| 1. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 2. |
- Cooper-Kuhn, Christiana M, 1971, et al.
(författare)
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Decreased neurogenesis after cholinergic forebrain lesion in the adult rat.
- 2004
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Ingår i: Journal of neuroscience research. - : Wiley. - 0360-4012 .- 1097-4547. ; 77:2, s. 155-65
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Tidskriftsartikel (refereegranskat)abstract
- Adult neurogenesis has been shown to be regulated by a multitude of extracellular cues, including hormones, growth factors, and neurotransmitters. The cholinergic system of the basal forebrain is one of the key transmitter systems for learning and memory. Because adult neurogenesis has been implicated in cognitive performance, the present work aims at defining the role of cholinergic input for adult neurogenesis by using an immunotoxic lesion approach. The immunotoxin 192IgG-saporin was infused into the lateral ventricle of adult rats to selectively lesion cholinergic neurons of the cholinergic basal forebrain (CBF), which project to the two main regions of adult neurogenesis: the dentate gyrus and the olfactory bulb. Five weeks after lesioning, neurogenesis, defined by the number of cells colocalized for bromodeoxyuridine (BrdU) and the neuronal nuclei marker NeuN, declined significantly in the granule cell layers of the dentate gyrus and olfactory bulb. Furthermore, immunotoxic lesions to the CBF led to increased numbers of apoptotic cells specifically in the subgranular zone, the progenitor region of the dentate gyrus, and within the periglomerular layer of the olfactory bulb. We propose that the cholinergic system plays a survival-promoting role for neuronal progenitors and immature neurons within regions of adult neurogenesis, similar to effects observed previously during brain development. As a working hypothesis, neuronal loss within the CBF system leads not only to cognitive deficits but may also alter on a cellular level the functionality of the dentate gyrus, which in turn may aggravate cognitive deficits.
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| 3. |
- Couillard-Despres, Sebastien, et al.
(författare)
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Doublecortin expression levels in adult brain reflect neurogenesis.
- 2005
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Ingår i: The European journal of neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 21:1, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- Progress in the field of neurogenesis is currently limited by the lack of tools enabling fast and quantitative analysis of neurogenesis in the adult brain. Doublecortin (DCX) has recently been used as a marker for neurogenesis. However, it was not clear whether DCX could be used to assess modulations occurring in the rate of neurogenesis in the adult mammalian central nervous system following lesioning or stimulatory factors. Using two paradigms increasing neurogenesis levels (physical activity and epileptic seizures), we demonstrate that quantification of DCX-expressing cells allows for an accurate measurement of modulations in the rate of adult neurogenesis. Importantly, we excluded induction of DCX expression during physiological or reactive gliogenesis and excluded also DCX re-expression during regenerative axonal growth. Our data validate DCX as a reliable and specific marker that reflects levels of adult neurogenesis and its modulation. We demonstrate that DCX is a valuable alternative to techniques currently used to measure the levels of neurogenesis. Importantly, in contrast to conventional techniques, analysis of neurogenesis through the detection of DCX does not require in vivo labelling of proliferating cells, thereby opening new avenues for the study of human neurogenesis under normal and pathological conditions.
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| 4. |
- Draganski, Bogdan, et al.
(författare)
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Temporal and spatial dynamics of brain structure changes during extensive learning.
- 2006
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Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 26:23, s. 6314-7
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Tidskriftsartikel (refereegranskat)abstract
- The current view regarding human long-term memory as an active process of encoding and retrieval includes a highly specific learning-induced functional plasticity in a network of multiple memory systems. Voxel-based morphometry was used to detect possible structural brain changes associated with learning. Magnetic resonance images were obtained at three different time points while medical students learned for their medical examination. During the learning period, the gray matter increased significantly in the posterior and lateral parietal cortex bilaterally. These structural changes did not change significantly toward the third scan during the semester break 3 months after the exam. The posterior hippocampus showed a different pattern over time: the initial increase in gray matter during the learning period was even more pronounced toward the third time point. These results indicate that the acquisition of a great amount of highly abstract information may be related to a particular pattern of structural gray matter changes in particular brain areas.
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| 5. |
- Haenssle, H A, et al.
(författare)
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Man against machine: diagnostic performance of a deep learning convolutional neural network for dermoscopic melanoma recognition in comparison to 58 dermatologists.
- 2018
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Ingår i: Annals of Oncology. - : Elsevier BV. - 1569-8041 .- 0923-7534. ; 29:8, s. 1836-1842
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Tidskriftsartikel (refereegranskat)abstract
- Deep learning convolutional neural networks (CNN) may facilitate melanoma detection, but data comparing a CNN's diagnostic performance to larger groups of dermatologists are lacking.Google's Inception v4 CNN architecture was trained and validated using dermoscopic images and corresponding diagnoses. In a comparative cross-sectional reader study a 100-image test-set was used (level-I: dermoscopy only; level-II: dermoscopy plus clinical information and images). Main outcome measures were sensitivity, specificity and area under the curve (AUC) of receiver operating characteristics (ROC) for diagnostic classification (dichotomous) of lesions by the CNN versus an international group of 58 dermatologists during level-I or -II of the reader study. Secondary end points included the dermatologists' diagnostic performance in their management decisions and differences in the diagnostic performance of dermatologists during level-I and -II of the reader study. Additionally, the CNN's performance was compared with the top-five algorithms of the 2016 International Symposium on Biomedical Imaging (ISBI) challenge.In level-I dermatologists achieved a mean (±standard deviation) sensitivity and specificity for lesion classification of 86.6% (±9.3%) and 71.3% (±11.2%), respectively. More clinical information (level-II) improved the sensitivity to 88.9% (±9.6%, P = 0.19) and specificity to 75.7% (±11.7%, P < 0.05). The CNN ROC curve revealed a higher specificity of 82.5% when compared with dermatologists in level-I (71.3%, P < 0.01) and level-II (75.7%, P < 0.01) at their sensitivities of 86.6% and 88.9%, respectively. The CNN ROC AUC was greater than the mean ROC area of dermatologists (0.86 versus 0.79, P < 0.01). The CNN scored results close to the top three algorithms of the ISBI 2016 challenge.For the first time we compared a CNN's diagnostic performance with a large international group of 58 dermatologists, including 30 experts. Most dermatologists were outperformed by the CNN. Irrespective of any physicians' experience, they may benefit from assistance by a CNN's image classification.This study was registered at the German Clinical Trial Register (DRKS-Study-ID: DRKS00013570; https://www.drks.de/drks_web/).
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| 6. |
- Heid, Iris M, et al.
(författare)
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Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960
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Tidskriftsartikel (refereegranskat)abstract
- Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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| 7. |
- Kuhn, Hans-Georg, 1961, et al.
(författare)
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Increased generation of granule cells in adult Bcl-2-overexpressing mice: a role for cell death during continued hippocampal neurogenesis
- 2005
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 22:8, s. 1907-1915
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Tidskriftsartikel (refereegranskat)abstract
- Programmed cell death is an important mechanism during brain development in order to control neuronal cell numbers and to correctly form neuronal circuitries. Programmed cell death is also present in neurogenic regions of the adult brain, and a significant portion of the adult-born cells is eliminated during the first months of maturation. We here address the question whether overexpression of the anti-apoptotic protein Bcl-2 would improve the survival of neural progenitor cells and, as a consequence, increase neurogenesis in the adult hippocampus. Transgenic animals, which express human Bcl-2 under the neuron-specific enolase promoter (NSE-huBcl-2), show a significant reduction of apoptotic cells in the hippocampal granule cell layer to about half of the wild-type level. These apoptotic cells are almost exclusively found in the zone of hippocampal progenitor activity and frequently co-label with the neuronal progenitor marker doublecortin (DCX). The rate of adult neurogenesis is doubled in the dentate gyrus of Bcl-2-overexpressing mice as demonstrated by quantification of progenitor cells using DCX and new neurons using bromodeoxyuridine (BrdU)/neuronal nuclei antigen (NeuN) double-labelling. The effect of Bcl-2 is limited to the late phase of progenitor maturation, as proliferation and early-phase progenitor cells were not affected. The increased level of neurogenesis leads to a significantly higher total number of granule cells in the dentate gyrus. These results underline the importance of developmental cell death during neurogenesis in the adult brain.
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| 8. |
- Kuhrmann, Marco, et al.
(författare)
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What Makes Agile Software Development Agile
- 2022
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Ingår i: IEEE Transactions on Software Engineering. - 0098-5589 .- 1939-3520. ; 48:9, s. 3523-3539
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Tidskriftsartikel (refereegranskat)abstract
- Together with many success stories, promises such as the increase in production speed and the improvement in stakeholders' collaboration have contributed to making agile a transformation in the software industry in which many companies want to take part. However, driven either by a natural and expected evolution or by contextual factors that challenge the adoption of agile methods as prescribed by their creator(s), software processes in practice mutate into hybrids over time. Are these still agile In this article, we investigate the question: what makes a software development method agile We present an empirical study grounded in a large-scale international survey that aims to identify software development methods and practices that improve or tame agility. Based on 556 data points, we analyze the perceived degree of agility in the implementation of standard project disciplines and its relation to used development methods and practices. Our findings suggest that only a small number of participants operate their projects in a purely traditional or agile manner (under 15%). That said, most project disciplines and most practices show a clear trend towards increasing degrees of agility. Compared to the methods used to develop software, the selection of practices has a stronger effect on the degree of agility of a given discipline. Finally, there are no methods or practices that explicitly guarantee or prevent agility. We conclude that agility cannot be defined solely at the process level. Additional factors need to be taken into account when trying to implement or improve agility in a software company. Finally, we discuss the field of software process-related research in the light of our findings and present a roadmap for future research.
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| 9. |
- Ried, Janina S., et al.
(författare)
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A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
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| 10. |
- Schänzer, Anne, et al.
(författare)
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Direct stimulation of adult neural stem cells in vitro and neurogenesis in vivo by vascular endothelial growth factor.
- 2004
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Ingår i: Brain pathology (Zurich, Switzerland). - 1015-6305. ; 14:3, s. 237-48
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Tidskriftsartikel (refereegranskat)abstract
- Hypoxia as well as global and focal ischemia are strong activators of neurogenesis in the adult mammalian central nervous system. Here we show that the hypoxia-inducible vascular endothelial growth factor (VEGF) and its receptor VEGFR-2/Flk-1 are expressed in clonally-derived adult rat neural stem cells in vitro. VEGF stimulated the expansion of neural stem cells whereas blockade of VEGFR-2/Flk-1-kinase activity reduced neural stem cell expansion. VEGF was also infused into the lateral ventricle to study changes in neurogenesis in the ventricle wall, olfactory bulb and hippocampus. Using a low dose (2.4 ng/d) to avoid endothelial proliferation and changes in vascular permeability, VEGF stimulated adult neurogenesis in vivo. After VEGF infusion, we observed reduced apoptosis but unaltered proliferation suggesting a survival promoting effect of VEGF in neural progenitor cells. Strong expression of VEGFR-2/Flk-1 was detected in the ventricle wall adjacent to the choroid plexus, a site of significant VEGF production, which suggests a paracrine function of endogenous VEGF on neural stem cells in vivo. We propose that VEGF acts as a trophic factor for neural stem cells in vitro and for sustained neurogenesis in the adult nervous system.These findings may have implications for the pathogenesis and therapy of neurodegenerative diseases.
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