We recently described glutathione peroxidase 4 (GPX4) as a promising target for killing therapy-resistant cancer cells via ferroptosis. The onset of therapy resistance by multiple types of treatment ...results in a stable cell state marked by high levels of polyunsaturated lipids and an acquired dependency on GPX4. Unfortunately, all existing inhibitors of GPX4 act covalently via a reactive alkyl chloride moiety that confers poor selectivity and pharmacokinetic properties. Here, we report our discovery that masked nitrile-oxide electrophiles, which have not been explored previously as covalent cellular probes, undergo remarkable chemical transformations in cells and provide an effective strategy for selective targeting of GPX4. The new GPX4-inhibiting compounds we describe exhibit unexpected proteome-wide selectivity and, in some instances, vastly improved physiochemical and pharmacokinetic properties compared to existing chloroacetamide-based GPX4 inhibitors. These features make them superior tool compounds for biological interrogation of ferroptosis and constitute starting points for development of improved inhibitors of GPX4.
Running has a positive impact on human health and is an accessible sport for most people. There is high demand for tracking running performance and progress for amateurs and professionals alike. The ...parameters velocity and distance are thereby of main interest. In this work, we evaluate the accuracy of four algorithms, which calculate the stride velocity and stride length during running using data of an inertial measurement unit (IMU) placed in the midsole of a running shoe. The four algorithms are based on stride time, foot acceleration, foot trajectory estimation, and deep learning, respectively. They are compared using two studies: a laboratory-based study comprising 2377 strides from 27 subjects with 3D motion tracking as a reference and a field study comprising 12 subjects performing a 3.2-km run in a real-world setup. The results show that the foot trajectory estimation algorithm performs best, achieving a mean error of 0.032 ± 0.274 m/s for the velocity estimation and 0.022 ± 0.157 m for the stride length. An interesting alternative for systems with a low energy budget is the acceleration-based approach. Our results support the implementation decision for running velocity and distance tracking using IMUs embedded in the sole of a running shoe.
Maximizing performance success in sports is about continuous learning and adaptation processes. Aside from physiological, technical and emotional performance factors, previous research focused on ...perceptual skills, revealing their importance for decision-making. This includes deriving relevant environmental information as a result of eye, head and body movement interaction. However, to evaluate visual exploratory activity (VEA), generally utilized laboratory settings have restrictions that disregard the representativeness of assessment environments and/or decouple coherent cognitive and motor tasks. In vivo studies, however, are costly and hard to reproduce. Furthermore, the application of elaborate methods like eye tracking are cumbersome to implement and necessitate expert knowledge to interpret results correctly. In this paper, we introduce a virtual reality-based reproducible assessment method allowing the evaluation of VEA. To give insights into perceptual-cognitive processes, an easily interpretable head movement-based metric, quantifying VEA of athletes, is investigated. Our results align with comparable in vivo experiments and consequently extend them by showing the validity of the implemented approach as well as the use of virtual reality to determine characteristics among different skill levels. The findings imply that the developed method could provide accurate assessments while improving the control, validity and interpretability, which in turn informs future research and developments.
Expeditious and high-yielding Nazarov cyclizations of 2-alkoxy-1,4-pentadien-3-ones are described. An example of a catalytic asymmetric Nazarov cyclization is presented.
A concise, stereoselective, and convergent total synthesis of the unnatural enantiomer of the neodolastane diterpenoid heptemerone B has been completed. Saponification of (−)-heptemerone afforded ...(−)-guanacastepene E. The absolute stereochemistry of (−)-heptemerone B was thus established as 5-(S), the same as (−)-guanacastepene E. The longest linear sequence of the synthesis comprises 17 (18) steps from simple known starting materials. Our general synthetic approach integrates a diverse set of reactions, including an intramolecular Heck reaction to create one quaternary stereocenter and a cuprate conjugate addition for the establishment of the other. The central seven-membered ring was closed with an uncommon electrochemical oxidation, whereas the five-membered ring was formed through ring-closing metathesis. The absolute configuration of the two key building blocks was established through an asymmetric reduction and an asymmetric ene reaction.
Fitness trackers and smart watches are frequently used to collect data in longitudinal medical studies. They allow continuous recording in real-life settings, potentially revealing previously ...uncaptured variabilities of biophysiological parameters and diseases. Adequate device accuracy is a prerequisite for meaningful research.
This study aims to assess the heart rate recording accuracy in two previously unvalidated devices: Fitbit Charge 4 and Samsung Galaxy Watch Active2.
Participants performed a study protocol comprising 5 resting and sedentary, 2 low-intensity, and 3 high-intensity exercise phases, lasting an average of 19 minutes 27 seconds. Participants wore two wearables simultaneously during all activities: Fitbit Charge 4 and Samsung Galaxy Watch Active2. Reference heart rate data were recorded using a medically certified Holter electrocardiogram. The data of the reference and evaluated devices were synchronized and compared at 1-second intervals. The mean, mean absolute error, mean absolute percentage error, Lin concordance correlation coefficient, Pearson correlation coefficient, and Bland-Altman plots were analyzed.
A total of 23 healthy adults (mean age 24.2, SD 4.6 years) participated in our study. Overall, and across all activities, the Fitbit Charge 4 slightly underestimated the heart rate, whereas the Samsung Galaxy Watch Active2 overestimated it (-1.66 beats per minute bpm/3.84 bpm). The Fitbit Charge 4 achieved a lower mean absolute error during resting and sedentary activities (seated rest: 7.8 vs 9.4; typing: 8.1 vs 11.6; laying down left: 7.2 vs 9.4; laying down back: 6.0 vs 8.6; and walking slowly: 6.8 vs 7.7 bpm), whereas the Samsung Galaxy Watch Active2 performed better during and after low- and high-intensity activities (standing up: 12.3 vs 9.0; walking fast: 6.1 vs 5.8; stairs: 8.8 vs 6.9; squats: 15.7 vs 6.1; resting: 9.6 vs 5.6 bpm).
Device accuracy varied with activity. Overall, both devices achieved a mean absolute percentage error of just <10%. Thus, they were considered to produce valid results based on the limits established by previous work in the field. Neither device reached sufficient accuracy during seated rest or keyboard typing. Thus, both devices may be eligible for use in respective studies; however, researchers should consider their individual study requirements.
Objective: Clinical urine tests are a key component of prenatal care. As of now, urine test strips are evaluated through a time consuming, often error-prone and operator-dependent visual color ...comparison of test strips and reference cards by medical staff. Methods and procedures: This work presents an automated pipeline for urinalysis with urine test strips using smartphone camera images in home environments, combining several image processing and color combination techniques. Our approach is applicable to off-the-shelf test strips in home conditions with no additional hardware required. For development and evaluation of our pipeline we collected image data from two sources: i) A user study (26 participants, 150 images) and ii) a lab study (135 images). Results: We trained a region-based convolutional neural network that is able to detect the urine test strip location and orientation in images with a wide variety of light conditions, backgrounds and perspectives with an accuracy of 85.5%. The reference card can be robustly detected through a feature matching approach in 98.6% of the images. Color comparison by Hue channel (0.81 F1-Score), Matching factor (0.80 F1-Score) and Euclidean distance (0.70 F1-Score) were evaluated to determine the urinalysis results. Conclusion: We show that an automated smartphone-based colorimetric analysis of urine test strips in a home environment is feasible. It facilitates examinations and provides the possibility to shift care into an at-home environment. Clinical impact: The findings demonstrate that routine urine examinations can be transferred into the home environment using a smartphone. Simultaneously, human error is avoided, accuracy is increased and medical staff is relieved.
Recent clinical data provided proof-of-concept for selective B-Raf inhibitors in treatment of B-RafV600E mutant melanoma. Pyrazolopyridine-type B-Raf inhibitors previously described by the authors ...are potent and selective but exhibit low solubility requiring the use of amorphous dispersion-based formulation for achieving efficacious drug exposures. Through structure-based design, we discovered a new class of highly potent aminopyrimidine-based B-Raf inhibitors with improved solubility and pharmacokinetic profiles. The hinge binding moiety possesses a basic center imparting high solubility at gastric pH, addressing the dissolution limitation observed with our previous series. In our search for an optimal linker-hinge binding moiety system, amide-linked thieno3,2-dpyrimidine analogues 32 and 35 (G945), molecules with desirable physicochemical properties, emerged as lead compounds with strong efficacy in a B-RafV600E mutant mouse xenograft model. Synthesis, SAR, lead selection, and evaluation of key compounds in animal studies will be described.
Herein we describe a novel series of ATP competitive B-Raf inhibitors based on the pyrazolo1,5-apyrimidine scaffold. These inhibitors exhibit both excellent cellular potency and striking B-Raf ...selectivity. Optimization led to the identification of compound 17, a potent, selective and orally available agent with improved physicochemical and pharmacokinetic properties.
The second most common cause of diving fatalities is cardiovascular diseases. Monitoring the cardiovascular system in actual underwater conditions is necessary to gain insights into cardiac activity ...during immersion and to trigger preventive measures. We developed a wearable, current-based electrocardiogram (ECG) device in the eco-system of the FitnessSHIRT platform. It can be used for normal/dry ECG measuring purposes but is specifically designed to allow underwater signal acquisition without having to use insulated electrodes. Our design is based on a transimpedance amplifier circuit including active current feedback. We integrated additional cascaded filter components to counter noise characteristics specific to the immersed condition of such a system. The results of the evaluation show that our design is able to deliver high-quality ECG signals underwater with no interferences or loss of signal quality. To further evaluate the applicability of the system, we performed an applied study with it using 12 healthy subjects to examine whether differences in the heart rate variability exist between sitting and supine positions of the human body immersed in water and outside of it. We saw significant differences, for example, in the RMSSD and SDSD between sitting outside the water (36 ms) and sitting immersed in water (76 ms) and the pNN50 outside the water (6.4%) and immersed in water (18.2%). The power spectral density for the sitting positions in the TP and HF increased significantly during water immersion while the LF/HF decreased significantly. No significant changes were found for the supine position.
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