| 3161. |
- Moreno, Claudia R. C., et al.
(författare)
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Sleep patterns in Amazon rubber tappers with and without electric light at home
- 2015
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Today's modern society is exposed to artificial electric lighting in addition to the natural light-dark cycle. Studies assessing the impact of electric light exposure on sleep and its relation to work hours are rare due to the ubiquitous presence of electricity. Here we report a unique study conducted in two phases in a homogenous group of rubber tappers living and working in a remote area of the Amazon forest, comparing those living without electric light (n = 243 in first phase; n = 25 in second phase) to those with electric light at home (n = 97 in first phase; n = 17 in second phase). Questionnaire data (Phase 1) revealed that rubber tappers with availability of electric light had significantly shorter sleep on work days (30 min/day less) than those without electric light. Analysis of the data from the Phase 2 sample showed a significant delay in the timing of melatonin onset in workers with electric light compared to those without electric light (p < 0.01). Electric lighting delayed sleep onset and reduced sleep duration during the work week and appears to interfere with alignment of the circadian timing system to the natural light/dark cycle.
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| 3162. |
- Moreno, Noelia, et al.
(författare)
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Rabbit hemorrhagic disease virus capsid, a versatile platform for foreign B-cell epitope display inducing protective humoral immune responses
- 2016
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 6:31844
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Tidskriftsartikel (refereegranskat)abstract
- Virus-like particles (VLPs), comprised of viral structural proteins devoid of genetic material, are tunable nanoparticles that can be chemically or genetically engineered, to be used as platforms for multimeric display of foreign antigens. Here, we report the engineering of chimeric VLPs, derived from rabbit hemorrhagic disease virus (RHDV) for presentation of foreign B-cell antigens to the immune system. The RHDV capsid comprises 180 copies of a single capsid subunit (VP60). To evaluate the ability of chimeric RHDV VLPs to elicit protective humoral responses against foreign antigens, we tested two B-cell epitopes: a novel neutralizing B-cell epitope, derived from feline calicivirus capsid protein, and a well characterized B-cell epitope from the extracellular domain of influenza A virus M2 protein (M2e). We generated sets of chimeric RHDV VLPs by insertion of the foreign B-cell epitopes at three different locations within VP60 protein (which involved different levels of surface accessibility) and in different copy numbers per site. The immunogenic potential of the chimeric VLPs was analyzed in the mouse model. The results presented here indicated that chimeric RHDV VLPs elicit potent protective humoral responses against displayed foreign B-cell epitopes, demonstrated by both, in vitro neutralization and in vivo protection against a lethal challenge.
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| 3163. |
- Moreno-Rabie, C, et al.
(författare)
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Radiographic predictors for MRONJ in oncologic patients undergoing tooth extraction
- 2022
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1, s. 11280-
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Tidskriftsartikel (refereegranskat)abstract
- Tooth extraction is a risk factor for the development of osteonecrosis of the jaw following treatment with antiresorptive drugs (ARDs), but not all extraction sites develop this pathology. Therefore, we aimed to identify local radiographic predictors of Medication-Related Osteonecrosis of the Jaw (MRONJ) in panoramic images of oncologic patients undergoing tooth extraction. Based on a retrospective longitudinal cohort study design, patients were included if undergoing one or more tooth extraction, with at least one administration of ARDs, and presence of pre- and post-operative panoramic radiographs. After data collection, blinded and independent observations were performed. Eleven distinct imaging-related parameters were assessed preoperatively and five postoperatively, at each extraction site. A case–control and subgroup analysis assessing MRONJ development was performed. Significance level is set to 0.05 (5%). A total of 77 oncologic patients were selected, undergoing 218 tooth extractions, from which 63 teeth (29%) in 39 patients (51%) developed MRONJ. Results showed that patients developed significantly more MRONJ with longer ARD treatment (p = 0.057), teeth with absent and incomplete endodontic fillings with caries, widened periodontal ligament space and/or periapical lesions (p = 0.005), and sclerotic and heterogenous bone patterns (p = 0.005). In conclusion, tooth extraction sites presenting with infections and bone sclerosis are at higher risk to develop MRONJ.
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| 3164. |
- Moretto, Luisa, et al.
(författare)
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Modular type I polyketide synthase acyl carrier protein domains share a common N-terminally extended fold
- 2019
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Acyl carrier protein (ACP) domains act as interaction hubs within modular polyketide synthase (PKS) systems, employing specific protein-protein interactions to present acyl substrates to a series of enzyme active sites. Many domains from the multimodular PKS that generates the toxin mycolactone display an unusually high degree of sequence similarity, implying that the few sites which vary may do so for functional reasons. When domain boundaries based on prior studies were used to prepare two isolated ACP segments from this system for studies of their interaction properties, one fragment adopted the expected tertiary structure, but the other failed to fold, despite sharing a sequence identity of 49%. Secondary structure prediction uncovered a previously undetected helical region (H0) that precedes the canonical helix-bundle ACP topology in both cases. This article reports the NMR solution structures of two N-terminally extended mycolactone mACP constructs, mH0ACPa and mH0ACPb, both of which possess an additional alpha-helix that behaves like a rigid component of the domain. The interactions of these species with a phosphopantetheinyl transferase and a ketoreductase domain are unaffected by the presence of H0, but a shorter construct that lacks the H0 region is shown to be substantially less thermostable than mH0ACPb. Bioinformatics analysis suggests that the extended H0-ACP motif is present in 98% of type I cis-acyltransferase PKS chain-extension modules. The polypeptide linker that connects an H0-ACP motif to the preceding domain must therefore be similar to 12 residues shorter than previously thought, imposing strict limits on ACP-mediated substrate delivery within and between PKS modules.
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| 3165. |
- Morgan, Daniel, et al.
(författare)
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Perturbation-based gene regulatory network inference to unravel oncogenic mechanisms
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- The gene regulatory network (GRN) of human cells encodes mechanisms to ensure proper functioning. However, if this GRN is dysregulated, the cell may enter into a disease state such as cancer. Understanding the GRN as a system can therefore help identify novel mechanisms underlying disease, which can lead to new therapies. To deduce regulatory interactions relevant to cancer, we applied a recent computational inference framework to data from perturbation experiments in squamous carcinoma cell line A431. GRNs were inferred using several methods, and the false discovery rate was controlled by the NestBoot framework. We developed a novel approach to assess the predictiveness of inferred GRNs against validation data, despite the lack of a gold standard. The best GRN was significantly more predictive than the null model, both in cross-validated benchmarks and for an independent dataset of the same genes under a different perturbation design. The inferred GRN captures many known regulatory interactions central to cancer-relevant processes in addition to predicting many novel interactions, some of which were experimentally validated, thus providing mechanistic insights that are useful for future cancer research.
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| 3166. |
- Morgan, N, et al.
(författare)
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Convolutional neural network for automatic maxillary sinus segmentation on cone-beam computed tomographic images
- 2022
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1, s. 7523-
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Tidskriftsartikel (refereegranskat)abstract
- An accurate three-dimensional (3D) segmentation of the maxillary sinus is crucial for multiple diagnostic and treatment applications. Yet, it is challenging and time-consuming when manually performed on a cone-beam computed tomography (CBCT) dataset. Recently, convolutional neural networks (CNNs) have proven to provide excellent performance in the field of 3D image analysis. Hence, this study developed and validated a novel automated CNN-based methodology for the segmentation of maxillary sinus using CBCT images. A dataset of 264 sinuses were acquired from 2 CBCT devices and randomly divided into 3 subsets: training, validation, and testing. A 3D U-Net architecture CNN model was developed and compared to semi-automatic segmentation in terms of time, accuracy, and consistency. The average time was significantly reduced (p-value < 2.2e−16) by automatic segmentation (0.4 min) compared to semi-automatic segmentation (60.8 min). The model accurately identified the segmented region with a dice similarity co-efficient (DSC) of 98.4%. The inter-observer reliability for minor refinement of automatic segmentation showed an excellent DSC of 99.6%. The proposed CNN model provided a time-efficient, precise, and consistent automatic segmentation which could allow an accurate generation of 3D models for diagnosis and virtual treatment planning.
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| 3167. |
- Morgan, Ruth A., et al.
(författare)
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Carbonyl reductase 1 catalyzes 20 beta-reduction of glucocorticoids, modulating receptor activation and metabolic complications of obesity
- 2017
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Carbonyl Reductase 1 (CBR1) is a ubiquitously expressed cytosolic enzyme important in exogenous drug metabolism but the physiological function of which is unknown. Here, we describe a role for CBR1 in metabolism of glucocorticoids. CBR1 catalyzes the NADPH-dependent production of 20 beta-dihydrocortisol (20 beta-DHF) from cortisol. CBR1 provides the major route of cortisol metabolism in horses and is up-regulated in adipose tissue in obesity in horses, humans and mice. We demonstrate that 20 beta-DHF is a weak endogenous agonist of the human glucocorticoid receptor (GR). Pharmacological inhibition of CBR1 in diet-induced obesity in mice results in more marked glucose intolerance with evidence for enhanced hepatic GR signaling. These findings suggest that CBR1 generating 20 beta-dihydrocortisol is a novel pathway modulating GR activation and providing enzymatic protection against excessive GR activation in obesity.
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| 3168. |
- Morger, Andrea, et al.
(författare)
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Studying and mitigating the effects of data drifts on ML model performance at the example of chemical toxicity data
- 2022
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Machine learning models are widely applied to predict molecular properties or the biological activity of small molecules on a specific protein. Models can be integrated in a conformal prediction (CP) framework which adds a calibration step to estimate the confidence of the predictions. CP models present the advantage of ensuring a predefined error rate under the assumption that test and calibration set are exchangeable. In cases where the test data have drifted away from the descriptor space of the training data, or where assay setups have changed, this assumption might not be fulfilled and the models are not guaranteed to be valid. In this study, the performance of internally valid CP models when applied to either newer time-split data or to external data was evaluated. In detail, temporal data drifts were analysed based on twelve datasets from the ChEMBL database. In addition, discrepancies between models trained on publicly-available data and applied to proprietary data for the liver toxicity and MNT in vivo endpoints were investigated. In most cases, a drastic decrease in the validity of the models was observed when applied to the time-split or external (holdout) test sets. To overcome the decrease in model validity, a strategy for updating the calibration set with data more similar to the holdout set was investigated. Updating the calibration set generally improved the validity, restoring it completely to its expected value in many cases. The restored validity is the first requisite for applying the CP models with confidence. However, the increased validity comes at the cost of a decrease in model efficiency, as more predictions are identified as inconclusive. This study presents a strategy to recalibrate CP models to mitigate the effects of data drifts. Updating the calibration sets without having to retrain the model has proven to be a useful approach to restore the validity of most models.
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| 3169. |
- Moriguchi, Daisuke, et al.
(författare)
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Clinical identification of the stimulus intensity to measure temporal summation of second pain
- 2022
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Temporal summation of second pain (TSSP) has been suggested as a psychophysical index for central sensitization, one of the critical mechanisms in the chronification of pain. However, there is no gold standard for protocols to measure TSSP. The purpose was to establish the stimulus intensity for measuring TSSP. Female patients with chronic myofascial temporomandibular disorders pain (n = 16) and healthy female volunteers with no pain (n = 15) participated. Pain thresholds (PT °C) were measured, and repetitive heat stimuli at three stimulus intensities (PT °C, PT + 1 °C, PT + 2 °C) were applied. TSSP parameters were quantified as TSSP magnitude (TSm) and TSSP frequency (TSf). In healthy female volunteers, pain ratings significantly decreased at PT °C (p < 0.050), besides TSm and TSf at PT + 2 °C were significantly higher than those at PT °C (p < 0.025). In chronic pain patients, pain ratings significantly increased at PT + 1 °C and PT + 2 °C (p < 0.050). At PT + 2 °C, TSm and TSf in chronic pain patients were significantly higher than those in healthy volunteers (p < 0.050). It could be helpful to measure TSSP with the stimulus intensity adjusted individually to the patient’s pain thresholds + 2 °C for assessing central sensitization.
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| 3170. |
- Morin, Maxim, et al.
(författare)
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Skin hydration dynamics investigated by electrical impedance techniques in vivo and in vitro
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 17218-
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Tidskriftsartikel (refereegranskat)abstract
- Skin is easily accessible for transdermal drug delivery and also attractive for biomarker sampling. These applications are strongly influenced by hydration where elevated hydration generally leads to increased skin permeability. Thus, favorable transdermal delivery and extraction conditions can be easily obtained by exploiting elevated skin hydration. Here, we provide a detailed in vivo and in vitro investigation of the skin hydration dynamics using three techniques based on electrical impedance spectroscopy. Good correlation between in vivo and in vitro results is demonstrated, which implies that simple but realistic in vitro models can be used for further studies related to skin hydration (e.g., cosmetic testing). Importantly, the results show that hydration proceeds in two stages. Firstly, hydration between 5 and 10 min results in a drastic skin impedance change, which is interpreted as filling of superficial voids in skin with conducting electrolyte solution. Secondly, a subtle impedance change is observed over time, which is interpreted as leveling of the water gradient across skin leading to structural relaxation/changes of the macromolecular skin barrier components. With respect to transdermal drug delivery and extraction of biomarkers; 1 h of hydration is suggested to result in beneficial and stable conditions in terms of high skin permeability and extraction efficiency.
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