Eukaryotic cells have developed surveillance mechanisms to prevent the expression of aberrant transcripts. An early surveillance checkpoint acts at the transcription site and prevents the release of ...mRNAs that carry processing defects. The exosome subunit Rrp6 is required for this checkpoint in Saccharomyces cerevisiae, but it is not known whether Rrp6 also plays a role in mRNA surveillance in higher eukaryotes.
We have developed an in vivo system to study nuclear mRNA surveillance in Drosophila melanogaster. We have produced S2 cells that express a human beta-globin gene with mutated splice sites in intron 2 (mut beta-globin). The transcripts encoded by the mut beta-globin gene are normally spliced at intron 1 but retain intron 2. The levels of the mut beta-globin transcripts are much lower than those of wild type (wt) ss-globin mRNAs transcribed from the same promoter. We have compared the expression of the mut and wt beta-globin genes to investigate the mechanisms that down-regulate the production of defective mRNAs. Both wt and mut beta-globin transcripts are processed at the 3', but the mut beta-globin transcripts are less efficiently cleaved than the wt transcripts. Moreover, the mut beta-globin transcripts are less efficiently released from the transcription site, as shown by FISH, and this defect is restored by depletion of Rrp6 by RNAi. Furthermore, transcription of the mut beta-globin gene is significantly impaired as revealed by ChIP experiments that measure the association of the RNA polymerase II with the transcribed genes. We have also shown that the mut beta-globin gene shows reduced levels of H3K4me3.
Our results show that there are at least two surveillance responses that operate cotranscriptionally in insect cells and probably in all metazoans. One response requires Rrp6 and results in the inefficient release of defective mRNAs from the transcription site. The other response acts at the transcription level and reduces the synthesis of the defective transcripts through a mechanism that involves histone modifications.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Bullous pemphigoid (BP) is the most common autoimmune blistering disease of the skin requiring skin and serum tests for a precise diagnosis.
Objectives
We analysed the sensitivity and ...specificity of BP-relevant parameters and the value of autoantibody titres during follow-up of BP patients.
Materials & methods
In a retrospective single-centre study, we included 200 consecutive patients with BP and 400 non-BP patients, and evaluated the test results of patients’ serum and skin. In addition, we followed patients’ autoantibody titres and clinical characteristics.
Results
BP180-ELISA revealed the highest sensitivity (85.0%; specificity: 93.9%), while BP230-ELISA demonstrated the lowest sensitivity (55.5%; specificity: 92.9%). Direct and indirect immunofluorescence showed comparable results for sensitivity (77.2%/72.7%) and specificity (94.9%/93.7%). The sensitivity for skin histology was 76.3% (specificity: 81.3%). Longitudinal analysis showed significant changes in autoantibody titres.
Conclusions
BP diagnostics should include serum tests for BP autoantibodies and skin immunofluorescence. Skin histology is supportive for diagnosis. Autoantibody titres are markers for disease activity.
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EMUNI, FZAB, KILJ, MFDPS, OBVAL, SBJE, SBMB, SBNM, UKNU, UPUK, VKSCE
Objectives
This study aimed to investigate the recovery of limb function following a single intra‐articular injection of platelet‐rich plasma or hyaluronic acid in dogs with cranial cruciate ligament ...rupture treated with tibial plateau levelling osteotomy compared to dogs receiving no injection intraoperatively.
Materials and Methods
Sixty‐two dogs with cranial cruciate ligament rupture, body weights of 20 to 40 kg, and no other orthopaedic conditions were enrolled in this prospective, randomised, double‐blind, controlled study at the small animal clinic at LMU Munich. All dogs underwent tibial plateau levelling osteotomy. Based on random allocation, they received either a single intra‐articular injection of platelet‐rich plasma, hyaluronic acid or no injection intraoperatively. Gait analysis, clinical examinations, radiography of the stifle joint for osteoarthritis progression and two validated owner questionnaires were compared among groups at three timepoints postoperatively (6 weeks, 3 and 6 months). Limb function was primarily assessed by measuring the ground reaction forces.
Results
At all times postoperatively, no differences were observed among groups regarding clinical examinations, osteoarthritis score values, ground reaction forces or owner questionnaires. All dogs showed significant improvement in limb function clinically, in all ground reaction forces and in the validated questionnaires. Osteoarthritis progressed minimally during rechecks in all dogs regardless of the additional injection or not.
Clinical Significance
All dogs treated with tibial plateau levelling osteotomy for cranial cruciate ligament rupture showed improvements in limb function. No additive effect on faster recovery was demonstrated with the additional intra‐articular injection of platelet‐rich plasma or hyaluronic acid. Addition of platelet‐rich plasma/hyaluronic acid injections during tibial plateau levelling osteotomy is unnecessary considering the lack of benefit observed up to 6 months postoperatively.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
This essay argues that teaching Landon’s poems in the context of their original volume publication allows for greater understanding of the ways in which all Romantic-era poets deploy multiple voices ...in their collected works. It focuses upon strategies for teaching Landon’s
(1829) but offers a model for student engagement with Romantic poetry more generally.
Expansion of a single repetitive DNA sequence, termed a tandem repeat (TR), is known to cause more than 50 diseases
. However, repeat expansions are often not explored beyond neurological and ...neurodegenerative disorders. In some cancers, mutations accumulate in short tracts of TRs, a phenomenon termed microsatellite instability; however, larger repeat expansions have not been systematically analysed in cancer
. Here we identified TR expansions in 2,622 cancer genomes spanning 29 cancer types. In seven cancer types, we found 160 recurrent repeat expansions (rREs), most of which (155/160) were subtype specific. We found that rREs were non-uniformly distributed in the genome with enrichment near candidate cis-regulatory elements, suggesting a potential role in gene regulation. One rRE, a GAAA-repeat expansion, located near a regulatory element in the first intron of UGT2B7 was detected in 34% of renal cell carcinoma samples and was validated by long-read DNA sequencing. Moreover, in preliminary experiments, treating cells that harbour this rRE with a GAAA-targeting molecule led to a dose-dependent decrease in cell proliferation. Overall, our results suggest that rREs may be an important but unexplored source of genetic variation in human cancer, and we provide a comprehensive catalogue for further study.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Electro-optical imaging sensors are widely distributed and used for many different tasks. Due to technical improvements, their pixel size has been steadily decreasing, resulting in a reduced ...saturation capacity. As a consequence, this progress makes them susceptible to intense point light sources. Developments in laser technology have led to very compact and powerful laser sources of any wavelength in the visible and near infrared spectral region, offered as laser pointers. The manifold of wavelengths makes it difficult to encounter sensor saturation over the complete operating waveband by conventional measures like absorption or interference filters. We present a concept for electro-optical sensors to suppress overexposure in the visible spectral region. The key element of the concept is a spatial light modulator in combination with wavelength multiplexing. This approach allows spectral filtering within a localized area in the field of view of the sensor. The system offers the possibility of automatic reduction of overexposure by monochromatic laser radiation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Introduction: Cultural factors were shown to be particularly relevant for the development and expression of posttraumatic stress. Recently, the concept of cultural scripts of trauma has been ...introduced, which proposes that trauma sequelae elements may be sequentially linked and specifically associated with cultural factors. Furthermore, a cascade model is proposed, including trauma exposure, demographic characteristics, cultural affiliation, and trauma-related value orientations as influencing factors of posttraumatic development. The purpose of this Network Project is to investigate cultural psychological factors that contribute to the expression of posttraumatic stress.Methods: The present Network Project implements a mixed methods approach and will be conducted in 5 different study sites, including Switzerland, Israel, Georgia, China, and East Africa. In sub-study I, the cultural scripts of traumatic stress inventories (CSTIs) will be developed. These scales provide a pool of trauma sequelae elements for each cultural group. For this purpose, focus groups with trauma survivors and trauma experts will be conducted and analysed using qualitative research methods. Sub-study II implements a validation analysis of the CSTIs and the empirical investigation of a cultural cascade model. This quantitative approach will include a larger sample of individuals who experienced traumatic life events.Discussion: This contribution is timely and enriches the knowledge of trauma and culture. Future publications of this Network Project will address trauma sequelae from a cultural perspective and provide diagnostic and psychotherapeutic implications.Introduction: Cultural factors were shown to be particularly relevant for the development and expression of posttraumatic stress. Recently, the concept of cultural scripts of trauma has been introduced, which proposes that trauma sequelae elements may be sequentially linked and specifically associated with cultural factors. Furthermore, a cascade model is proposed, including trauma exposure, demographic characteristics, cultural affiliation, and trauma-related value orientations as influencing factors of posttraumatic development. The purpose of this Network Project is to investigate cultural psychological factors that contribute to the expression of posttraumatic stress.Methods: The present Network Project implements a mixed methods approach and will be conducted in 5 different study sites, including Switzerland, Israel, Georgia, China, and East Africa. In sub-study I, the cultural scripts of traumatic stress inventories (CSTIs) will be developed. These scales provide a pool of trauma sequelae elements for each cultural group. For this purpose, focus groups with trauma survivors and trauma experts will be conducted and analysed using qualitative research methods. Sub-study II implements a validation analysis of the CSTIs and the empirical investigation of a cultural cascade model. This quantitative approach will include a larger sample of individuals who experienced traumatic life events.Discussion: This contribution is timely and enriches the knowledge of trauma and culture. Future publications of this Network Project will address trauma sequelae from a cultural perspective and provide diagnostic and psychotherapeutic implications.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Cold spray is an additive manufacturing and coating process in which powder particles are accelerated to supersonic speeds without melting them and then deposit on a surface to form a layer of a ...coating. Process parameters and materials affect the characteristics of manufactured parts and therefore must be chosen with care. Machine learning (ML) techniques have been specifically applied in additive manufacturing for tasks such as predicting and characterizing porosity. Machine learning algorithms can learn how a variation in the input spray parameters affects annotated output data, such as experimentally measured part properties. In this work, a dataset was developed from experiments reported in published academic papers, to train ML algorithms for the porosity prediction of cold spray manufactured parts. Data cleaning steps, such as null value replacement and categorical feature handling, were applied to prepare the dataset for the training of different ML models. The dataset was split into training and testing portions, and floating feature selection and hyperparameter optimization were performed using parts of the training set. A final evaluation of all trained models, using the test portion of the dataset, showed that a prediction accuracy with an average deviation of 0-2% porosity of the predicted values compared to the true values can be achieved.
Graphical Abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose: To evaluate the efficacy and toxicity of erlotinib plus bevacizumab in patients with metastatic breast cancer (MBC), targeting
the epidermal growth factor receptor (EGFR/HER1) and the ...vascular endothelial growth factor (VEGF) pathway.
Experimental Design: Thirty-eight patients with MBC were enrolled and treated at two institutions with erlotinib, a small molecule EGFR tyrosine
kinase inhibitor (150 mg p.o. daily) plus bevacizumab, an anti-VEGF antibody (15 mg/kg i.v. every 3 weeks). Patients had one
to two prior chemotherapy regimens for metastatic disease. The primary end point was response rate by Response Evaluation
Criteria in Solid Tumors criteria using a Simon 2-stage design. Secondary end points included toxicity, time to progression,
response duration, and stabilization of disease of ≥26 weeks. Correlative studies were done on tumor tissue, including EGFR
expression and mutation analysis.
Results: One patient achieved a partial response for 52+ months. Fifteen patients had stable disease at first evaluation at 9 weeks;
4 of these patients had stable disease beyond 26 weeks. Median time to progression was 11 weeks (95% confidence interval,
8-18 weeks). Diarrhea of any grade was observed in 84% of patients (grade 3 in 3%); 76% experienced grade 1 or 2 skin rash,
and 18% developed hypertension (grade 3 in 11%). The level of EGFR expression was not predictive of response to therapy.
Conclusions: The combination of erlotinib and bevacizumab was well-tolerated but had limited activity in unselected patients with previously
treated MBC. Biomarkers are needed to identify those MBC patients likely to respond to anti-EGFR/HER1 plus anti-VEGF therapy.
T helper (Th) cells producing interleukin (IL)-17, IL-22, and tumor necrosis factor (TNF) form the key T cell population driving psoriasis pathogenesis. They orchestrate the inflammation in the skin ...that results in the proliferation of keratinocytes and endothelial cells. Besides Th17 cells, other immune cells that are capable of producing IL-17-associated cytokines participate in psoriatic inflammation. Recent advances in psoriasis research improved our understanding of the cellular and molecular players that are involved in Th17 pathology and inflammatory pathways in the skin. The inflammation-driving actions of TNF in psoriasis are already well known and antibodies against TNF are successful in the treatment of Th17-mediated psoriatic skin inflammation. A further key cytokine with potent IL-17-/IL-22-promoting properties is IL-23. Therapeutics directly neutralizing IL-23 or IL-17 itself are now extending the therapeutic spectrum of antipsoriatic agents and further developments are on the way. The enormous progress in psoriasis research allows us to control this Th17-mediated inflammatory skin disease in many patients.
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