-2 and arenaviruses rely on GP cleavage by PCs furin and subtilisin kexin isozyme-1/site-1 protease (SKI-1/S1P), respectively. We report improved luciferase-based reporter cell lines, named luminescent inducible proprotein convertase reporter cells that we employ to monitor PC activity in its authentic subcellular compartment. Using these sensor lines we screened a small compound library in high-throughput manner. We identified 23 FDA-approved small molecules, among them monensin which displayed broad activity against furin and SKI-1/S1P. Monensin inhibited arenaviruses and SARS-CoV-2 in a dose-dependent manner. We observed a strong reduction in infectious particle release upon monensin treatment with little effect on released genome copies. This was reflected by inhibition of SARS-CoV-2 spike processing suggesting the release of immature particles. In a proof of concept experiment using human precision cut lung slices, monensin potently inhibited SARS-CoV-2 infection, evidenced by reduced infectious particle release. We propose that our PC sensor pipeline is a suitable tool to identify broad-spectrum antivirals with therapeutic potential to combat current and future emerging viruses.

Targeting sphingolipid metabolism with the sphingosine kinase inhibitor SKI-II overcomes hypoxia-induced chemotherapy resistance in glioblastoma cells: effects on cell death, self-renewal, and invasion.

BACKGROUND: Glioblastoma patients commonly develop resistance to temozolomide chemotherapy. Hypoxia, which supports chemotherapy resistance, favors the expansion of glioblastoma stem cells (GSC), contributing to tumor relapse. Because of a deregulated sphingolipid metabolism, glioblastoma tissues contain high levels of the pro-survival sphingosine-1-phosphate and low levels of the pro-apoptotic ceramide. The latter can be metabolized to sphingosine-1-phosphate by sphingosine kinase (SK) 1 that is overexpressed in glioblastoma. The small molecule SKI-II inhibits SK and dihydroceramide desaturase 1, which converts dihydroceramide to ceramide. We previously reported that SKI-II combined with temozolomide induces caspase-dependent cell death, preceded by dihydrosphingolipids accumulation and autophagy in normoxia. In the present study, we investigated the effects of a low-dose combination of temozolomide and SKI-II under normoxia and hypoxia in glioblastoma cells and patient-derived GCSs. METHODS: Drug synergism was analyzed with the Chou-Talalay Combination Index method. Dose-effect curves of each drug were determined with the Sulforhodamine B colorimetric assay. Cell death mechanisms and autophagy were analyzed by immunofluorescence, flow cytometry and western blot; sphingolipid metabolism alterations by mass spectrometry and gene expression analysis. GSCs self-renewal capacity was determined using extreme limiting dilution assays and invasion of glioblastoma cells using a 3D spheroid model. RESULTS: Temozolomide resistance of glioblastoma cells was increased under hypoxia. However, combination of temozolomide (48 µM) with SKI-II (2.66 µM) synergistically inhibited glioblastoma cell growth and potentiated glioblastoma cell death relative to single treatments under hypoxia. This low-dose combination did not induce dihydrosphingolipids accumulation, but a decrease in ceramide and its metabolites. It induced oxidative and endoplasmic reticulum stress and triggered caspase-independent cell death. It impaired the self-renewal capacity of temozolomide-resistant GSCs, especially under hypoxia. Furthermore, it decreased invasion of glioblastoma cell spheroids. CONCLUSIONS: This in vitro study provides novel insights on the links between sphingolipid metabolism and invasion, a hallmark of cancer, and cancer stem cells, key drivers of cancer. It demonstrates the therapeutic potential of approaches that combine modulation of sphingolipid metabolism with first-line agent temozolomide in overcoming tumor growth and relapse by reducing hypoxia-induced resistance to chemotherapy and by targeting both differentiated and stem glioblastoma cells.

Triplications of chromosome 1p36.3, including the genes GABRD and SKI, are associated with a developmental disorder and a facial gestalt.

Triplication of chromosomal region 1p36.3 is a rare genomic rearrangement. In this report, we delineate the phenotypic spectrum associated with 1p36.3 triplications. We describe four patients with microtriplications of variable size, but with a strong phenotypic overlap, and compare them to previously described patients with an isolated triplication or duplication of this region. The 1p36.3 triplication syndrome is associated with a distinct phenotype, characterized by global developmental delay, moderate intellectual disability, seizures, behavioral problems, and specific facial dysmorphic features, including ptosis, hypertelorism, and arched eyebrows. The de novo occurrence of these microtriplications demonstrates the reduced reproductive fitness associated with this genotype, in contrast to 1p36.3 duplications which are mostly inherited and can be associated with similar facial features but with a less severe developmental phenotype. The shared triplicated region encompasses four disease-related genes of which GABRD and SKI are most likely to contribute to the phenotype.

Key transition technology of ski jumping based on inertial motion unit, kinematics and dynamics.

BACKGROUND: The development and innovation of biomechanical measurement methods provide a solution to the problems in ski jumping research. At present, research on ski jumping mostly focuses on the local technical characteristics of different phases, but studies on the technology transition process are less. OBJECTIVES: This study aims to evaluate a measurement system (i.e. the merging of 2D video recording, inertial measurement unit and wireless pressure insole) that can capture a wide range of sport performance and focus on the key transition technical characteristics. METHODS: The application validity of the Xsens motion capture system in ski jumping was verified under field conditions by comparing the lower limb joint angles of eight professional ski jumpers during the takeoff phase collected by different motion capture systems (Xsens and Simi high-speed camera). Subsequently, the key transition technical characteristics of eight ski jumpers were captured on the basis of the aforementioned measurement system. RESULTS: Validation results indicated that the joint angle point-by-point curve during the takeoff phase was highly correlated and had excellent agreement (0.966 ≤ r ≤ 0.998, P < 0.001). Joint root-mean-square error (RMSE) differences between model calculations were 5.967° for hip, 6.856° for knee and 4.009° for ankle. CONCLUSIONS: Compared with 2D video recording, the Xsens system shows excellent agreement to ski jumping. Furthermore, the established measurement system can effectively capture the key transition technical characteristics of athletes, particularly in the dynamic changes of straight turn into arc in inrun, the adjustment of body posture and ski movement during early flight and landing preparation.

Test-retest reliability of ski-specific aerobic, sprint, and neuromuscular performance tests in highly trained cross-country skiers.

PURPOSE: Laboratory tests are commonly performed by cross-country (XC) skiers due to the challenges of obtaining reliable performance indicators on snow. However, only a few studies have reported reliability data for ski-specific test protocols. Therefore, this study examined the test-retest reliability of ski-specific aerobic, sprint, and neuromuscular performance tests. METHODS: Thirty-nine highly trained XC skiers (26 men and 13 women, age: 22 ± 4 years, V̇O2max : 70.1 ± 4.5 and 58.8 ± 4.4 mL·kg-1 ·min-1 , respectively) performed two test trials within 6 days of a diagonal V̇O2max test, n = 27; skating graded exercise test to assess the second lactate threshold (LT2 ), n = 27; 24-min double poling time trial (24-min DP, n = 25), double poling sprint test (SprintDP1 , n = 27), and 1-min self-paced skating sprint test (Sprint1-min , n = 26) using roller skis on a treadmill, and an upper-body strength test (UB-ST, n = 27) to assess peak power (Ppeak ) with light, medium, and heavy loads. For each test, the coefficient of variation (CV), intraclass correlation coefficient (ICC), and minimal detectable change (MDC) were calculated. RESULTS: V̇O2max demonstrated good-to-excellent reliability (CV = 1.4%; ICC = 0.99; MDC = 112 mL·min-1 ), whereas moderate-to-excellent reliability was found for LT2 (CV = 3.1%; ICC = 0.95). Performance during 24-min DP, SprintDP1 , and Sprint1-min showed good-to-excellent reliability (CV = 1.0%-2.3%; ICC = 0.96-0.99). Absolute reliability for UB-ST Ppeak was poor (CV = 4.9%-7.8%), while relative reliability was excellent (ICC = 0.93-0.97) across the loads. CONCLUSION: In highly trained XC skiers, sport-specific aerobic and sprint performance tests demonstrated high test-retest reliability, while neuromuscular performance for the upper body was less reliable. Using the presented protocols, practitioners can assess within- and between-season changes in relevant performance indicators.