Association between exposure to radioactive iodine after the Chernobyl accident and thyroid volume in Belarus 10-15 years later

Background While there is a robust literature on environmental exposure to iodine-131 (131I) in childhood and adolescence and the risk of thyroid cancer and benign nodules, little is known about its effects on thyroid volume. Methods To assess the effect of 131I dose to the thyroid on the volume of the thyroid gland, we examined the data from the baseline screening of the Belarusian-American Cohort Study of residents of Belarus who were exposed to the Chernobyl fallout at ages ≤18 years. Thyroid dose estimates were based on individual thyroid activity measurements made shortly after the accident and dosimetric data from questionnaires obtained 10-15 years later at baseline screening. During baseline screening, thyroid gland volume was assessed from thyroid ultrasound measurements. The association between radiation dose and thyroid volume was modeled using linear regression where radiation dose was expressed with power terms to address non-linearity. The model was adjusted for attained age, sex, and place of residence, and their modifying effects were examined. Results The analysis was based on 10,703 subjects. We found a statistically significant positive association between radiation dose and thyroid volume (P < 0.001). Heterogeneity of association was observed by attained age (P < 0.001) with statistically significant association remaining only in the subgroup of ≥18 years at screening (P < 0.001). For this group, increase in dose from 0.0005 to 0.15 Gy was associated with a 1.27 ml (95% CI: 0.46, 2.07) increase in thyroid volume. The estimated effect did not change with increasing doses above 0.15 Gy. Conclusions This is the first study to examine the association between 131I dose to the thyroid gland and thyroid volume in a population of individuals exposed during childhood and systematically screened 10-15 years later. It provides evidence for a moderate statistically significant increase in thyroid volume among those who were ≥ 18 years at screening. Given that this effect was observed at very low doses and was restricted to a narrow dose range, further studies are necessary to better understand the effect.

Role of synovial fibroblast subsets across synovial pathotypes in rheumatoid arthritis: a deconvolution analysis

ObjectivesTo integrate published single-cell RNA sequencing (scRNA-seq) data and assess the contribution of synovial fibroblast (SF) subsets to synovial pathotypes and respective clinical characteristics in treatment-naïve early arthritis.MethodsIn this in silico study, we integrated scRNA-seq data from published studies with additional unpublished in-house data. Standard Seurat, Harmony and Liger workflow was performed for integration and differential gene expression analysis. We estimated single cell type proportions in bulk RNA-seq data (deconvolution) from synovial tissue from 87 treatment-naïve early arthritis patients in the Pathobiology of Early Arthritis Cohort using MuSiC. SF proportions across synovial pathotypes (fibroid, lymphoid and myeloid) and relationship of disease activity measurements across different synovial pathotypes were assessed.ResultsWe identified four SF clusters with respective marker genes: PRG4+ SF (CD55, MMP3, PRG4, THY1neg); CXCL12+ SF (CXCL12, CCL2, ADAMTS1, THY1low); POSTN+ SF (POSTN, collagen genes, THY1); CXCL14+ SF (CXCL14, C3, CD34, ASPN, THY1) that correspond to lining (PRG4+ SF) and sublining (CXCL12+ SF, POSTN+ + and CXCL14+ SF) SF subsets. CXCL12+ SF and POSTN+ + were most prominent in the fibroid while PRG4+ SF appeared highest in the myeloid pathotype. Corresponding, lining assessed by histology (assessed by Krenn-Score) was thicker in the myeloid, but also in the lymphoid pathotype + the fibroid pathotype. PRG4+ SF correlated positively with disease severity parameters in the fibroid, POSTN+ SF in the lymphoid pathotype whereas CXCL14+ SF showed negative association with disease severity in all pathotypes.ConclusionThis study shows a so far unexplored association between distinct synovial pathologies and SF subtypes defined by scRNA-seq. The knowledge of the diverse interplay of SF with immune cells will advance opportunities for tailored targeted treatments.

Structure, dynamics, and inhibition of Staphylococcus aureus m1A22-tRNA methyltransferase

The enzyme m1A22-tRNA methyltransferase (TrmK) catalyses the transfer of a methyl group from SAM to the N1 of adenine 22 in tRNAs. TrmK is essential for Staphylococcus aureus survival during infection, but has no homologue in mammals, making it a promising target for antibiotic development. Here we describe the structural and functional characterisation of S. aureus TrmK. Crystal structures are reported for S. aureus TrmK apoenzyme and in complexes with SAM and SAH. Isothermal titration calorimetry showed that SAM binds to the enzyme with favourable but modest enthalpic and entropic contributions, whereas SAH binding leads to an entropic penalty compensated by a large favourable enthalpic contribution. Molecular dynamics simulations point to specific motions of the C-terminal domain being altered by SAM binding, which might have implications for tRNA recruitment. Activity assays for S. aureus TrmK-catalysed methylation of WT and position 22 mutants of tRNALeu demonstrate that the enzyme requires an adenine at position 22 of the tRNA. Intriguingly, a small RNA hairpin of 18 nucleotides is methylated by TrmK depending on the position of the adenine. In-silico screening of compounds suggested plumbagin as a potential inhibitor of TrmK, which was confirmed by activity measurements. Furthermore, LC-MS indicated the protein was covalently modified by one equivalent of the inhibitor, and proteolytic digestion coupled with LC-MS identified Cys92, in the vicinity of the SAM-binding site, as the sole residue modified. These results these results identify a cryptic binding pocket of S. aureus TrmK and lay the foundation for future structure-based drug discovery.

Multiplex, translaminar imaging in the spinal cord of behaving mice

While the spinal cord is known to play critical roles in sensorimotor processing, including pain-related signaling, corresponding activity patterns in genetically defined cell types across spinal laminae have remained elusive. Calcium imaging has enabled cellular activity measurements in behaving rodents but is currently limited to superficial regions. Using chronically implanted microprisms, we imaged sensory and motor evoked activity in regions and at speeds inaccessible by other high-resolution imaging techniques. To enable translaminar imaging in freely behaving animals through implanted microprisms, we additionally developed wearable microscopes with custom-compound microlenses. This new integrated system addresses multiple challenges of previous wearable microscopes, including their limited working distance, resolution, contrast, and achromatic range. The combination of these innovations allowed us to uncover that dorsal horn astrocytes in behaving mice show somatosensory program-dependent and lamina-specific calcium excitation. Additionally, we show that tachykinin precursor 1 (Tac1)-expressing neurons exhibit upper laminae-restricted activity to acute mechanical pain but not locomotion.

Artificial Intelligence Approaches to Determine Graphite Nodularity in Ductile Iron

The complex metallurgical interrelationships in the production of ductile cast iron can lead to enormous differences in graphite formation and local microstructure by small variations during production. Artificial intelligence algorithms were used to describe graphite formation, which is influenced by a variety of metallurgical parameters. Moreover, complex physical relationships in the formation of graphite morphology are also controlled by boundary conditions of processing, the effect of which can hardly be assessed in everyday foundry operations. The influence of relevant input parameters can be predetermined using artificial intelligence based on conditions and patterns that occur simultaneously. By predicting the local graphite formation, measures to stabilise production were defined and thereby the accuracy of structure simulations improved. In course of this work, the most important dominating variables, from initial charging to final casting, were compiled and analysed with the help of statistical regression methods to predict the nodularity of graphite spheres. We compared the accuracy of the prediction by using Linear Regression, Gaussian Process Regression, Regression Trees, Boosted Trees, Support Vector Machines, Shallow Neural Networks and Deep Neural Networks. As input parameters we used 45 characteristics of the production process consisting of the basic information including the composition of the charge, the overheating time, the type of melting vessel, the type of the inoculant, the fading, and the solidification time. Additionally, the data of several thermal analysis, oxygen activity measurements and the final chemical analysis were included.Initial programme designs using machine learning algorithms based on neural networks achieved encouraging results. To improve the degree of accuracy, this algorithm was subsequently adapted and refined for the nodularity of graphite.

Cerebral Oxygenation and Activity During Surgical Repair of Neonates With Congenital Diaphragmatic Hernia: A Center Comparison Analysis

Background and aim: Neonatal brain monitoring is increasingly used due to reports of brain injury perioperatively. Little is known about the effect of sedatives (midazolam) and anesthetics (sevoflurane) on cerebral oxygenation (rScO2) and cerebral activity. This study aims to determine these effects in the perioperative period.Methods: This is an observational, prospective study in two tertiary pediatric surgical centers. All neonates with a congenital diaphragmatic hernia received perioperative cerebral oxygenation and activity measurements. Patients were stratified based on intraoperatively administrated medication: the sevoflurane group (continuous sevoflurane, bolus fentanyl, bolus rocuronium) and the midazolam group (continuous midazolam, continuous fentanyl, and continuous vecuronium).Results: Intraoperatively, rScO2 was higher in the sevoflurane compared to the midazolam group (84%, IQR 77–95 vs. 65%, IQR 59–76, p = &lt; 0.001), fractional tissue oxygen extraction was lower (14%, IQR 5–21 vs. 31%, IQR 29–40, p = &lt; 0.001), the duration of hypoxia was shorter (2%, IQR 0.4–9.6 vs. 38.6%, IQR 4.9–70, p = 0.023), and cerebral activity decreased more: slow delta: 2.16 vs. 4.35 μV2 (p = 0.0049), fast delta: 0.73 vs. 1.37 μV2 (p = &lt; 0.001). In the first 30 min of the surgical procedure, a 3-fold increase in fast delta (10.48–31.22 μV2) and a 5-fold increase in gamma (1.42–7.58 μV2) were observed in the midazolam group.Conclusion: Sevoflurane-based anesthesia resulted in increased cerebral oxygenation and decreased cerebral activity, suggesting adequate anesthesia. Midazolam-based anesthesia in neonates with a more severe CDH led to alarmingly low rScO2 values, below hypoxia threshold, and increased values of EEG power during the first 30 min of surgery. This might indicate conscious experience of pain. Integrating population-pharmacokinetic models and multimodal neuromonitoring are needed for personalized pharmacotherapy in these vulnerable patients.Trial Registration:https://www.trialregister.nl/trial/6972, identifier: NL6972.

The New Pharmacological Chaperones PBXs Increase α-Galactosidase A Activity in Fabry Disease Cellular Models

Fabry disease is an X-linked multisystemic disorder caused by the impairment of lysosomal α-Galactosidase A, which leads to the progressive accumulation of glycosphingolipids and to defective lysosomal metabolism. Currently, Fabry disease is treated by enzyme replacement therapy or the orally administrated pharmacological chaperone Migalastat. Both therapeutic strategies present limitations, since enzyme replacement therapy has shown low half-life and bioavailability, while Migalastat is only approved for patients with specific mutations. The aim of this work was to assess the efficacy of PBX galactose analogues to stabilize α-Galactosidase A and therefore evaluate their potential use in Fabry patients with mutations that are not amenable to the treatment with Migalastat. We demonstrated that PBX compounds are safe and effective concerning stabilization of α-Galactosidase A in relevant cellular models of the disease, as assessed by enzymatic activity measurements, molecular modelling, and cell viability assays. This experimental evidence suggests that PBX compounds are promising candidates for the treatment of Fabry disease caused by mutations which affect the folding of α-Galactosidase A, even for GLA variants that are not amenable to the treatment with Migalastat.

Measurement Performance of Activity Measurements with Newer Generation of Apple Watch in Wheelchair Users with Spinal Cord Injury

Background The level of physical activity (PA) of people with spinal cord injury (SCI) has an impact on long-term complications. Currently, PA is mostly assessed by interviews. Wearable activity trackers are promising tools to objectively measure PA under everyday conditions. The only off-the-shelf, wearable activity tracker with specific measures for wheelchair users is the Apple Watch. Objectives This study analyzes the measurement performance of Apple Watch Series 4 for wheelchair users and compares it with an earlier generation of the device. Methods Fifteen participants with subacute SCI during their first in-patient phase followed a test course using their wheelchair. The number of wheelchair pushes was counted manually by visual inspection and with the Apple Watch. Difference between the Apple Watch and the rater was analyzed with mean absolute percent error (MAPE) and a Bland–Altman plot. To compare the measurement error of Series 4 and an older generation of the device a t-test was calculated using data for Series 1 from a former study. Results The average of differences was 12.33 pushes (n = 15), whereas participants pushed the wheelchair 138.4 times on average (range 86–271 pushes). The range of difference and the Bland–Altman plot indicate an overestimation by Apple Watch. MAPE is 9.20% and the t-test, testing for an effect of Series 4 on the percentage of error compared with Series 1, was significant with p < 0.05. Conclusion Series 4 shows a significant improvement in measurement performance compared with Series 1. Series 4 can be considered as a promising data source to capture the number of wheelchair pushes on even grounds. Future research should analyze the long-term measurement performance during everyday conditions of Series 4.