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Off-target interactions of drugs with the human ether-à-go-go related gene 1 (hERG1) channel have been associated with severe cardiotoxic conditions leading to the withdrawal of many drugs from the market over the last decades. Consequently, predicting drug-induced hERG-liability is now a prerequisite in any drug discovery campaign. Understanding the atomic level interactions of drug with the channel is essential to guide the efficient development of safe drugs. Here we utilize the recent cryo-EM structure of the hERG channel and describe an integrated computational workflow to characterize different drug-hERG interactions. The workflow employs various structure-based approaches and provides qualitative and quantitative insights into drug binding to hERG. Our protocol accurately differentiated the strong blockers from weak and revealed three potential anchoring sites in hERG. Drugs engaging in all these sites tend to have high affinity towards hERG. Our results were cross-validated using a fluorescence polarization kit binding assay and with electrophysiology measurements on the wild-type (WT-hERG) and on the two hERG mutants (Y652A-hERG and F656A-hERG), using the patch clamp technique on HEK293 cells. Finally, our analyses show that drugs binding to hERG disrupt and hijack certain native—structural networks in the channel, thereby, gaining more affinity towards hERG.

Many voltage-dependent ion channels are regulated by accessory proteins. We recently reported powerful regulation of Kv1.2 potassium channels by the amino acid transporter Slc7a5. In this study, we report that Kv1.1 channels are also regulated by Slc7a5, albeit with different functional outcomes. In heterologous expression systems, Kv1.1 exhibits prominent current enhancement ('disinhibition') with holding potentials more negative than −120 mV. Knockdown of endogenous Slc7a5 leads to larger Kv1.1 currents and strongly attenuates the disinhibition effect, suggesting that Slc7a5 regulation of Kv1.1 involves channel inhibition that can be reversed by supraphysiological hyperpolarizing voltages. We investigated chimeric combinations of Kv1.1 and Kv1.2, demonstrating that exchange of the voltage-sensing domain controls the sensitivity and response to Slc7a5, and localize a specific position in S1 with prominent effects on Slc7a5 sensitivity. Overall, our study highlights multiple Slc7a5-sensitive Kv1 subunits, and identifies the voltage-sensing domain as a determinant of Slc7a5 modulation of Kv1 channels.

Daily use of wholegrain foods is generally recommended due to strong epidemiological evidence of reduced risk of chronic diseases. Cereal grains, especially the bran part, have a high content of dietary fiber (DF). Cereal DF is an umbrella concept of heterogeneous polysaccharides of variable chemical composition and molecular weight, which are combined in a complex network in cereal cell walls. Cereal DF and its distinct components influence food digestion throughout the gastrointestinal tract and influence nutrient absorption and other physiological reactions. After repeated consumption of especially whole grain cereal foods, these effects manifest in well-demonstrated health benefits. As cereal DF is always consumed in the form of processed cereal food, it is important to know the effects of processing on DF to understand, safeguard and maximize these health effects. Endogenous and microbial enzymes, heat and mechanical energy during germination, fermentation, baking and extrusion destructurize the food and DF matrix and affect the quantity and properties of grain DF components: arabinoxylans (AX), beta-glucans, fructans and resistant starch (RS). Depolymerization is the most common change, leading to solubilization and loss of viscosity of DF polymers, which influences postprandial responses to food. Extensive hydrolysis may also remove oligosaccharides and change the colonic fermentability of DF. On the other hand, aggregation may also occur, leading to an increased amount of insoluble DF and the formation of RS. To understand the structure–function relationship of DF and to develop foods with targeted physiological benefits, it is important to invest in thorough characterization of DF present in processed cereal foods. Such understanding also demands collaborative work between food and nutritional sciences.

Background Cryptosporidium sp. are common intracellular parasites responsible of severe diarrhea in T-cell-immunocompromised patients. We report the first case of a woman who contracted cryptosporidiosis after treatment with fingolimod, a drug labeled for multiple sclerosis and responsible for marked lymphopenia. Case presentation A 60-year-old woman was admitted for abdominal pain diarrhea and fever. The patient suffered from multiple sclerosis and had been treated with fingolimod from august 2017 to september 2018 time of occurrence of the first digestive symptoms. Stool culture was negative but parasitological examination was positive for Cryptosporidium sp. Blood biological examination profound lymphopenia of 240/mm 3 [17 CD4/mm 3 (7%) and 32 CD8/mm 3 (14%)]. Fingolimod was stopped, and the patient was put on nitazoxanide 500 mg bid for 7 days. The diarrhea resolved and no relapse was observed. Six other cases were found in the Pharmacovigilance database. Conclusion Physicians should be aware of this association and screen for Cryptosporidium in cases of diarrhea in patients treated with fingolimod. Patients should be aware of this risk and advise to take appropriate measures to avoid such contamination.

Anomalous-fading rates were measured in K-feldspars separated from 49 sediment samples, mainly from North America. The intensity of the optically stimulated luminescence was found to decrease linearly with the logarithm of time since irradiation between 2 days and ∼1 year of storage at room temperature. Anomalous-fading rates ranged from 2% to 10% per decade, a decade being a factor of 10 in time since irradiation. The sample provenances were sufficiently varied that anomalous fading appears to be ubiquitous. We have experimented with correction of optical ages for anomalous fading on the assumption that the observed fading can be extrapolated a further four decades in time. The corrected ages are in satisfactory agreement with independent ages. These results are restricted to the low-dose region of the dose response and are not expected to be applicable to samples older than ∼20-50 ka.

The North Tehran Fault (NTF) is located at the southernmost piedmont of Central Alborz and crosses the northern suburbs of the Tehran metropolis and adjacent cities, where ∼15 million people live. Extending over a length of about 110 km, the NTF stands out as a major active fault and represents an important seismic hazard for the Iranian capital after historical seismicity. In order to characterize the activity of the NTF in terms of kinematics, magnitude and recurrence intervals of earthquakes, we carried out a first paleoseismological study of the fault within its central part between Tehran and Karaj cities. We opened a trench across a 3 m‐high fault scarp affecting Quaternary deposits. Our study shows that the scarp is the result of repeated events along a main N115°E trending shallow dipping thrust fault, associated with secondary ruptures. From the trench analysis and Infrared Stimulated Luminescence (IRSL) dating of fault‐related sediments, we interpreted between 6 and 7 surface‐rupturing events that occurred during the past 30 kyrs. Their magnitudes (estimated from the displacements along the faults) are comprised between 6.1 and 7.2. The two last events – the largest ‐ occurred during the past 7.9 ± 1.2 ka, which yields a Holocene slip rate of ∼0.3 mm/yr. The 7 earthquakes scenario suggests a regular periodicity with a mean recurrence interval of ∼3.8 kyrs. However, the two most recent events could correspond to the two largest historical earthquakes recorded in the area (in 312–280 B.C. and 1177 A.D.), and therefore suggest that the NTF activity is not regular. Key Points The first paleoseismological study along the North Tehran, Iran 6‐7 events occurred in the past 30 kyrs with magnitudes between 6.1 and 7.2 Mean return period is 3.8 kyrs, but irregular activity is likely

A linear frequency modulated transducer was earlier proposed for use in surface acoustic wave (SAW) tags and sensors. This reported work demonstrates that the hyperbolically frequency modulated (HFM) transducer has significant advantages for such devices often operating in a wide range of temperatures. The HFM transducer is practically insensitive to wide temperature variations, which expand or compress signals in time. Owing to the exponential change of the varying period with the electrode number, the expansion of the length of all the periods is equivalent to just a shift in time and the compressed signal remains practically unchanged in shape, just slightly shifted. Such a shift has no importance for SAW sensors/tags, which usually operate on the difference of delays of the compressed peaks.

Recent developments in luminescence technologies applied to sediment dating is used to better constrain the age of archaeological events. Suitable geoarchaeological material includes sediments and fired objects, such as pottery and burnt stones. The assessment of archaeological ages illustrated here are based on single aliquot regeneration (SAR), with both infrared and blue stimulation on the same fine-grained aliquot being detected. These new approaches in optical dating were tested on polymineralic extracts of an Archaic burnt stone, a Woodland ceramic, and a soil containing Plano artefacts. The results demonstrate that whether or not these sites had yielded datable radiocarbon material, luminescence would have provided a reliable chronological framework given that the appropriate procedures to correct anomalous fading are incorporated.

The relationship between static foot structure characteristics and knee joint biomechanics during walking, or the biomechanical response to wedged insoles are currently unknown. In this study, 3D foot scanning, dual X-ray absorptiometry and gait analysis methods were used to determine structural parameters of the foot and assess their relation to knee joint loading and biomechanical response to wedged insoles in 30 patients with knee osteoarthritis. In multiple linear regression models, foot fat content, height of the medial longitudinal arch and static hind foot angle were not associated with the magnitude of the knee adduction moment (R2 = 0.24, p = 0.060), knee adduction angular impulse (R2 = 0.21, p = 0.099) or 3D resultant knee moment (R2 = 0.23, p = 0.073) during gait. Furthermore, these foot structure parameters were not associated with the patients’ biomechanical response to medial or lateral wedge footwear insoles (all p < 0.01). These findings suggest that static foot structure is not associated with gait mechanics at the knee, and that static foot structure alone cannot be utilized to predict an individual’s biomechanical response to wedged footwear insoles in patients with knee osteoarthritis.

A sensor system using ultra-wideband frequency technology and passive surface acoustic wave (SAW) sensors/tags has been demonstrated experimentally. The system operates with a frequency bandwidth of 500 MHz, which results in compressed RF pulses of about 2 ns duration, including just a few sinusoids with amplitude modulation. A correlation method is developed to measure the delay between two echoes with high resolution, avoiding the phase ambiguity problem. For temperature, deformation or other measurand a simple structure including only two reflectors is sufficient. This method is used in a system which simultaneously remotely measures a few temperature sensors with a resolution of 0.1°C. The operation of the system in a strongly reflecting environment (inside a metal box) is demonstrated.