| 1. |
- Breznau, Nate, et al.
(författare)
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Observing many researchers using the same data and hypothesis reveals a hidden universe of uncertainty
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:44
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Tidskriftsartikel (refereegranskat)abstract
- This study explores how researchers analytical choices affect the reliability of scientific findings. Most discussions of reliability problems in science focus on systematic biases. We broaden the lens to emphasize the idiosyncrasy of conscious and unconscious decisions that researchers make during data analysis. We coordinated 161 researchers in 73 research teams and observed their research decisions as they used the same data to independently test the same prominent social science hypothesis: that greater immigration reduces support for social policies among the public. In this typical case of social science research, research teams reported both widely diverging numerical findings and substantive conclusions despite identical start conditions. Researchers expertise, prior beliefs, and expectations barely predict the wide variation in research outcomes. More than 95% of the total variance in numerical results remains unexplained even after qualitative coding of all identifiable decisions in each teams workflow. This reveals a universe of uncertainty that remains hidden when considering a single study in isolation. The idiosyncratic nature of how researchers results and conclusions varied is a previously underappreciated explanation for why many scientific hypotheses remain contested. These results call for greater epistemic humility and clarity in reporting scientific findings.
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| 2. |
- Zhang, Tongwu, et al.
(författare)
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Cell-type-specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes
- 2018
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 28:11, s. 1621-1635
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Tidskriftsartikel (refereegranskat)abstract
- Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type-specific regulatory landscape of human melanocytes, which give rise to melanoma but account for <5% of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335 cis-eQTL SNPs prior to linkage disequilibrium (LD) pruning and 4997 eGenes (FDR < 0.05). Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissue types, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were unique to melanocytes compared to those of GTEx skin tissues or TCGA melanomas. The melanocyte data set also identified trans-eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through cis-regulation of IRF4. Melanocyte eQTLs are enriched in cis-regulatory signatures found in melanocytes as well as in melanoma-associated variants identified through genome-wide association studies. Melanocyte eQTLs also colocalized with melanoma GWAS variants in five known loci. Finally, a transcriptome-wide association study using melanocyte eQTLs uncovered four novel susceptibility loci, where imputed expression levels of five genes (ZFP90, HEBP1, MSC, CBWD1, and RP11-383H13.1) were associated with melanoma at genome-wide significant P-values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings, and present a robust database for genomic research of melanoma risk and melanocyte biology.
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| 3. |
- Steele, K M, et al.
(författare)
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Characteristics associated with improved knee extension after strength training for individuals with cerebral palsy and crouch gait.
- 2012
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Ingår i: Journal of pediatric rehabilitation medicine. - 1875-8894. ; 5:2, s. 99-106
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Tidskriftsartikel (refereegranskat)abstract
- Muscle weakness may contribute to crouch gait in individuals with cerebral palsy, and some individuals participate in strength training programs to improve crouch gait. Unfortunately, improvements in muscle strength and gait are inconsistent after completing strength training programs. The purpose of this study was to examine changes in knee extensor strength and knee extension angle during walking after strength training in individuals with cerebral palsy who walk in crouch gait and to determine subject characteristics associated with these changes. A literature review was performed of studies published since January 2000 that included strength training, three-dimensional motion analysis, and knee extensor strength measurements for individuals with cerebral palsy. Three studies met these criteria and individual subject data was obtained from the authors for thirty crouch gait subjects. Univariate regression analyses were performed to determine which of ten physical examination and motor performance variables were associated with changes in strength and knee extension during gait. Change in knee extensor strength ranged from a 25% decrease to a 215% increase, and change in minimum knee flexion angle during gait ranged from an improvement of 9° more knee extension to 15° more knee flexion. Individuals without hamstring spasticity had greater improvement in knee extension after strength training. Hamstring spasticity was associated with an undesired increase in knee flexion during walking. Subject-specific factors such as hamstring spasticity may be useful for predicting which subjects will benefit from strength training to improve crouch gait.
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| 4. |
- Yang, S. H., et al.
(författare)
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Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation
- 2005
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Ingår i: Proc Natl Acad Sci U S A. ; 102:29, s. 10291-10296
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Tidskriftsartikel (refereegranskat)abstract
- Hutchinson-Gilford progeria syndrome (HGPS), a progeroid syndrome in children, is caused by mutations in LMNA (the gene for prelamin A and lamin C) that result in the deletion of 50 aa within prelamin A. In normal cells, prelamin A is a "CAAX protein" that is farnesylated and then processed further to generate mature lamin A, which is a structural protein of the nuclear lamina. The mutant prelamin A in HGPS, which is commonly called progerin, retains the CAAX motif that triggers farnesylation, but the 50-aa deletion prevents the subsequent processing to mature lamin A. The presence of progerin adversely affects the integrity of the nuclear lamina, resulting in misshapen nuclei and nuclear blebs. We hypothesized that interfering with protein farnesylation would block the targeting of progerin to the nuclear envelope, and we further hypothesized that the mislocalization of progerin away from the nuclear envelope would improve the nuclear blebbing phenotype. To approach this hypothesis, we created a gene-targeted mouse model of HGPS, generated genetically identical primary mouse embryonic fibroblasts, and we then examined the effect of a farnesyltransferase inhibitor on nuclear blebbing. The farnesyltransferase inhibitor mislocalized progerin away from the nuclear envelope to the nucleoplasm, as determined by immunofluoresence microscopy, and resulted in a striking improvement in nuclear blebbing (P < 0.0001 by chi(2) statistic). These studies suggest a possible treatment strategy for HGPS.
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| 5. |
- Aquino, Caroline D., et al.
(författare)
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Influence of test methodology on the characterization of the parallel-to-grain timber embedment strength and foundation modulus of dowels
- 2024
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Ingår i: Wood Material Science & Engineering. - : Taylor & Francis Group. - 1748-0272 .- 1748-0280.
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Tidskriftsartikel (refereegranskat)abstract
- A reliable determination of the embedment strength and foundation modulus of timber elements is critical for the design and safety assessment of joints in timber structures. However, the existence of various test configurations for characterising the embedding properties of large diameter steel fasteners in timber elements poses challenges in directly comparing and utilising available test data. This paper aims to provide an insight into the influence of embedment property test methods, comparing experimental results from different test setups within the guidelines of the EN 383 and ASTM D 5764-97a standards for European softwood species, Scots pine wood (Pinus sylvestris) and Norway spruce (Picea abies). In addition to the test guidelines, the thickness of the specimen and the application of the load was evaluated within the protocols. A comprehensive statistical analysis was performed to identify statistically significant differences between the groups evaluated. The results of the analysis revealed disagreement between the standards in the evaluation of the strength of the embedding, highlighting the potential bias inserted by the experimental setup and protocol. Furthermore, it was proven that the thickness of the specimens influences both the embedding strength and the foundation modulus of the wood species tested. Finally, no distinctions were observed between tensile and compressive loading within the guidelines of the EN 383 standard.
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| 6. |
- Bacchin, Taneha K., et al.
(författare)
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A multi-scale approach in the planning and design of water sensitive environments
- 2013
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Ingår i: Proceedings 8th International Conference NOVATECH Lyon.
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Konferensbidrag (refereegranskat)abstract
- A spatial analytical framework to support landscape planning and urban design practices was introduced in this study aiming to integrate different scales of analysis and their effect when retrofitting Water Sensitive Urban Design (WSUD) in the existing urban environment. The multi-scale analyses are performed using a geographic information system (GIS) platform to capture landscape patterns (spatial structure and composition) and processes (e.g. water cycle). The macro-scale analysis at the urban catchment level allows the development of planning strategies and performance objectives for the urbanized landscape, whilst the meso-scale, comprising the ecological (green) corridors, connects core areas conveying surface flows across the sub-catchments. At the neighbourhood scale, urban form parameters measured the territorial depth (permeability) between public and private land and the suitability of each site to retrofit Water Sensitive Urban Design. The feasibility to improve or extend the existing green-blue landscape matrix is assessed, and its implications discussed, by using a sequence of landscape metrics, land suitability and network analysis techniques. The study focused on modelling opportunities for the introduction of landscape features designed to improve surface stormwater management and, at the same time, provide multiple ecosystem services.
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| 7. |
- Berghauser Pont, Meta, 1972, et al.
(författare)
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Quantitative comparison of cities : Distribution of street and building types based on density and centrality measures
- 2017
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Ingår i: Proceedings - 11th International Space Syntax Symposium, SSS 2017. - : Instituto Superior Tecnico, Departamento de Engenharia Civil, Arquitetura e Georrecursos. - 9789729899447 ; 2, s. 44.1-44.18
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Konferensbidrag (refereegranskat)abstract
- It has been argued that different urban configurations-planned vs. organic, treelike vs. grid like-perform differently when it comes to the intensity and distribution of pedestrian flows, built density and land uses. However, definitions of urban configurations are often rather abstract, ill-defined and at worse end in fixed stereotypes hiding underlying spatial complexity. Recent publications define morphological typologies based on quantitative variables (e.g. Barthelemy, 2015; Serra, 2013a; Gil et al., 2012; Berghauser Pont and Haupt, 2010) and solve some of these shortcomings. These approaches contribute to the discussion of types in two ways: firstly, they allow for the definition of types based on multiple variables in a precise and repeattable manner, enabling the study of large samples and the comparison between both cities and regions; secondly, they frame design choices in terms of types without being fixed and so open up for design explorations where the relation between the variables can be challenged to propose new types. This paper explores the typologies defined by Serra (2013a) and Berghauser Pont and Haupt (2010) further, as these target two of the most important morphological entities of urban form, namely the street network and the building structure. The purpose is to gain a better understanding of how types are composed and distributed within and across different cities. The method is based on GIS and statistical modeling of four cities to allow for a comparative analysis of four cities: Amsterdam, London, Stockholm and Gothenburg. For the street network, we process the Road-Centre-line maps to obtain a clean network model, then run segment angular analysis to calculate the space syntax measures of betweenness at different metric radii, defining the "centrality palimpsest" (Serra, 2013a). For the building structure, we process elevation data to obtain building height, then run accessible density analysis for all building density metrics (FSI, GSI, OSR, L) using the Place Syntax Tool (Berghauser Pont and Marcus, 2014). The street and building types are defined using cluster analysis (unsupervised classification), following a similar approach to Serra (2013a). The result is a typology of street ('paths') and building types ('places'), with different profiles of centrality and density across scales. The spatial distribution and frequency of these types across the four cities gives an objective summary of their spatial structure, identifying common as well as unique traits.
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| 8. |
- Berghauser Pont, Meta, 1972, et al.
(författare)
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The spatial distribution and frequency of street, plot and building types across five European cities
- 2019
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Ingår i: Environment and Planning B-Urban Analytics and City Science. - : SAGE Publications. - 2399-8083 .- 2399-8091. ; 46:7, s. 1226-1242
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Tidskriftsartikel (refereegranskat)abstract
- Typologies have always played an important role in urban planning and design practice and formal studies have been central to the field of urban morphology. These studies have predominantly been of a historical-qualitative nature and do not support quantitative comparisons between urban areas and between different cities, nor offer the precise and comprehensive descriptions needed by those engaged in urban planning and design practice. To describe contemporary urban forms, which are more diffuse and often elude previous historic typologies, systematic quantitative methods can be useful but, until recently, these have played a limited role in typo-morphological studies. This paper contributes to recent developments in this field by integrating multi-variable geometric descriptions with inter-scalar relational descriptions of urban form. It presents typologies for three key elements of urban form (streets, plots and buildings) in five European cities, produced using statistical clustering methods. In a first instance, the resulting typologies contribute to a better understanding of the characteristics of streets, plots and buildings. In particular, the results offer insight into patterns between the types (i.e. which types are found in combination and which not) and provide a new large scale comparative analysis across five European cities. To conclude, a link between quantitative analysis and theory is established, by testing two well-known theoretical propositions in urban morphology: the concept of the burgage cycle and the theory of natural movement.
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| 9. |
- Eldesoky, Ahmed H.M., et al.
(författare)
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The suitability of the urban local climate zone classification scheme for surface temperature studies in distinct macroclimate regions
- 2021
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Ingår i: Urban Climate. - : Elsevier BV. - 2212-0955. ; 37
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Tidskriftsartikel (refereegranskat)abstract
- The Local Climate Zone (LCZ) classification scheme, initially designed to distinguish between standard built (urban) and non-built (land cover) types in terms of screen-level air temperature relevant for urban heat island (UHI) studies, has been widely used for land surface temperature (LST) and surface urban heat island (SUHI) studies. However, some concerns remain about the global suitability of the scheme for LST and SUHI studies in different macroclimate regions. By analyzing and comparing a large number of representative LCZ sites and multi-year remotely-sensed LST data, the aim of this work is twofold. Firstly, to study the suitability of the LCZ scheme, with a focus on the built types, for surface temperature studies in four distinct macroclimate regions, namely, the tropical, the arid, the temperate and the cold. Secondly, to understand the influence of the macroclimate region on the LST and SUHI characteristics of the standard LCZ built types. Results show that the urban LCZ standard scheme is applicable, with varying degrees, to all macroclimate regions other than the arid, where a LCZ subclassification might be essential. Also, it has been demonstrated that most LCZ built types exhibit significantly different LST and SUHI characteristics across the remaining macroclimate regions.
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| 10. |
- Eriksson, Hanna M., 1987-
(författare)
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Intracellular vesicles induced by monotopic membrane protein in Escherichia coli
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The monotopic membrane protein alMGS, a glycosyltransferase catalyzing glucolipid synthesis in Acholeplasma laidlawii, was overexpressed in Escherichia coli. Optimization of basic growth parameters was performed, and a novel method for detergent and buffer screening using a small size-exclusion chromatography was developed. This resulted in a tremendous increase in protein yields, as well as the unexpected discovery that the protein induces intracellular vesicle formation in E. coli. This was confirmed by sucrose density separation and Cryo-TEM of membranes, and the properties of the vesicles were analyzed using SDS-PAGE, western blot and lipid composition analysis. It is concluded that both alMGS and alDGS, the next enzyme in glucolipid pathway, have the ability to make the membrane bend and eventually form vesicles. This is likely due to structural and electrostatic properties, such as the way the proteins penetrate the membrane interface and thereby expand one monolayer. The highly positively charged binding surfaces of the glycosyltransferases may bind negatively charged lipids, such as Phosphatidylglycerol (PG), in the membrane and withdraw it from the general pool of lipids. This would increase the overall lipid synthesis, since PG is a pace-keeper, and the local concentration of nonbilayer prone lipids, such as Phosphatidylethanolamine, can increase and also induce bending of the membrane. The formation of surplus membrane inside the E. coli cell was used to develop a generic method for overexpression of membrane proteins. A proof-of-principle experiment with a test set of twenty membrane proteins from E. coli resulted in elevated expression levels for about half of the set. Thus, we believe that this method will be a useful tool for overexpression of many membrane proteins. By engineering E. coli mutants with different lipid compositions, fine-tuning membrane properties for different proteins is also possible.
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| 11. |
- Fong, L. G., et al.
(författare)
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Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice
- 2004
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Ingår i: Proc Natl Acad Sci U S A. ; 101:52, s. 18111-18116
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Tidskriftsartikel (refereegranskat)abstract
- Zmpste24 is a metalloproteinase required for the processing of prelamin A to lamin A, a structural component of the nuclear lamina. Zmpste24 deficiency results in the accumulation of prelamin A within cells, a complete loss of mature lamin A, and misshapen nuclear envelopes. Zmpste24-deficient (Zmpste24(-/-)) mice exhibit retarded growth, alopecia, micrognathia, dental abnormalities, osteolytic lesions in bones, and osteoporosis, which are phenotypes shared with Hutchinson-Gilford progeria syndrome, a human disease caused by the synthesis of a mutant prelamin A that cannot undergo processing to lamin A. Zmpste24(-/-) mice also develop muscle weakness. We hypothesized that prelamin A might be toxic and that its accumulation in Zmpste24(-/-) mice is responsible for all of the disease phenotypes. We further hypothesized that Zmpste24(-/-) mice with half-normal levels of prelamin A (Zmpste24(-/-) mice with one Lmna knockout allele) would be subjected to less toxicity and be protected from disease. Thus, we bred and analyzed Zmpste24(-/-)Lmna(+/-) mice. As expected, prelamin A levels in Zmpste24(-/-)Lmna(+/-) cells were significantly reduced. Zmpste24(-/-)Lmna(+/-) mice were entirely normal, lacking all disease phenotypes, and misshapen nuclei were less frequent in Zmpste24(-/-)Lmna(+/-) cells than in Zmpste24(-/-) cells. These data suggest that prelamin A is toxic and that reducing its levels by as little as 50% provides striking protection from disease.
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| 12. |
- Fong, L. G., et al.
(författare)
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Prelamin A and lamin A appear to be dispensable in the nuclear lamina
- 2006
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Ingår i: J Clin Invest. ; 116:3, s. 743-752
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Tidskriftsartikel (refereegranskat)abstract
- Lamin A and lamin C, both products of Lmna, are key components of the nuclear lamina. In the mouse, a deficiency in both lamin A and lamin C leads to slow growth, muscle weakness, and death by 6 weeks of age. Fibroblasts deficient in lamins A and C contain misshapen and structurally weakened nuclei, and emerin is mislocalized away from the nuclear envelope. The physiologic rationale for the existence of the 2 different Lmna products lamin A and lamin C is unclear, although several reports have suggested that lamin A may have particularly important functions, for example in the targeting of emerin and lamin C to the nuclear envelope. Here we report the development of lamin C-only mice (Lmna(LCO/LCO)), which produce lamin C but no lamin A or prelamin A (the precursor to lamin A). Lmna(LCO/LCO) mice were entirely healthy, and Lmna(LCO/LCO) cells displayed normal emerin targeting and exhibited only very minimal alterations in nuclear shape and nuclear deformability. Thus, at least in the mouse, prelamin A and lamin A appear to be dispensable. Nevertheless, an accumulation of farnesyl-prelamin A (as occurs with a deficiency in the prelamin A processing enzyme Zmpste24) caused dramatically misshapen nuclei and progeria-like disease phenotypes. The apparent dispensability of prelamin A suggested that lamin A-related progeroid syndromes might be treated with impunity by reducing prelamin A synthesis. Remarkably, the presence of a single Lmna(LCO) allele eliminated the nuclear shape abnormalities and progeria-like disease phenotypes in Zmpste24-/- mice. Moreover, treating Zmpste24-/- cells with a prelamin A-specific antisense oligonucleotide reduced prelamin A levels and significantly reduced the frequency of misshapen nuclei. These studies suggest a new therapeutic strategy for treating progeria and other lamin A diseases.
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| 13. |
- Himmelmann, Kate, 1959, et al.
(författare)
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Dyskinetic cerebral palsy: a population-based study of children born between 1991 and 1998
- 2007
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Ingår i: Dev Med Child Neurol. - 0012-1622. ; 49:4, s. 246-51
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to describe the epidemiology, aetiology, and clinical findings in dyskinetic cerebral palsy (CP)in a population-based follow-up study of children born between 1991 and 1998. Age range at ascertainment was 4 to 8 years and prevalence was 0.27 per 1000 live-births. Forty-eight children were examined (27 males, 21 females; mean age 9y, range 5-13y). Thirty-nine had dystonic CP and nine a choreo-athetotic subtype. Primitive reflexes were present in 43 children and spasticity in 33. Gross Motor Function Classification System levels were: Level IV, n= 10 and Level V, n= 28. The rate of learning disability (n= 35) and epilepsy (n= 30) increased with the severity of the motor disability. Thirty-eight children had anarthria. Peri- or neonatal adverse events had been present in 34 of 42 children born at >or=34 weeks' gestation. Motor impairment was most severe in this group. Placental abruption or uterine rupture had occurred in 8 participants and 19 of the 42 near-term/term children required assisted ventilation, compared with 1% and 12% respectively in other CP types. Neuroimaging in 39 children born at >or=34 weeks revealed isolated, late third trimester lesions in 24 and a combination of early and late third trimester lesions in seven. Dyskinetic CP is the dominant type of CP found in term-born, appropriate-for-gestational-age children with severe impairments who have frequently experienced adverse perinatal events.
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| 14. |
- Meta, M., et al.
(författare)
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Protein farnesyltransferase inhibitors and progeria
- 2006
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Ingår i: Trends Mol Med. - : Elsevier BV. ; 12:10, s. 480-487
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Tidskriftsartikel (refereegranskat)abstract
- Genetic mutations that lead to an accumulation of farnesyl-prelamin A cause progeroid syndromes, including Hutchinson-Gilford progeria syndrome. It seemed possible that the farnesylated form of prelamin A might be toxic to mammalian cells, accounting for all the disease phenotypes that are characteristic of progeria. This concept led to the hypothesis that protein farnesyltransferase inhibitors (FTIs) might ameliorate the disease phenotypes of progeria in mouse models. Thus far, two different mouse models of progeria have been examined. In both models, FTIs improved progeria-like disease phenotypes. Here, prelamin A post-translational processing is discussed and several mutations underlying human progeroid syndromes are described. In addition, recent data showing that FTIs ameliorate disease phenotypes in a pair of mouse models of progeria are discussed.
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| 15. |
- Yang, S. H., et al.
(författare)
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A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation
- 2006
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Ingår i: J Clin Invest. ; 116:8, s. 2115-2121
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Tidskriftsartikel (refereegranskat)abstract
- Hutchinson-Gilford progeria syndrome (HGPS) is caused by the production of a truncated prelamin A, called progerin, which is farnesylated at its carboxyl terminus. Progerin is targeted to the nuclear envelope and causes misshapen nuclei. Protein farnesyltransferase inhibitors (FTI) mislocalize progerin away from the nuclear envelope and reduce the frequency of misshapen nuclei. To determine whether an FTI would ameliorate disease phenotypes in vivo, we created gene-targeted mice with an HGPS mutation (LmnaHG/+) and then examined the effect of an FTI on disease phenotypes. LmnaHG/+ mice exhibited phenotypes similar to those in human HGPS patients, including retarded growth, reduced amounts of adipose tissue, micrognathia, osteoporosis, and osteolytic lesions in bone. Osteolytic lesions in the ribs led to spontaneous bone fractures. Treatment with an FTI increased adipose tissue mass, improved body weight curves, reduced the number of rib fractures, and improved bone mineralization and bone cortical thickness. These studies suggest that FTIs could be useful for treating humans with HGPS.
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