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The genetic integrity of each organism depends on the faithful segregation of its genome during mitosis. To meet this challenge, a cellular surveillance mechanism, termed the spindle assembly checkpoint (SAC), evolved that monitors the correct attachment of chromosomes and blocks progression through mitosis if corrections are needed. While the central role of the SAC for genome integrity is well established, its functional dissection has been hampered by the limited availability of appropriate small molecule inhibitors. Using a fluorescence polarization-based screen, we identify Mad2 inhibitor-1 (M2I-1), the first small molecule inhibitor targeting the binding of Mad2 to Cdc20, an essential protein-protein interaction (PPI) within the SAC. Based on computational and biochemical analyses, we propose that M2I-1 disturbs conformational dynamics of Mad2 critical for complex formation with Cdc20. Cellular studies revealed that M2I-1 weakens the SAC response, indicating that the compound might be active in cells. Thus, our study identifies the SAC specific complex formation between Mad2 and Cdc20 as a protein-protein interaction that can be targeted by small molecules.
BACKGROUND: Reproducible measurements of tendon structural properties are a prerequisite for accurate diagnosis of tendon disorders and for determination of their mechanical properties. Despite the widely used application of Ultrasonography (US) in musculoskeletal assessment, its operator dependency and lack of standardization influences the consistency of the measurement.
OBJECTIVE: To evaluate the intra-rater reproducibility of a standardized US method assessing the structural properties of the Achilles tendon (AT).
METHODS: Sixteen asymptomatic participants were positioned prone on an isokinetic dynamometer with the knee extended and ankle at 90. flexion. US was used to assess AT-length, cross-sectional area (CSA), and AT-elongation during isometric plantarflexion contraction. The intra-rater reproducibility was assessed by ICC (2.1), Test-Retest Variability (TRV, %), Bland-Altman analyses (Bias +/- LoA [1.96*SD]), and Standard-Error of Measurement (SEM).
RESULTS: Measurements of AT-length demonstrated an ICC of 0.93, TRV of 4.5 +/- 3.9%, Bias +/- LoA of -2.8 +/- 25.0 mm and SEM of 6.6 mm. AT-CSA showed an ICC of 0.79, TRV of 8.7 +/- 9.6%, Bias +/- LoA of 1.7 +/- 19.4 mm(2) and SEM of 5.3 mm(2). AT-elongation revealed an ICC of 0.92, TRV of 12.9 +/- 8.9%, Bias +/- LoA of 0.3 +/- 5.7 mm and SEM of 1.5 mm.
CONCLUSIONS: The presented methodology allows a reproducible assessment of Achilles tendon structural properties when performed by a single rater.
Subcutaneous adipose tissue (SAT) measurements with ultrasound have recently been introduced to assess body fat in elite athletes. However, appropriate protocols and data on various groups of athletes are missing. We investigated intra-rater reliability of SAT measurements using ultrasound in elite canoe athletes. 25 international level canoeists (18 male, 7 female; 23 +/- 4 years; 81 +/- 11 kg; 1.83 +/- 0.09 m; 20 +/- 3 training h/wk) were measured on 2 consecutive days. SAT was assessed with B-mode ultrasound at 8 sites (ISAK): triceps, subscapular, biceps, iliac crest, supraspinal, abdominal, front thigh, medial calf, and quantified using image analysis software. Data was analyzed descriptively (mean +/- SD, [range]). Coefficient of variation (CV %), intraclass correlation coefficient (ICC, 2.1) and absolute (LoA) and ratio limits of agreement (RLoA) were calculated for day-to-day reliability. Mean sum of SAT thickness was 30.0 +/- 19.4 mm [8.0, 80.1 mm], with 3.9 +/- 1.8 mm [1.2 mm subscapular, 8.0 mm abdominal] for individual sites. CV for the sum of sites was 4.7 %, ICC 0.99, LoA 1.7 +/- 3.6 mm, RLoA 0.940 (*/divided by 1.155). Measuring SAT with ultrasound has proved to have excellent day-to-day reliability in elite canoe athletes. Recommendations for standardization of the method will further increase accuracy and reproducibility.
Achilles (AT) and patellar tendons (PT) are commonly affected by tendinopathy in adult athletes but prevalence of symptoms and morphological changes in adolescents is unclear. The study aimed to determine prevalence of tendinopathy and intratendinous changes in ATs and PTs of adolescent athletes. A total of 760 adolescent athletes (13.0 +/- 1.9 years; 160 +/- 13cm; 50 +/- 14kg) were examined. History, local clinical examination, and longitudinal Doppler ultrasound analysis for both ATs and PTs were performed including identification of intratendinous echoic changes and vascularization. Diagnosis of tendinopathy was complied clinically in case of positive history of tendon pain and tendon pain on palpation. Achilles tendinopathy was diagnosed in 1.8% and patellar tendinopathy in 5.8%. Vascularizations were visible in 3.0% of ATs and 11.4% of PTs, hypoechogenicities in 0.7% and 3.2% as well as hyperechogenicities in 0% and 0.3%, respectively. Vascularizations and hypoechogenicities were statistically significantly more often in males than in females (P0.02). Subjects with patellar tendinopathy had higher prevalence of structural intratendinous changes than those without PT symptoms (P0.001). In adolescent athletes, patellar tendinopathy is three times more frequent compared with Achilles tendinopathy. Longitudinal studies are necessary to investigate physiological or pathological origin of vascularizations and its predictive value in development of tendinopathy.
Tendinopathies are frequently the cause of chronic, load-dependent complaints of the lower extremity. Commonly, the large tendons of the ankle and knee joints are affected, especially the Achilles and patellar tendons. Repeated overuse in sports and/or daily activities is assumed as the aetiology. Besides the clinical examination including a comprehensive anamnesis of pain and training/loading, sonographic imaging has a high training/loading relevance for the diagnosis of tendon pathologies of the lower extremity. Training concepts are considered in first line as the treatment of choice. A combination with physical therapy interventions can be useful. In cases of a more severe pathology and long-standing complaints multimodal therapeutic options should be employed. The use of surgical treatment procedures should only be taken into account in case of failed response to conservative treatment.
G349.7+0.2 is a young Galactic supernova remnant (SNR) located at the distance of 11.5 kpc and observed across the entire electromagnetic spectrum from radio to high energy (HE; 0.1 GeV < E < 100 GeV) gamma-rays. Radio and infrared observations indicate that the remnant is interacting with a molecular cloud. In this paper, the detection of very high energy (VHE, E > 100 GeV) gamma-ray emission coincident with this SNR with the High Energy Stereoscopic System (HESS.) is reported. This makes it one of the farthest Galactic SNR ever detected in this domain. An integral flux F(E > 400 GeV) = (6.5 +/- 1.1(stat) +/- 1.3(syst)) x 10-11 ph cm(-2) s(-1) corresponding to similar to 0.7% of that of the Crab Nebula and to a luminosity of similar to 10(34) erg s(-1) above the same energy threshold, and a steep photon index Gamma(VHE) = 2.8 +/- 0.27(stat) +/- 0.20(syst) are measured. The analysis of more than 5 yr of Fermi-LAT data towards this source shows a power-law like spectrum with a best-fit photon index Gamma(HE) = 2.2 +/- 0.04.2(stat-0.31sys)(+0.13), The combined gamma-ray spectrum of 0349.7+0.2 can be described by either a broken power law (I3PL) or a power law with exponential (or sub exponential) cutoff (PLC). In the former case, the photon break energy is found at E-br,E-gamma = 551(-30)(+70) GeV, slightly higher than what is usually observed in the HE/VHE gamma-ray emitting middle-aged SNRs known to be interacting with molecular clouds. In the latter case. the exponential (respectively sub-exponential) cutoff energy is measured at E-cat,E-gamma = 1.4(-0.55)(+1.6) (respectively 0.35(-0.21)(+0.75)) TeV. A pion decay process resulting from the interaction of the accelerated protons and nuclei with the dense surrounding medium is clearly the preferred scenario to explain the gamma-ray emission. The BPL with a spectral steepening of 0.5-1 and the PLC provide equally good fits to the data. The product or the average gas density and the total energy content of accelerated protons and nuclei amounts to nu W-p similar to 5 x 10(51) erg cm(-3)
The gamma-ray spectrum of the low-frequency-peaked BL Lac (LBL) object AP Librae is studied, following the discovery of very-high-energy (VHE; E > 100 GeV) gamma-ray emission up to the TeV range by the H.E.S.S. experiment. Thismakes AP Librae one of the few VHE emitters of the LBL type. The measured spectrum yields a flux of (8.8 +/- 1.5(stat) +/- 1.8(sys)) x 10(-12) cm(-2) s(-1) above 130 GeV and a spectral index of Gamma = 2.65 +/- 0.19(stat) +/- 0.20(sys). This study also makes use of Fermi-LAT observations in the high energy (HE, E > 100 MeV) range, providing the longest continuous light curve (5 years) ever published on this source. The source underwent a flaring event between MJD 56 306-56 376 in the HE range, with a flux increase of a factor of 3.5 in the 14 day bin light curve and no significant variation in spectral shape with respect to the low-flux state. While the H.E.S.S. and (low state) Fermi-LAT fluxes are in good agreement where they overlap, a spectral curvature between the steep VHE spectrum and the Fermi-LAT spectrum is observed. The maximum of the gamma-ray emission in the spectral energy distribution is located below the GeV energy range.
The Large Magellanic Cloud, a satellite galaxy of the Milky Way, has been observed with the High Energy Stereoscopic System (H.E.S.S.) above an energy of 100 billion electron volts for a deep exposure of 210 hours. Three sources of different types were detected: the pulsar wind nebula of the most energetic pulsar known, N 157B; the radio-loud supernova remnant N 132D; and the largest nonthermal x-ray shell, the superbubble 30 Dor C. The unique object SN 1987A is, unexpectedly, not detected, which constrains the theoretical framework of particle acceleration in very young supernova remnants. These detections reveal the most energetic tip of a g-ray source population in an external galaxy and provide via 30 Dor C the unambiguous detection of g-ray emission from a superbubble.
An annihilation signal of dark matter is searched for from the central region of the Milky Way. Data acquired in dedicated on-off observations of the Galactic center region with H.E.S.S. are analyzed for this purpose. No significant signal is found in a total of similar to 9 h of on-off observations. Upper limits on the velocity averaged cross section, <sigma upsilon >, for the annihilation of dark matter particles with masses in the range of similar to 300 GeV to similar to 10 TeV are derived. In contrast to previous constraints derived from observations of the Galactic center region, the constraints that are derived here apply also under the assumption of a central core of constant dark matter density around the center of the Galaxy. Values of <sigma upsilon > that are larger than 3 x 10(-24) cm(3)/s are excluded for dark matter particles with masses between similar to 1 and similar to 4 TeV at 95% C.L. if the radius of the central dark matter density core does not exceed 500 pc. This is the strongest constraint that is derived on <sigma upsilon > for annihilating TeV mass dark matter without the assumption of a centrally cusped dark matter density distribution in the search region.