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- Casar Borota, Olivera, et al.
(författare)
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Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations
- 2021
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Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 106:4, s. 1183-1194
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Tidskriftsartikel (refereegranskat)abstract
- Context: Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors. Objective: To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs. Design: We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored. Results: Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs. Conclusion: ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors.
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- Dominoni, Davide M., et al.
(författare)
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Why conservation biology can benefit from sensory ecology
- 2020
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Ingår i: Nature Ecology & Evolution. - : Springer Science and Business Media LLC. - 2397-334X. ; 4:4, s. 502-511
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Tidskriftsartikel (refereegranskat)abstract
- Anthropogenic sensory pollutants, such as noise, light and chemicals, are affecting biodiversity. This Perspective uses an understanding of animal sensory ecology to explore how these impacts can be mitigated. Global expansion of human activities is associated with the introduction of novel stimuli, such as anthropogenic noise, artificial lights and chemical agents. Progress in documenting the ecological effects of sensory pollutants is weakened by sparse knowledge of the mechanisms underlying these effects. This severely limits our capacity to devise mitigation measures. Here, we integrate knowledge of animal sensory ecology, physiology and life history to articulate three perceptual mechanisms-masking, distracting and misleading-that clearly explain how and why anthropogenic sensory pollutants impact organisms. We then link these three mechanisms to ecological consequences and discuss their implications for conservation. We argue that this framework can reveal the presence of 'sensory danger zones', hotspots of conservation concern where sensory pollutants overlap in space and time with an organism's activity, and foster development of strategic interventions to mitigate the impact of sensory pollutants. Future research that applies this framework will provide critical insight to preserve the natural sensory world.
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- Leenhardt, R., et al.
(författare)
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A guide for assessing the clinical relevance of findings in small bowel capsule endoscopy : analysis of 8064 answers of international experts to an illustrated script questionnaire
- 2021
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Ingår i: Clinics and Research in Hepatology and Gastroenterology. - : Elsevier BV. - 2210-7401. ; 45:6
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Tidskriftsartikel (refereegranskat)abstract
- Background and aim: Although recommended, the P-score used for assessing the pertinence / relevance of findings seen in small bowel (SB) capsule endoscopy (CE) is based on a low level of knowledge. The aim of this study was to evaluate the clinical relevance of the most frequent SBCE findings through an illustrated script questionnaire. Materials and Methods: Sixteen types of SBCE findings were illustrated four times each in three different settings (occult and overt obscure gastrointestinal bleeding and suspected Crohn's disease), and with a variable number (n = 1/n = 2–5/n ≥ 6), thus providing a questionnaire with 192 scenarios and 576 illustrated questions. Fifteen international experts were asked to rate the finding's relevance for each question as very unlikely (−2) / unlikely (−1) / doubtful (0) / likely (+1) / very likely (+2). The median score (≤−0.75, between -0.75 and 0.75, or ≥0.75) obtained for each scenario determined a low (P0), intermediate (P1) or high (P2) relevance, respectively. Results: 8064 answers were analyzed. Participation and completion rates were 93% and 100%, respectively. In overt or occult OGIB, resultant P2 findings were 'typical angiectasia', 'deep ulceration', 'stenosis', and'blood', whatever their numbers, and 'superficial ulcerations' when multiple. While in suspected CD, consensus P2 lesions were 'deep ulceration' and 'stenosis' whatever their numbers, and 'aphthoid erosions' and 'superficial ulcerations' when multiple. Conclusion: This study establishes a guide for the evaluation of relevance of SBCE findings. It represents a step forward for SB-CE interpretation and is intended to be used as a tool for teaching and academic research.
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- Tokarew, JM, et al.
(författare)
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Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites
- 2021
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Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 141:5, s. 725-754
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Tidskriftsartikel (refereegranskat)abstract
- The mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions and that these are reflected in its posttranslational modifications. We found that in post mortem human brain, including in the Substantia nigra, parkin is largely insoluble after age 40 years; this transition is linked to its oxidation, such as at residues Cys95 and Cys253. In mice, oxidative stress induces posttranslational modifications of parkin cysteines that lower its solubility in vivo. Similarly, oxidation of recombinant parkin by hydrogen peroxide (H2O2) promotes its insolubility and aggregate formation, and in exchange leads to the reduction of H2O2. This thiol-based redox activity is diminished by parkin point mutants, e.g., p.C431F and p.G328E. In prkn-null mice, H2O2 levels are increased under oxidative stress conditions, such as acutely by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxin exposure or chronically due to a second, genetic hit; H2O2 levels are also significantly increased in parkin-deficient human brain. In dopamine toxicity studies, wild-type parkin, but not disease-linked mutants, protects human dopaminergic cells, in part through lowering H2O2. Parkin also neutralizes reactive, electrophilic dopamine metabolites via adduct formation, which occurs foremost at the primate-specific residue Cys95. Further, wild-type but not p.C95A-mutant parkin augments melanin formation in vitro. By probing sections of adult, human midbrain from control individuals with epitope-mapped, monoclonal antibodies, we found specific and robust parkin reactivity that co-localizes with neuromelanin pigment, frequently within LAMP-3/CD63+ lysosomes. We conclude that oxidative modifications of parkin cysteines are associated with protective outcomes, which include the reduction of H2O2, conjugation of reactive dopamine metabolites, sequestration of radicals within insoluble aggregates, and increased melanin formation. The loss of these complementary redox effects may augment oxidative stress during ageing in dopamine-producing cells of mutant PRKN allele carriers, thereby enhancing the risk of Parkinson’s-linked neurodegeneration.
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- Al Mahmeed, W, et al.
(författare)
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Promoting a Syndemic Approach for Cardiometabolic Disease Management During COVID-19: The CAPISCO International Expert Panel
- 2021
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Ingår i: Frontiers in cardiovascular medicine. - : Frontiers Media SA. - 2297-055X. ; 8, s. 787761-
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Tidskriftsartikel (refereegranskat)abstract
- Efforts in the fight against COVID-19 are achieving success in many parts of the world, although progress remains slow in other regions. We believe that a syndemic approach needs to be adopted to address this pandemic given the strong apparent interplay between COVID-19, its related complications, and the socio-structural environment. We have assembled an international, multidisciplinary group of researchers and clinical practitioners to promote a novel syndemic approach to COVID-19: the CArdiometabolic Panel of International experts on Syndemic COvid-19 (CAPISCO). This geographically diverse group aims to facilitate collaborative-networking and scientific exchanges between researchers and clinicians facing a multitude of challenges on different continents during the pandemic. In the present article we present our “manifesto”, with the intent to provide evidence-based guidance to the global medical and scientific community for better management of patients both during and after the current pandemic.
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- Gialluisi, A, et al.
(författare)
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Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia
- 2021
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 26:7, s. 3004-3017
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Tidskriftsartikel (refereegranskat)abstract
- Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40–60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p < 2.8 × 10−6) enrichment of associations at the gene level, forLOC388780(20p13; uncharacterized gene), and forVEPH1(3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20–25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (atpT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase;p = 8 × 10−13), bipolar disorder (1.53[1.44; 1.63];p = 1 × 10−43), schizophrenia (1.36[1.28; 1.45];p = 4 × 10−22), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30];p = 3 × 10−12), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96];p = 5 × 10−4), educational attainment (0.86[0.82; 0.91];p = 2 × 10−7), and intelligence (0.72[0.68; 0.76];p = 9 × 10−29). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.
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| 10. |
- Hollandi, R., et al.
(författare)
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nucleAIzer : A Parameter-free Deep Learning Framework for Nucleus Segmentation Using Image Style Transfer
- 2020
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Ingår i: Cell Systems. - : Elsevier BV. - 2405-4712. ; 10:5, s. 453-458.e6
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Tidskriftsartikel (refereegranskat)abstract
- Single-cell segmentation is typically a crucial task of image-based cellular analysis. We present nucleAIzer, a deep-learning approach aiming toward a truly general method for localizing 2D cell nuclei across a diverse range of assays and light microscopy modalities. We outperform the 739 methods submitted to the 2018 Data Science Bowl on images representing a variety of realistic conditions, some of which were not represented in the training data. The key to our approach is that during training nucleAIzer automatically adapts its nucleus-style model to unseen and unlabeled data using image style transfer to automatically generate augmented training samples. This allows the model to recognize nuclei in new and different experiments efficiently without requiring expert annotations, making deep learning for nucleus segmentation fairly simple and labor free for most biological light microscopy experiments. It can also be used online, integrated into CellProfiler and freely downloaded at www.nucleaizer.org. A record of this paper's transparent peer review process is included in the Supplemental Information. Microscopy image analysis of single cells can be challenging but also eased and improved. We developed a deep learning method to segment cell nuclei. Our strategy is adapting to unexpected circumstances automatically by synthesizing artificial microscopy images in such a domain as training samples.
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