| 1. |
- Mold, Jeff E., et al.
(författare)
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Divergent clonal differentiation trajectories establish CD8(+) memory T cell heterogeneity during acute viral infections in humans
- 2021
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 35:8
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Tidskriftsartikel (refereegranskat)abstract
- The CD8(+) T cell response to an antigen is composed of many T cell clones with unique T cell receptors, together forming a heterogeneous repertoire of effector and memory cells. How individual T cell clones contribute to this heterogeneity throughout immune responses remains largely unknown. In this study, we longitudinally track human CD8(+) T cell clones expanding in response to yellow fever virus (YFV) vaccination at the single-cell level. We observed a drop in clonal diversity in blood from the acute to memory phase, suggesting that clonal selection shapes the circulating memory repertoire. Clones in the memory phase display biased differentiation trajectories along a gradient from stem cell to terminally differentiated effector memory fates. In secondary responses, YFV- and influenza-specific CD8(+) T cell clones are poised to recapitulate skewed differentiation trajectories. Collectively, we show that the sum of distinct clonal phenotypes results in the multifaceted human T cell response to acute viral infections.
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| 2. |
- Ali, Zaheer, et al.
(författare)
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Intussusceptive Vascular Remodeling Precedes Pathological Neovascularization
- 2019
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : Lippincott Williams & Wilkins. - 1079-5642 .- 1524-4636. ; 39:7, s. 1402-1418
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Tidskriftsartikel (refereegranskat)abstract
- Objective—Pathological neovascularization is crucial for progression and morbidity of serious diseases such as cancer, diabetic retinopathy, and age-related macular degeneration. While mechanisms of ongoing pathological neovascularization have been extensively studied, the initiating pathological vascular remodeling (PVR) events, which precede neovascularization remains poorly understood. Here, we identify novel molecular and cellular mechanisms of preneovascular PVR, by using the adult choriocapillaris as a model.Approach and Results—Using hypoxia or forced overexpression of VEGF (vascular endothelial growth factor) in the subretinal space to induce PVR in zebrafish and rats respectively, and by analyzing choriocapillaris membranes adjacent to choroidal neovascular lesions from age-related macular degeneration patients, we show that the choriocapillaris undergo robust induction of vascular intussusception and permeability at preneovascular stages of PVR. This PVR response included endothelial cell proliferation, formation of endothelial luminal processes, extensive vesiculation and thickening of the endothelium, degradation of collagen fibers, and splitting of existing extravascular columns. RNA-sequencing established a role for endothelial tight junction disruption, cytoskeletal remodeling, vesicle- and cilium biogenesis in this process. Mechanistically, using genetic gain- and loss-of-function zebrafish models and analysis of primary human choriocapillaris endothelial cells, we determined that HIF (hypoxia-induced factor)-1α-VEGF-A-VEGFR2 signaling was important for hypoxia-induced PVR.Conclusions—Our findings reveal that PVR involving intussusception and splitting of extravascular columns, endothelial proliferation, vesiculation, fenestration, and thickening is induced before neovascularization, suggesting that identifying and targeting these processes may prevent development of advanced neovascular disease in the future.Visual Overview—An online visual overview is available for this article.
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| 3. |
- Alin, Niklas, 1963, et al.
(författare)
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3D Unsteady Computations for Submarine-Like Bodies
- 2005
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Ingår i: 43rd AIAA Aerospace Sciences Meeting and Exhibit, Reno, Nevada, Jan. 10-13, 2005. ; , s. 353-369
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Konferensbidrag (refereegranskat)abstract
- Results from a computational study using Unsteady Reynolds Averaged Navier Stokes (URANS) models and Large Eddy Simulation (LES) of flows past submarine-like bodies are here presented. The aims are to evaluate URANS and LES for high-Re number hydrodynamic flows, to investigate the influence of the turbulence and subgrid turbulence modeling, and to discuss some features of submarine hydrodynamics. For this purpose we have chosen to examine the flow past a prolate spheroid at 10° and 20° angle of attack at a body length Re number of 4-106, and the flow past the DARPA-2 Suboff bare hull and fully appended hull configurations at a body length Re number of 12-106. For both cases experimental data is available for comparison. One finite element and one finite volume flow solver has been used - both with the capability of employing a range of turbulence models and with the capacity of using unstructured and hybrid grids. Better agreement between predictions and experimental data is obtained with LES than with the URANS models, but at a considerably higher price, due to the finer grids and finer temporal resolution in LES.
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| 4. |
- Ambrosetti, Elena, et al.
(författare)
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A DNA-nanoassembly-based approach to map membrane protein nanoenvironments
- 2020
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Ingår i: Nature Nanotechnology. - Stockholm : Karolinska Institutet, Dept of Medical Biochemistry and Biophysics. - 1748-3387 .- 1748-3395. ; 120:3, s. 273A-274A
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Tidskriftsartikel (refereegranskat)abstract
- Most proteins at the plasma membrane are not uniformly distributed but localize to dynamic domains of nanoscale dimensions. To investigate their functional relevance, there is a need for methods that enable comprehensive analysis of the compositions and spatial organizations of membrane protein nanodomains in cell populations. Here we describe the development of a non-microscopy based method for ensemble analysis of membrane protein nanodomains. The method, termed NANOscale DEciphEring of membrane Protein nanodomains (NanoDeep), is based on the use of DNA nanoassemblies to translate membrane protein organization information into a DNA sequencing readout. Using NanoDeep, we characterised the nanoenvironments of Her2, a membrane receptor of critical relevance in cancer. Importantly, we were able to modulate by design the inventory of proteins analysed by NanoDeep. NanoDeep has the potential to provide new insights into the roles of the composition and spatial organization of protein nanoenvironments in the regulation of membrane protein function.
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| 5. |
- Andersson, Emmelie, et al.
(författare)
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Förutsättningar för krisberedskap och totalförsvar i Sverige
- 2017
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Denna rapport beskriver utvecklingen av totalförsvaret och framväxten av området samhällsskydd och beredskap. Den ska ge en övergripande bild av hur det ser ut idag på lokal, regional och nationell nivå inom krisberedskap och totalförsvar. Det bör nämnas att rapporten främst fokuserar på utvecklingen av och förändringar i den civila delen i totalförsvaret samt på samhällsskydd och beredskap.Syftet är att ge läsaren en förståelse för dagens krisberedskap och totalförsvar. För att få en uppfattning för varför vi befinner oss där vi är idag, är det av vikt att ha med sig en bild av historiska händelser, förändrade hotbilder och av de beslut (och ickebeslut) som fattats.Författarna vill betona att rapporten ingalunda ger en komplett bild av krisberedskap eller totalförsvar, utan är tänkt att skapa intresse, kunskap och förståelse på ett övergripande plan.Rapporten ska främst ses som ett stöd för högskolestudenter, beslutsfattare och handläggare genom att ge en översiktlig beskrivning över de system och funktioner som utgör svensk krisberedskap och totalförsvar. Rapporten kan läsas i sin helhet, men kan också användas som ett slags uppslagsverk för den läsare som är intresserad av en särskild tidsperiod, händelse eller ett beslut.
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| 6. |
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| 7. |
- Asp, Viktoria, 1982-, et al.
(författare)
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Besten besegrad : Utvärdering av krishanteringen under skogsbränderna i Ljusdal 2018
- 2019
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Rapport (populärvet., debatt m.m.)abstract
- Skogsbränderna i Ljusdal utgjorde det största brandområdet i Sverige under sommaren 2018. Omkring 200 personer evakuerades. Räddningstjänster från flera delar av Sverige medverkade och internationellt stöd kom från 10 länder. Räddningsinsatsen pågick i 27dagar och innefattade som mest 1300 personer. Efter nio dagar övertog Länsstyrelsen i Gävleborgs län ansvaret för kommunal räddningstjänst.Utvärderingen bedömer i vilken utsträckning Länsstyrelsen i Gävleborgs län har arbetat enligt författningarna och riktlinjerna som finns kopplat till dess ansvarsområde under och efter olyckor och kriser. Mycket i krishanteringen fungerade bra. Inom sju av nio områdenhar länsstyrelsen i hög eller i mycket hög utsträckning uppfyllt sitt ansvar. Inom tvåområden har länsstyrelsen i begränsad utsträckning uppfyllt sitt ansvar.Områden där länsstyrelsen i mycket hög utsträckning har uppfyllt sitt ansvarTiB-funktion (initiera och samordna det inledande arbetet för att upptäcka,verifiera, larma och informera vid allvarliga kriser som berör länet)Omgående kunna upprätta en ledningsfunktionInom sitt geografiska områdesansvar verka för samordning av efterarbetetOmråden där länsstyrelsen i hög utsträckning har uppfyllt sitt ansvar• Samlad regional lägesbild (innan övertagandet)Fungera som sammanhållande funktion och verka för samordning och gemensam inriktning under krisenÖvertagande av kommunal räddningstjänstInformation till allmänhet och mediaOmråden där länsstyrelsen i begränsad utsträckning har uppfyllt sitt ansvarSamlad regional lägesbild (efter övertagandet)Intern informationssamordningI utvärderingen dras också slutsatser utifrån utmaningarna som länsstyrelsen mötte samtnågra slutsatser av vikt för krishanteringssystemet. Ett urval presenteras nedan.Inledningsvis hämmades länsstyrelsens arbete med regional lägesbild av att Ljusdalskommun hade svårt att formulera en lokal lägesbild. Genom flera proaktiva åtgärder lyckades dock länsstyrelsen skapa en lägesbild utifrån vilken insatserna kunde dimensioneras.Övertagandet av kommunal räddningstjänst har i all väsentlighet hanterats på ett bra sätt. Möjligen hade övertagandet kunnat ske något tidigare, men övertagandet har sannolikt underlättats av att avvakta och den operativa insatsen har kunnat fortgå ostörd avlänsstyrelsen. Förberedelserna för övertagande borde däremot ha involverat länsstyrelsensstab i betydligt högre utsträckning.Länsstyrelsen har efter övertagandet två roller att hantera: dels ansvaret förräddningsinsatsen, dels det geografiska områdesansvaret inom krisberedskapen. Det medför att det blir svåra avvägningar mellan räddningstjänst och krishantering. I både Gävleborg och i Västmanland 2014 har vissa inblandade kritiserat att hanteringen haft för stort brandfokus. Att räddningsinsatsen har brandfokus och leds av personer med stor erfarenhet av att leda stora räddningsinsatser är lämpligt, men att integrera länsstyrelsensstab med räddningsinsatsens innebär en risk att länsstyrelsens roll och ansvar i krisberedskapen faller undan.Det är en utmaning att organisera ledning av en stor insats. Länsstyrelsens organisation före övertagandet kom snabbt igång och utformades utifrån rådande planer och erfarenheter av övningar. Däremot har inte alltid länsledningen och länsstyrelsens stab arbetat helt integrerat. Stabsorganisationen efter övertagandet sattes upp ad hoc. Den stabsstruktur som väljs måste kompletteras med processer som är enhetliga och som övas regelbundet. Detta gäller både inom respektive funktion, men framförallt sådana processer som knyter samman flera funktioner som för att integrera strategiskt och operativt ledarskap, för att följa upp arbetet, för kommunikation och enhetliga budskap samt för planering på kort, medel och lång sikt.Frivilliga fick ersättning efter både sommarens bränder och skogsbranden i Västmanland 2014. Ersättningar till frivilliga riskerar att sätta standard och förväntningar till nästa kris. I framtiden kommer det antagligen bli nödvändigt att göra skillnad inom gruppen frivilliga mellan dem som medverkar med någon form av avtal, och därmed har rätt till ersättning, och de frivilliga som gör ideella insatser. De ekonomiska konsekvenserna av frivilliga riskerar annars att bli allt för långtgående. Hur frivilligfrågan hanteras har en nära koppling till de drabbade och allmänhetens förtroende för insatsen och krishanteringen.Rapporten består av tre delar: 1) en beskrivning av händelseförloppet utifrån särskilt relevanta teman, 2) en diskussion om vilka lärdomar som kan dras utifrån hanteringen och 3) en utvärdering av Länsstyrelsen i Gävleborgs läns arbete utifrån dess ansvar ochuppdrag.
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| 8. |
- Barkfeldt, Carl, 1985-, et al.
(författare)
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Accounting-based valuation and market efficiency testing
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- This study investigates a testing methodology of market efficiency based on accounting-based fundamental valuation. In particular, the methodology is based on an investment strategy where stocks with high (low) V/P-ratios are assigned into long (short) portfolios. We conjecture that under the assumption of independence between the portfolio assignment and systematic risk, a positive net-zero hedge return from such investing strategy is inconsistent with market efficiency. We estimate fundamental values based on the residual income valuation model in Gode and Ohlson (2004) via the state-space framework. Hence, our estimation accommodates time variations in both discount rates and abnormal earnings dynamics on a firm level. We implement the investment strategy on a sample of U.S. stocks spanning the period 1980–2017 and find a significant positive monthly hedge return. To substantiate our results, we estimate a standard five-factor model. The five-factor regressions indicate a significant positive abnormal return (intercept). Moreover, the factor loadings (coefficients) are all insignificant, suggesting that the investment strategy has no exposure to systematic risk. In sum, these results appear anomalous with respect to market efficiency, at least as given by the five-factor model.
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| 9. |
- Barkfeldt, Carl, 1985-
(författare)
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Asset Mispricing
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This dissertation studies the pricing of stocks in capital markets. It comprises five chapters, where the first serves as an introduction. The subsequent four chapters are each written as self-contained research papers. While the theory of efficient markets serves as the theoretical foundation, I approach the research from a conceptual starting point that recognizes market mispricing.The first paper investigates a testing methodology of market efficiency based on fundamental valuation. The methodology is based on an investment strategy where stocks with high (low) V/P-ratios are assigned into long (short) portfolios. We conjecture that under the assumption of independence between the portfolio assignment and systematic risk, a positive return from such investing strategy is inconsistent with market efficiency. We estimate fundamental values based on a flexible residual income valuation model via the state-space framework and implement the investment strategy on a sample of U.S. stocks spanning 1980–2017. The implementation shows a significant positive monthly return. Moreover, the results are substantiated in a standard five-factor model. In sum, these results appear anomalous with respect to market efficiency, at least as given by the five-factor model.The second paper examines whether improvements in earnings forecasting translate into improvements in implied cost of capital estimates of expected returns. I attain high-performing earnings forecasting via a machine learning approach. In particular, I implement and evaluate six popular machine learning methods to forecast earnings. The evaluation demonstrates that the machine learning algorithms can generate earnings forecasts that consistently outperform state-of-the-art benchmarks. Moreover, I estimate the implied cost of capital on a sample of U.S. stocks spanning 2000–2017. The general result indicates that improvements in earnings forecasting do not translate into improvements in return predictability. While issues with the implied cost of capital methodology could explain the results, another possible explanation is market mispricing.The third paper compares the performance between the implied cost of capital and factor model approaches in estimating the cost of capital in an inefficient market. I conduct the comparison in a Monte Carlo simulation experiment. The simulation results indicate that the implied cost of capital approach is more robust to market inefficiency.The fourth paper analyzes investor learning of cash flow expectations in the context of market efficiency. I argue that the bias-variance tradeoff translates into inefficiencies in market pricing. Moreover, in a simple model, I prove that these inefficiencies can be exploited by an investor aware of whether market prices exhibit a bias or suboptimal variance.
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| 10. |
- Barrow, Devon, et al.
(författare)
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Automatic robust estimation for exponential smoothing : Perspectives from statistics and machine learning
- 2020
-
Ingår i: Expert systems with applications. - : Elsevier. - 0957-4174 .- 1873-6793. ; 160
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in automating the production of a large number of forecasts, as often required in many business applications, is the need for robust and reliable predictions. Increased noise, outliers and structural changes in the series, all too common in practice, can severely affect the quality of forecasting. We investigate ways to increase the reliability of exponential smoothing forecasts, the most widely used family of forecasting models in business forecasting. We consider two alternative sets of approaches, one stemming from statistics and one from machine learning. To this end, we adapt M-estimators, boosting and inverse boosting to parameter estimation for exponential smoothing. We propose appropriate modifications that are necessary for time series forecasting while aiming to obtain scalable algorithms. We evaluate the various estimation methods using multiple real datasets and find that several approaches outperform the widely used maximum likelihood estimation. The novelty of this work lies in (1) demonstrating the usefulness of M-estimators, (2) and of inverse boosting, which outperforms standard boosting approaches, and (3) a comparative look at statistics versus machine learning inspired approaches.
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| 11. |
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| 12. |
- Björklund, Åsa K., et al.
(författare)
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The heterogeneity of human CD127(+) innate lymphoid cells revealed by single-cell RNA sequencing
- 2016
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Ingår i: Nature Immunology. - : Springer Science and Business Media LLC. - 1529-2908 .- 1529-2916. ; 17:4, s. 451-460
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Tidskriftsartikel (refereegranskat)abstract
- Innate lymphoid cells (ILCs) are increasingly appreciated as important participants in homeostasis and inflammation. Substantial plasticity and heterogeneity among ILC populations have been reported. Here we have delineated the heterogeneity of human ILCs through single-cell RNA sequencing of several hundreds of individual tonsil CD127(+) ILCs and natural killer (NK) cells. Unbiased transcriptional clustering revealed four distinct populations, corresponding to ILC1 cells, ILC2 cells, ILC3 cells and NK cells, with their respective transcriptomes recapitulating known as well as unknown transcriptional profiles. The single-cell resolution additionally divulged three transcriptionally and functionally diverse subpopulations of ILC3 cells. Our systematic comparison of single-cell transcriptional variation within and between ILC populations provides new insight into ILC biology during homeostasis, with additional implications for dysregulation of the immune system.
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| 13. |
- Böiers, Charlotta, et al.
(författare)
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Lymphomyeloid Contribution of an Immune-Restricted Progenitor Emerging Prior to Definitive Hematopoietic Stem Cells.
- 2013
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Ingår i: Cell Stem Cell. - : Elsevier BV. - 1934-5909 .- 1875-9777. ; 13:5, s. 535-548
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Tidskriftsartikel (refereegranskat)abstract
- In jawed vertebrates, development of an adaptive immune-system is essential for protection of the born organism against otherwise life-threatening pathogens. Myeloid cells of the innate immune system are formed early in development, whereas lymphopoiesis has been suggested to initiate much later, following emergence of definitive hematopoietic stem cells (HSCs). Herein, we demonstrate that the embryonic lymphoid commitment process initiates earlier than previously appreciated, prior to emergence of definitive HSCs, through establishment of a previously unrecognized entirely immune-restricted and lymphoid-primed progenitor. Notably, this immune-restricted progenitor appears to first emerge in the yolk sac and contributes physiologically to the establishment of lymphoid and some myeloid components of the immune-system, establishing the lymphomyeloid lineage restriction process as an early and physiologically important lineage-commitment step in mammalian hematopoiesis.
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| 14. |
- Chivukula, Indira V, et al.
(författare)
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Decoding breast cancer tissue-stroma interactions using species-specific sequencing.
- 2015
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- Decoding transcriptional effects of experimental tissue-tissue or cell-cell interactions is important; for example, to better understand tumor-stroma interactions after transplantation of human cells into mouse (xenografting). Transcriptome analysis of intermixed human and mouse cells has, however, frequently relied on the need to separate the two cell populations prior to transcriptome analysis, which introduces confounding effects on gene expression.
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| 15. |
- Ehrenberg, Måns, et al.
(författare)
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Systems Biology is Taking
- 2003
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Ingår i: Genome Research. ; 13, s. 2377-2380
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Tidskriftsartikel (refereegranskat)
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| 16. |
- Enroth, Stefan, 1976-
(författare)
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The Nucleosome as a Signal Carrying Unit : From Experimental Data to Combinatorial Models of Transcriptional Control
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The human genome consists of over 3 billion nucleotides and would be around 2 meters long if uncoiled and laid out. Each human somatic cell contains all this in their nucleus which is only around 5 µm across. This extreme compaction is largely achieved by wrapping the DNA around a histone octamer, the nucleosome. Still, the DNA is accessible to the transcriptional machinery and this regulation is highly dynamic and change rapidly with, e.g. exposure to drugs. The individual histone proteins can carry specific modifications such as methylations and acetylations. These modifications are a major part of the epigenetic status of the DNA which contributes significantly to the transcriptional status of a gene - certain modifications repress transcription and others are necessary for transcription to occur. Specific histone methylations and acetylations have also been implicated in more detailed regulation such as inclusion/exclusion of individual exons, i.e. splicing. Thus, the nucleosome is involved in chromatin remodeling and transcriptional regulation – both directly from steric hindrance but also as a signaling platform via the epigenetic modifications. In this work, we have developed tools for storage (Paper I) and normalization (Paper II) of next generation sequencing data in general, and analyzed nucleosome locations and histone modification in particular (Paper I, III and IV). The computational tools developed allowed us as one of the first groups to discover well positioned nucleosomes over internal exons in such wide spread organisms as worm, mouse and human. We have also provided biological insight into how the epigenetic histone modifications can control exon expression in a combinatorial way. This was achieved by applying a Monte Carlo feature selection system in combination with rule based modeling of exon expression. The constructed model was validated on data generated in three additional cell types suggesting a general mechanism.
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| 17. |
- Fritsch, Daniel J., et al.
(författare)
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Experimental and Computational Study of 2D Smooth Wall Turbulent Boundary Layers in Pressure Gradient
- 2022
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Ingår i: AIAA Science and Technology Forum and Exposition, AIAA SciTech Forum 2022. - Reston, Virginia : American Institute of Aeronautics and Astronautics.
-
Konferensbidrag (refereegranskat)abstract
- This paper describes a collaborative experimental and computational study of smooth wall boundary layers in a systematic family of favorable and adverse pressure gradients. The objective is to advance turbulence modeling of these flows, in particular the effects of pressure gradients that can be classified as non-equilibrium. This collaboration is a component of the larger NATO AVT-349 Research Task Group. Experiments under this effort are conducted at Virginia Tech and computational efforts are presented from Virginia Tech, the German Aerospace Center (DLR), the University of Melbourne, Chalmers University of Technology, the Maritime Research Institute Netherlands (MARIN) in conjunction with the University of Lisbon Instituto Superior Técnico (IST) (MARIN/IST), and the Sirehna Naval Group. This paper describes some of the key elements of the experimental and computational approaches, the efforts made for cross-discipline collaboration, verification, and validation, and reports on some initial results and findings. The agreement between various RANS solutions and RANS turbulence models and between RANS solutions and experiment are generally good, but questions remain as to the efficacy of RANS modeling for non-equilibrium boundary layer flows and some potential directions for future investigations are suggested.
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| 18. |
- García-Mayoral, Ricardo, et al.
(författare)
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Modeling of high-Re, incompressible, non-equilibrium, rough-wall boundary layers for naval applications under NATO-AVT349
- 2022
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Ingår i: AIAA Science and Technology Forum and Exposition, AIAA SciTech Forum 2022. - Reston, Virginia : American Institute of Aeronautics and Astronautics.
-
Konferensbidrag (refereegranskat)abstract
- This paper discusses the modeling activity of the NATO-STO Research Task Group AVT-349. The aim of this group is to improve the understanding and modeling of boundary layers in the complex flow around water vehicles. As such, the focus is on incompressible, high-Reynolds-number flows that can be subject to non-equilibrium conditions such as strong pressure gradients, three-dimensionality, and surface roughness and heterogeneity. The Task Group has identified a reduced number of simpler problems in which the above conditions can be studied separately and in controlled environments. These include two-dimensional rough-wall boundary layers under both zero and non-zero pressure gradients, two-dimensional smooth-wall boundary layers subject to pressure gradients, and boundary layers around smooth bodies of revolution and three-dimensional obstacles. An experimental and computational data set is being assembled for further analysis and insight into the flow mechanisms involved, as well as the shortcomings of state-of-the-art models. This paper gives an outlook of the modeling effort within the Task Group, as well its different objectives. These include predicting the effect of roughness in equilibrium conditions; assessing the applicability and/or extension of equilibrium models and predictions to non-equilibrium conditions, in particular when outer-layer similarity is lost; the development of near-wall models based on a reduced-order resolvent framework; and the use of machine-aided methods in closure models.
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| 19. |
- Giustacchini, Alice, et al.
(författare)
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Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia
- 2017
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Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 23:6, s. 692-
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Tidskriftsartikel (refereegranskat)abstract
- Recent advances in single-cell transcriptomics are ideally placed to unravel intratumoral heterogeneity and selective resistance of cancer stem cell (SC) subpopulations to molecularly targeted cancer therapies. However, current single-cell RNA-sequencing approaches lack the sensitivity required to reliably detect somatic mutations. We developed a method that combines high-sensitivity mutation detection with whole-transcriptome analysis of the same single cell. We applied this technique to analyze more than 2,000 SCs from patients with chronic myeloid leukemia (CML) throughout the disease course, revealing heterogeneity of CML-SCs, including the identification of a subgroup of CML-SCs with a distinct molecular signature that selectively persisted during prolonged therapy. Analysis of nonleukemic SCs from patients with CML also provided new insights into cell-extrinsic disruption of hematopoiesis in CML associated with clinical outcome. Furthermore, we used this single-cell approach to identify a blast-crisis-specific SC population, which was also present in a subclone of CML-SCs during the chronic phase in a patient who subsequently developed blast crisis. This approach, which might be broadly applied to any malignancy, illustrates how single-cell analysis can identify subpopulations of therapy-resistant SCs that are not apparent through cell-population analysis.
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| 20. |
- He, Bing, et al.
(författare)
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Single-cell RNA sequencing reveals the mesangial identity and species diversity of glomerular cell transcriptomes
- 2021
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Molecular characterization of the individual cell types in human kidney as well as model organisms are critical in defining organ function and understanding translational aspects of biomedical research. Previous studies have uncovered gene expression profiles of several kidney glomerular cell types, however, important cells, including mesangial (MCs) and glomerular parietal epithelial cells (PECs), are missing or incompletely described, and a systematic comparison between mouse and human kidney is lacking. To this end, we use Smart-seq2 to profile 4332 individual glomerulus-associated cells isolated from human living donor renal biopsies and mouse kidney. The analysis reveals genetic programs for all four glomerular cell types (podocytes, glomerular endothelial cells, MCs and PECs) as well as rare glomerulus-associated macula densa cells. Importantly, we detect heterogeneity in glomerulus-associated Pdgfrb-expressing cells, including bona fide intraglomerular MCs with the functionally active phagocytic molecular machinery, as well as a unique mural cell type located in the central stalk region of the glomerulus tuft. Furthermore, we observe remarkable species differences in the individual gene expression profiles of defined glomerular cell types that highlight translational challenges in the field and provide a guide to design translational studies. The molecular identity of renal glomerular cells is poorly characterized and rodent glomerulopathy models translate poorly to humans. Here, the authors show molecular signatures of glomerulus-associated cells using single cell RNA sequencing and highlight differences between mouse and human cells.
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| 21. |
- He, Changli, et al.
(författare)
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Dickey-Fuller type of tests against non-linear dynamic models
- 2006
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Ingår i: Oxford Bulletin of Economics and Statistics. - : Blackwell Publishing Ltd. - 0305-9049 .- 1468-0084. ; 68:s1, s. 835-861
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Tidskriftsartikel (refereegranskat)abstract
- In this paper, we introduce several test statistics testing the null hypothesis of a random walk (with or without drift) against models that accommodate a smooth nonlinear shift in the level, the dynamic structure and the trend. We derive analytical limiting distributions for all the tests. The power performance of the tests is compared with that of the unit-root tests by Phillips and Perron [Biometrika (1988), Vol. 75, pp. 335–346], and Leybourne, Newbold and Vougas [Journal of Time Series Analysis (1998), Vol. 19, pp. 83–97]. In the presence of a gradual change in the deterministics and in the dynamics, our tests are superior in terms of power.
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| 22. |
- He, Changli, et al.
(författare)
-
Dickey-Fuller type of tests against nonlinear dynamic models
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- In this paper we introduce several test statistics of testing the null hypotheses of a random walk (with or without drift) against models that accommodate a smooth nonlinear shift in the level, the dynamic structure, and the trend. We derive analytical limiting distributions for all tests. Finite sample properties are examined. The performance of the tests is compared to that of the classical unit root tests by Dickey-Fuller and Phillips and Perron, and is found to be superior in terms of power.
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| 23. |
- He, Changli, et al.
(författare)
-
Testing parameter constancy in unit root autoregressive models against multiple continuous structural changes
- 2012
-
Ingår i: Econometric Reviews. - New York : Taylor & Francis. - 0747-4938 .- 1532-4168. ; 31:1, s. 34-59
-
Tidskriftsartikel (refereegranskat)abstract
- This article considers tests for logistic smooth transition autoregressive (LSTAR) models accommodating multiple time dependent transitions between regimes when the data generating process is a random walk. The asymptotic null distributions of the tests, in contrast to the standard results in Lin and Teräsvirta (1994), are nonstandard. Monte Carlo experiments reveal that the tests have modest size distortions and satisfactory power against LSTAR models with multiple smooth breaks. The tests are applied to Swedish unemployment rates and the hysteresis hypothesis is over-turned in favour of an LSTAR model with two transitions between extreme regimes.
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| 24. |
- Hunt, George, et al.
(författare)
-
Comprehensive interrogation of a Drosophila embryonic patterning network reveals the impact of chromatin state on tissue-specific burst kinetics and RNA Polymerase II promoter-proximal pause release
- 2024
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Formation of tissue-specific transcriptional programs underlies multicellular development, but how the chromatin landscape influences transcription is not fully understood. Here we comprehensively resolve differential transcriptional and chromatin states during Drosophila dorsoventral (DV) patterning. We find that RNA Polymerase II pausing is established at DV promoters prior to zygotic genome activation (ZGA), that pausing persists irrespective of cell fate, but that release into productive elongation is tightly regulated and accompanied by tissue-specific P-TEFb recruitment. DV enhancers acquire distinct tissue-specific chromatin states through CBP-mediated histone acetylation that predict the transcriptional output of target genes, whereas promoter states are more tissue invariant. Transcriptome-wide inference of burst kinetics in different cell types revealed that while DV genes are generally characterized by a high burst size, either burst size or frequency can differ between tissues. The data suggest that pausing is established by pioneer transcription factors prior to ZGA and that release from pausing is imparted by enhancer chromatin state to regulate bursting in a tissue-specific manner in the early embryo. Our results uncover how developmental patterning is orchestrated by tissue-specific bursts of transcription from Pol II primed promoters in response to enhancer regulatory cues.
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| 25. |
- Hunt, George, et al.
(författare)
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Tissue-specific RNA Polymerase II promoter-proximal pause release and burst kinetics in a Drosophila embryonic patterning network
- 2024
-
Ingår i: Genome Biology. - : BioMed Central (BMC). - 1465-6906 .- 1474-760X. ; 25:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Formation of tissue-specific transcriptional programs underlies multicellular development, including dorsoventral (DV) patterning of the Drosophila embryo. This involves interactions between transcriptional enhancers and promoters in a chromatin context, but how the chromatin landscape influences transcription is not fully understood.Results: Here we comprehensively resolve differential transcriptional and chromatin states during Drosophila DV patterning. We find that RNA Polymerase II pausing is established at DV promoters prior to zygotic genome activation (ZGA), that pausing persists irrespective of cell fate, but that release into productive elongation is tightly regulated and accompanied by tissue-specific P-TEFb recruitment. DV enhancers acquire distinct tissue-specific chromatin states through CBP-mediated histone acetylation that predict the transcriptional output of target genes, whereas promoter states are more tissue-invariant. Transcriptome-wide inference of burst kinetics in different cell types revealed that while DV genes are generally characterized by a high burst size, either burst size or frequency can differ between tissues.Conclusions: The data suggest that pausing is established by pioneer transcription factors prior to ZGA and that release from pausing is imparted by enhancer chromatin state to regulate bursting in a tissue-specific manner in the early embryo. Our results uncover how developmental patterning is orchestrated by tissue-specific bursts of transcription from Pol II primed promoters in response to enhancer regulatory cues.
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| 26. |
- Irani, Mohammad, 1980-
(författare)
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Essays on Mergers and Acquisitions and Event Studies
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This dissertation consists of three studies on the anticipation of mergers and acquisitions (M&As) and its impact on takeover event studies. Article I investigates whether the market can anticipate both takeovers and their payment forms prior to their announcement dates. This article also proposes a new time-series approach for detecting the ex-ante deal-anticipation and payment-form anticipation dates. The results indicate that the majority of deals and their payment forms are anticipated much earlier than has been documented in previous takeover studies. Moreover, controlling for the anticipation dates matters for explaining the choice of payment method in M&As.Article II studies how assuming that M&As are unpredictable during the estimation window affects the measurement of abnormal returns. The results show that a part of takeover synergy is indeed incorporated into the stock prices during the estimation window of previous studies, around the deal-anticipation dates. This article estimates the parameters of the expected return model from the pre-anticipation period to control the consequences of ex-ante anticipation on the estimates of abnormal returns. Using the anticipation-adjusted approach significantly improves the estimation of the event-window abnormal returns, and provides new insights into some well-documented takeover results.Article III examines how the abnormal returns are affected when a standard event study assumes that the parameters of the expected return model are stable. Using a sample of firm takeovers, the results indicate that the parameters are indeed unstable. This article introduces a time-varying market model to account for the dynamics of merging likelihood when it estimates the abnormal returns. The findings show that the stability assumption causes a standard event study to overestimate significantly the abnormal returns to the target and acquirer shareholders.
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| 27. |
- Isaksson, Martin, et al.
(författare)
-
mmWave Beam Selection in Analog Beamforming Using Personalized Federated Learning
- 2023
-
Ingår i: Proceedings - 2023 IEEE Future Networks World Forum: Future Networks: Imagining the Network of the Future, FNWF 2023. - : Institute of Electrical and Electronics Engineers Inc.. - 9798350324587
-
Konferensbidrag (refereegranskat)abstract
- Using analog beamforming in mmWave frequency bands we can focus the energy towards a receiver to achieve high throughput. However, this requires the network to quickly find the best downlink beam configuration in the face of non-IID data. We propose a personalized Federated Learning (FL) method to address this challenge, where we learn a mapping between uplink Sub-6GHz channel estimates and the best downlink beam in heterogeneous scenarios with non-IID characteristics. We also devise FedLion, a FL implementation of the Lion optimization algorithm. Our approach reduces the signalling overhead and provides superior performance, up to 33.6% higher accuracy than a single FL model and 6 % higher than a local model.
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| 28. |
- Jensen, Lasse, et al.
(författare)
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Disruption of the Extracellular Matrix Progressively Impairs Central Nervous System Vascular Maturation Downstream of beta-Catenin Signaling
- 2019
-
Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : LIPPINCOTT WILLIAMS & WILKINS. - 1079-5642 .- 1524-4636. ; 39:7, s. 1432-1447
-
Tidskriftsartikel (refereegranskat)abstract
- Objective- The Wnt/beta-catenin pathway orchestrates development of the blood-brain barrier, but the downstream mechanisms involved at different developmental windows and in different central nervous system (CNS) tissues have remained elusive. Approach and Results- Here, we create a new mouse model allowing spatiotemporal investigations of Wnt/beta-catenin signaling by induced overexpression of Axin1, an inhibitor of beta-catenin signaling, specifically in endothelial cells (Axin1(iEC)-(OE)). AOE (Axin1 overexpression) in Axin1(iEC)-(OE) mice at stages following the initial vascular invasion of the CNS did not impair angiogenesis but led to premature vascular regression followed by progressive dilation and inhibition of vascular maturation resulting in forebrain-specific hemorrhage 4 days post-AOE. Analysis of the temporal Wnt/beta-catenin driven CNS vascular development in zebrafish also suggested that Axin1(iEC)-(OE) led to CNS vascular regression and impaired maturation but not inhibition of ongoing angiogenesis within the CNS. Transcriptomic profiling of isolated, beta-catenin signaling-deficient endothelial cells during early blood-brain barrier-development (E11.5) revealed ECM (extracellular matrix) proteins as one of the most severely deregulated clusters. Among the 20 genes constituting the forebrain endothelial cell-specific response signature, 8 (Adamtsl2, Apod, Ctsw, Htra3, Pglyrp1, Spock2, Ttyh2, and Wfdc1) encoded bona fide ECM proteins. This specific beta-catenin-responsive ECM signature was also repressed in Axin1(iEC)-(OE) and endothelial cell-specific beta-catenin-knockout mice (Ctnnb1-KOiEC) during initial blood-brain barrier maturation (E14.5), consistent with an important role of Wnt/beta-catenin signaling in orchestrating the development of the forebrain vascular ECM. Conclusions- These results suggest a novel mechanism of establishing a CNS endothelium-specific ECM signature downstream of Wnt-beta-catenin that impact spatiotemporally on blood-brain barrier differentiation during forebrain vessel development.
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| 29. |
- Jun, Seong-Hwan, et al.
(författare)
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Reconstructing clonal tree for phylo-phenotypic characterization of cancer using single-cell transcriptomics
- 2023
-
Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- Functional characterization of the cancer clones can shed light on the evolutionary mechanisms driving cancer's proliferation and relapse mechanisms. Single-cell RNA sequencing data provide grounds for understanding the functional state of cancer as a whole; however, much research remains to identify and reconstruct clonal relationships toward characterizing the changes in functions of individual clones. We present PhylEx that integrates bulk genomics data with co-occurrences of mutations from single-cell RNA sequencing data to reconstruct high-fidelity clonal trees. We evaluate PhylEx on synthetic and well-characterized high-grade serous ovarian cancer cell line datasets. PhylEx outperforms the state-of-the-art methods both when comparing capacity for clonal tree reconstruction and for identifying clones. We analyze high-grade serous ovarian cancer and breast cancer data to show that PhylEx exploits clonal expression profiles beyond what is possible with expression-based clustering methods and clear the way for accurate inference of clonal trees and robust phylo-phenotypic analysis of cancer. The functional changes of individual clones in single cell RNA sequencing (scRNA-seq) data remain elusive. Here, the authors develop PhylEx that integrates bulk genomics data with co-occurrences of mutations revealed by scRNA-seq data and apply it to high-grade serous ovarian cancer cell line and breast cancer datasets.
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| 30. |
- Kadkhodaei, Banafsheh, et al.
(författare)
-
Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons
- 2013
-
Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 110:6, s. 2360-2365
-
Tidskriftsartikel (refereegranskat)abstract
- Developmental transcription factors important in early neuron specification and differentiation often remain expressed in the adult brain. However, how these transcription factors function to mantain appropriate neuronal identities in adult neurons and how transcription factor dysregulation may contribute to disease remain largely unknown. The transcription factor Nurr1 has been associated with Parkinson's disease and is essential for the development of ventral midbrain dopamine (DA) neurons. We used conditional Nurr1 gene-targeted mice in which Nurr1 is ablated selectively in mature DA neurons by treatment with tamoxifen. We show that Nurr1 ablation results in a progressive pathology associated with reduced striatal DA, impaired motor behaviors, and dystrophic axons and dendrites. We used laser-microdissected DA neurons for RNA extraction and next-generation mRNA sequencing to identify Nurr1-regulated genes. This analysis revealed that Nurr1 functions mainly in transcriptional activation to regulate a battery of genes expressed in DA neurons. Importantly, nuclear-encoded mitochondrial genes were identified as the major functional category of Nurr1-regulated target genes. These studies indicate that Nurr1 has a key function in sustaining high respiratory function in these cells, and that Nurr1 ablation in mice recapitulates early features of Parkinson's disease.
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| 31. |
- Kee, Nigel, et al.
(författare)
-
Single-Cell Analysis Reveals a Close Relationship between Differentiating Dopamine and Subthalamic Nucleus Neuronal Lineages
- 2017
-
Ingår i: Cell Stem Cell. - : Elsevier BV. - 1934-5909 .- 1875-9777. ; 20:1, s. 29-40
-
Tidskriftsartikel (refereegranskat)abstract
- Stem cell engineering and grafting of mesencephalic dopamine (mesDA) neurons is a promising strategy for brain repair in Parkinson's disease (PD). Refinement of differentiation protocols to optimize this approach will require deeper understanding of mesDA neuron development. Here, we studied this process using transcriptome-wide single-cell RNA sequencing of mouse neural progenitors expressing the mesDA neuron determinant Lmx1a. This approach resolved the differentiation of mesDA and neighboring neuronal lineages and revealed a remarkably close relationship between developing mesDA and subthalamic nucleus (STN) neurons, while also highlighting a distinct transcription factor set that can distinguish between them. While previous hESC mesDA differentiation protocols have relied on markers that are shared between the two lineages, we found that application of these highlighted markers can help to refine current stem cell engineering protocols, increasing the proportion of appropriately patterned mesDA progenitors. Our results, therefore, have important implications for cell replacement therapy in PD.
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| 32. |
- Larsson, Anton J M, et al.
(författare)
-
X-chromosome upregulation is driven by increased burst frequency
- 2019
-
Ingår i: Nature Structural & Molecular Biology. - Stockholm : Karolinska Institutet, Dept of Medical Biochemistry and Biophysics. - 1545-9993 .- 1545-9985.
-
Tidskriftsartikel (refereegranskat)abstract
- Ohno's hypothesis postulates that X-chromosome upregulation rectifies X-dose imbalance relative to autosomal genes, present in two active copies per cell. Here we dissected X-upregulation into kinetics of transcription, inferred from allele-specific single-cell RNA-sequencing (scRNAseq) data from somatic mouse cells. We confirmed increased X-chromosome expression in female and male somatic cells, and remarkably found that the X-chromosome achieved upregulation by elevated burst frequencies. By monitoring differentiating female embryonic stem cells, we found that elevated burst frequency established on the active X-chromosome as X-inactivation occurred on the other allele. This provides mechanistic insights into X-chromosome upregulation.
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| 33. |
- Luis, Tiago C., et al.
(författare)
-
Initial seeding of the embryonic thymus by immune-restricted lympho-myeloid progenitors
- 2016
-
Ingår i: Nature Immunology. - : Springer Science and Business Media LLC. - 1529-2908 .- 1529-2916. ; 17:12, s. 1424-1435
-
Tidskriftsartikel (refereegranskat)abstract
- The final stages of restriction to the T cell lineage occur in the thymus after the entry of thymus-seeding progenitors (TSPs). The identity and lineage potential of TSPs remains unclear. Because the first embryonic TSPs enter a non-vascularized thymic rudiment, we were able to directly image and establish the functional and molecular properties of embryonic thymopoiesis-initiating progenitors (T-IPs) before their entry into the thymus and activation of Notch signaling. T-IPs did not include multipotent stem cells or molecular evidence of T cell-restricted progenitors. Instead, single-cell molecular and functional analysis demonstrated that most fetal T-IPs expressed genes of and had the potential to develop into lymphoid as well as myeloid components of the immune system. Moreover, studies of embryos deficient in the transcriptional regulator RBPJ demonstrated that canonical Notch signaling was not involved in pre-thymic restriction to the T cell lineage or the migration of T-IPs.
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| 34. |
- Lunde, Asger, et al.
(författare)
-
Calculating the damage of a cartel subject to transition periods: The international uranium cartel in the 1970s
- 2019
-
Ingår i: Energy Economics. - : Elsevier. - 0140-9883. ; 84
-
Tidskriftsartikel (refereegranskat)abstract
- The theory about cartel pricing and descriptive price statistics suggests that the price path over a cartel life cycle can be subject to gradual, non-linear transitions where the price path moves from (to) the non-collusive to (from) the maximum collusive equilibrium. Ignoring such transitions can lead to biased estimates of the cartel and damage effects. Smooth transition regression (STR) models are a class of models well suited to capture such transitions, also under realistic conditions when the transition start and end dates are uncertain, and when the two transitions are asymmetric. We evaluate the international uranium cartel during the 1970s, using both the mainstream approach based on a linear specification with a dummy variable to capture the cartel, and an STR model. We are the first to use STR models in the evaluation of a cartel/damage effect. Using the STR model, we find that the damage effect is about 18 times higher as compared to the mainstream model.
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| 35. |
- Lundin, Elin, 1983-
(författare)
-
RNA-based spatial characterization of cell and tissue heterogeneity
- 2020
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Technical advances in cell biology have revolutionized the field of cell biology. With new technology it is now possible to address scientific questions in cell biology at the molecular level. Single-cell RNA-sequencing can reveal transcriptomic information for single cells and spatially resolved transcriptomic technology can visualize thousands or millions of cells and transcripts for spatial molecular profiling. The work in this thesis describes the technological development from traditional in situ hybridization to the current state-of-the-art technology for spatial multiplexed gene expression analysis. This development has enabled RNA-based molecular characterization of cells and tissues with the spatial dimension maintained. The work included in the thesis highlights the potential and the advantages of padlock-probe-based technology for spatial RNA-based profiling of cells and tissues. Furthermore, it demonstrates the possibilities arising from the inherent ability of padlock probes to distinguish between transcripts based on differences in single nucleotides.The study in paper I investigates the prevalence of Enterovirus species B in patients with Crohn’s disease by a chromogenic in situ hybridization assay combined with immunohistochemistry to detect viral RNA and proteins directly in tissue samples.In paper II, padlock probes were used to study the spatial gene expression of gene homologs from the X and Y chromosome in human embryonic nervous tissue. Furthermore, a strategy was devised to visualize and evaluate spatial expression patterns.The padlock probe-based approach for multiplexed spatial transcriptional profiling, in situ sequencing, was applied in paper III to study the regional and cell-type-specific dynamics of A-to-I RNA editing in the developing mouse brain.In paper IV, a technical characterization of padlock probes was performed with the aim of determining how to design a padlock probe to obtain optimal detection efficiency.The work in this thesis demonstrates the dramatic shift in how biological questions in cell and tissue biology can be addressed, enabled by the technological evolution of traditional in situ hybridization assays into high-throughput, multiplexed spatial transcription profiling.
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| 36. |
- Malenczyk, Katarzyna, et al.
(författare)
-
A TRPV1-to-secretagogin regulatory axis controls pancreatic β-cell survival by modulating protein turnover
- 2017
-
Ingår i: EMBO Journal. - : EMBO. - 0261-4189 .- 1460-2075. ; 36:14, s. 1993-2176
-
Tidskriftsartikel (refereegranskat)abstract
- Ca2+-sensor proteins are generally implicated in insulin release through SNARE interactions. Here, secretagogin, whose expression in human pancreatic islets correlates with their insulin content and the incidence of type 2 diabetes, is shown to orchestrate an unexpectedly distinct mechanism. Single-cell RNA-seq reveals retained expression of the TRP family members in β-cells from diabetic donors. Amongst these, pharmacological probing identifies Ca2+-permeable transient receptor potential vanilloid type 1 channels (TRPV1) as potent inducers of secretagogin expression through recruitment of Sp1 transcription factors. Accordingly, agonist stimulation of TRPV1s fails to rescue insulin release from pancreatic islets of glucose intolerant secretagogin knock-out(-/-) mice. However, instead of merely impinging on the SNARE machinery, reduced insulin availability in secretagogin-/- mice is due to β-cell loss, which is underpinned by the collapse of protein folding and deregulation of secretagogin-dependent USP9X deubiquitinase activity. Therefore, and considering the desensitization of TRPV1s in diabetic pancreata, a TRPV1-to-secretagogin regulatory axis seems critical to maintain the structural integrity and signal competence of β-cells.
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| 37. |
- Mattsson, T. R., et al.
(författare)
-
Quantifying the anomalous self-diffusion in molybdenum with first-principles simulations
- 2009
-
Ingår i: Physical Review B. Condensed Matter and Materials Physics. - : American Physical Society. - 1098-0121 .- 1550-235X. ; 80:22
-
Tidskriftsartikel (refereegranskat)abstract
- First-principles molecular-dynamics simulations based on a recently developed exchange-correlation functional show that self-diffusion in the refractory metal molybdenum is associated with strongly temperature-dependent activation energies for vacancy formation and migration. While static calculations of self-diffusion rates based on transition-state theory deviate systematically from experiments, with up to two orders of magnitude, the current results are accurate to within a mean deviation of 4 over the experimental range in temperature.
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| 38. |
- Moberg, Christina, et al.
(författare)
-
De unga gör helt rätt när de stämmer staten : 1 620 forskare och lärare i forskarvärlden: Vi ställer oss bakom Auroras klimatkrav
- 2022
-
Ingår i: Aftonbladet. - : Aftonbladet. ; :2022-12-07
-
Tidskriftsartikel (populärvet., debatt m.m.)abstract
- Vi, 1 620 forskare samt lärare vid universitet och högskolor, är eniga med de unga bakom Auroramålet: De drabbas och riskerar att drabbas allvarligt av klimatkrisen under sin livstid. De klimatåtgärder vi vidtar i närtid avgör deras framtid. Sverige måste ta ansvar och göra sin rättvisa andel av det globala klimatarbetet. I strid med Parisavtalet ökar utsläppen av växthusgaser i en takt som gör att 1,5-gradersmålet kan överskridas om några år. De globala effekterna blir allt mer synliga med ständiga temperaturrekord, smältande isar, havshöjning och extremväder som torka, förödande bränder och skyfall med enorma översvämningar, som i Pakistan nyligen. Försörjningen av befolkningen utsätts för allvarliga hot i många länder.Minskningen av den biologiska mångfalden är extrem. Klimatkrisen är enligt WHO det största hotet mot människors hälsa i hela världen och barn utgör en särskilt sårbar grupp. Med Sveriges nordliga läge sker uppvärmningen här dubbelt så fort som det globala genomsnittet. Det förskjuter utbredningsområden för växtlighet och sjukdomsbärande insekter och ökar förekomsten av extremväder såsom värmeböljor, skogsbränder och översvämningar samt av många olika sorters infektioner och allergier. När extremväder ökar, ökar även stressen och risken för mental ohälsa. Värmeböljor ökar risken för sjukdom och död hos sårbara grupper som äldre, små barn och personer med kroniska sjukdomar. De negativa effekterna på hälsan kommer att öka i takt med klimatkrisen och barn riskerar att drabbas av ackumulerade negativa hälsoeffekter under hela sina liv. Redan i dag är mer än hälften av unga mellan 12 och 18 år i Sverige ganska eller mycket oroliga för klimat och miljö. Detta är förståeligt när våra beslutsfattare inte gör vad som krävs.Den juridiska och moraliska grunden för arbetet mot klimatförändringarna är att varje land måste göra sin rättvisa andel av det globala klimatarbetet. Centralt i det internationella klimatramverket är att rika länder med höga historiska utsläpp, däribland Sverige, måste gå före resten av världen. Dessa länder måste också bidra till att finansiera klimatomställningen i länderna i det Globala Syd, som är minst ansvariga för klimatkrisen men drabbas hårdast. Denna rättviseprincip är tydlig i Parisavtalet och var en het diskussionsfråga under COP27 i Sharm el-Sheikh, men lyser med sin frånvaro i det svenska klimatarbetet. Sverige har satt mål för att minska sina utsläpp. Men de är helt otillräckliga: minskningstakten är för låg och målen tillåter samtidigt att åtgärder skjuts på framtiden. Dessutom exkluderas merparten av Sveriges utsläpp från de svenska nationella utsläppsmålen; bland annat utelämnas utsläpp som svensk konsumtion orsakar utanför Sveriges gränser, utsläpp från utrikes transporter och utsläpp från markanvändning och skogsbruk, exempelvis utsläpp från förbränning av biobränslen eller utsläpp från dikade våtmarker (Prop. 2016/17:146 s.25-28).Sverige saknar dessutom ett eget mål för att öka upptaget av växthusgaser genom utökat skydd och restaurering av ekosystem, något som krävs för att begränsa de värsta konsekvenserna av klimatkrisen (IPCC s.32). Trots dessa låga ambitioner misslyckas Sverige med att nå sina utsläppsmål, konstaterar både Klimatpolitiska rådet och Naturvårdsverket. En klimatpolitik i linje med Parisavtalet kräver både att alla typer av växthusgasutsläpp minskar samtidigt som – inte i stället för – upptaget av växthusgaser maximeras: i dag misslyckas Sverige på bägge fronter.Slutsatsen är tydlig. Sverige vidtar inte de åtgärder som krävs för att skydda barns och ungdomars rättigheter enligt Europakonventionen till skydd för de mänskliga rättigheterna. Detta medför allvarliga risker för liv och hälsa för unga generationer, människor i andra länder och särskilt utsatta grupper. Detta kan inte fortsätta. Därför ställer vi oss bakom Auroras krav att Sverige börjar göra sin rättvisa andel och omedelbart sätter igång ett omfattande och långtgående klimatarbete som vilar på vetenskaplig grund och sätter rättvisa i centrum.
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| 39. |
- Mold, Jeff E., et al.
(författare)
-
Clonally heritable gene expression imparts a layer of diversity within cell types
- 2024
-
Ingår i: Cell systems. - : Elsevier BV. - 2405-4720. ; 15:2, s. 149-
-
Tidskriftsartikel (refereegranskat)abstract
- Cell types can be classified according to shared patterns of transcription. Non-genetic variability among individual cells of the same type has been ascribed to stochastic transcriptional bursting and transient cell states. Using high-coverage single-cell RNA profiling, we asked whether long-term, heritable differences in gene expression can impart diversity within cells of the same type. Studying clonal human lymphocytes and mouse brain cells, we uncovered a vast diversity of heritable gene expression patterns among different clones of cells of the same type in vivo. We combined chromatin accessibility and RNA profiling on different lymphocyte clones to reveal thousands of regulatory regions exhibiting interclonal variation, which could be directly linked to interclonal variation in gene expression. Our findings identify a source of cellular diversity, which may have important implications for how cellular populations are shaped by selective processes in development, aging, and disease. A record of this paper's transparent peer review process is included in the supplemental information.
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| 40. |
- Ngara, Mtakai, et al.
(författare)
-
Exploring parasite heterogeneity using single-cell RNA-seq reveals a gene signature among sexual stage Plasmodium falciparum parasites
- 2018
-
Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 371:1, s. 130-138
-
Tidskriftsartikel (refereegranskat)abstract
- The malaria parasite has a complex lifecycle, including several events of differentiation and stage progression, while actively evading immunity in both its mosquito and human hosts. Important parasite gene expression and regulation during these events remain hidden in rare populations of cells. Here, we combine a capillary-based platform for cell isolation with single-cell RNA-sequencing to transcriptionally profile 165 single infected red blood cells (iRBCs) during the intra-erythrocytic developmental cycle (IDC). Unbiased analyses of single-cell data grouped the cells into eight transcriptional states during IDC. Interestingly, we uncovered a gene signature from the single iRBC analyses that can successfully discriminate between developing asexual and sexual stage parasites at cellular resolution, and we verify five, previously undefined, gametocyte stage specific genes. Moreover, we show the capacity of detecting expressed genes from the variable gene families in single parasites, despite the sparse nature of data. In total, the single parasite transcriptomics holds promise for molecular dissection of rare parasite phenotypes throughout the malaria lifecycle.
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| 41. |
- Reinius, Björn, et al.
(författare)
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Abundance of female-biased and paucity of male-biased somatically expressed genes on the mouse X-chromosome.
- 2012
-
Ingår i: BMC genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: Background: Empirical evaluations of sexually dimorphic expression of genes on the mammalian X-chromosome are needed to understand the evolutionary forces and the gene-regulatory mechanisms controlling this chromosome. We performed a large-scale sex-bias expression analysis of genes on the X-chromosome in six different somatic tissues from mouse. Results: Our results show that the mouse X-chromosome is enriched with female-biased genes and depleted of male-biased genes. This suggests that feminisation as well as de-masculinisation of the X-chromosome has occurred in terms of gene expression in non-reproductive tissues. Several mechanisms may be responsible for the control of female-biased expression on chromosome X, and escape from X-inactivation is a main candidate. We confirmed escape in case of Tmem29 using RNA-FISH analysis. In addition, we identified novel female-biased non-coding transcripts located in the same female-biased cluster as the well-known coding X-inactivation escapee Kdm5c, likely transcribed from the transition-region between active and silenced domains. We also found that previously known escapees only partially explained the overrepresentation of female-biased X-genes, particularly for tissue-specific female-biased genes. Therefore, the gene set we have identified contains tissue-specific escapees and/or genes controlled by other sexually skewed regulatory mechanisms. Analysis of gene age showed that evolutionarily old X-genes (>100 myr, preceding the radiation of placental mammals) are more frequently female-biased than younger genes. Conclusion: Altogether, our results have implications for understanding both gene regulation and gene evolution of mammalian X-chromosomes, and suggest that the final result in terms of the X-gene composition (masculinisation versus feminisation) is a compromise between different evolutionary forces acting on reproductive and somatic tissues.
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| 42. |
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| 43. |
- Sahlén, Pelin, et al.
(författare)
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Genome-wide mapping of promoter-anchored interactions with close to single-enhancer resolution
- 2015
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Although the locations of promoters and enhancers have been identified in several cell types, we still have limited information on their connectivity. We developed HiCap, which combines a 4-cutter restriction enzyme Hi-C with sequence capture of promoter regions. Applying the method to mouse embryonic stem cells, we identified promoter-anchored interactions involving 15,905 promoters and 71,984 distal regions. The distal regions were enriched for enhancer marks and transcription, and had a mean fragment size of only 699 bp - close to single-enhancer resolution. High-resolution maps of promoter-anchored interactions with HiCap will be important for detailed characterizations of chromatin interaction landscapes.
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| 44. |
- Saikkonen, Pentti, et al.
(författare)
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Testing for a Unit Root in Noncausal Autoregressive Models
- 2015
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Ingår i: Journal of Time Series Analysis. - : Wiley: 12 months. - 1467-9892 .- 0143-9782.
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Tidskriftsartikel (refereegranskat)abstract
- This work develops maximum likelihood-based unit root tests in the noncausal autoregressive (NCAR) model with a non-Gaussian error term formulated by Lanne and Saikkonen (2011, Journal of Time Series Econometrics 3, Issue 3, Article 2). Finite-sample properties of the tests are examined via Monte Carlo simulations. The results show that the size properties of the tests are satisfactory and that clear power gains against stationary NCAR alternatives can be achieved in comparison with available alternative tests. In an empirical application to a Finnish interest rate series, evidence in favour of an NCAR model with leptokurtic errors is found.
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| 45. |
- Sandberg, Rickard
(författare)
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Analyses of genomic and gene expression signatures
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Biology has entered a challenging, information-intense period where computational experiments are complementing traditional experiments. A plethora of new techniques have allowed biological processes to be investigated on a global scale. The data analysis has become non-trivial, but crucial in order to draw the appropriate conclusions from these experiments. This thesis combines molecular biology techniques, with a focus on computational techniques, to investigate gene expression profiles and genome signatures. The technological breakthrough with high-density oligonucleotide arrays and cDNA microarrays has enabled the parallel monitoring of the expression levels of thousands of mRNA transcripts. Using high-density oligonucleotide arrays of mRNA from different regions of the adult mouse brain, we identified both region-specific- and strain-specific (129SvEv and C57bl/6) gene expression differences. These genes with strain-specific differential expression are candidates to be involved in the behavioural differences between 129SvEv and C57bl/6. In two reference gene expression studies, we primarily compared the gene expression profiles of cell lines with their corresponding normal and tumor tissues. We estimated the degree of differential expression between cell lines and tissues, and the expression of tissue-specific genes in cell lines. Secondly, we also developed a method to measure tumor and tissue characteristic gene expression in individual cell lines. In pharmaceutical screening programs and in experimental research, when cell lines are used as model systems, the proposed Tissue Similarity Index can be an important tool in the selection of the most appropriate cell lines. Each prokaryote genome has a species-specific bias in the occurrence of short nucleotide motifs, known as its genomic signatures. We demonstrated that genomic signatures where detectable in short DNA sequences and designed a naive Bayesian classifier that identified the correct species origin of DNA sequences based on the genomic signature representation. The classification of DNA sequences was applied to the identification of horizontal gene transfer events. Further, the species-specificity of other sequence biases, such as codon bias, G+C content, and amino acid bias in relation to the genomic signatures were quantified.
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| 46. |
- Sandberg, Rickard
(författare)
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Convergence to stochastic power integrals for dependent heterogeneous processes
- 2009
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Ingår i: Econometric Theory. - : Cambridge University Press. - 0266-4666. ; 25:3, s. 739-747
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Tidskriftsartikel (refereegranskat)abstract
- Building on work of Hansen (1992, Econometric Theory 8, 489–501), we show weak convergence for power transformations of integrated processes, with possibly serially correlated and heterogeneously distributed increments, to stochastic power integrals. The theory is applicable when testing the unit root or cointegration hypothesis in nonlinear systems by regression-based test statistics.
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| 47. |
- Sandberg, Rickard
(författare)
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Critical values for linearity tests in time-varying smooth transition autoregressive models when data are highly persistent
- 2008
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Ingår i: Econometrics Journal. - : Wiley. - 1368-423X .- 1368-4221. ; 11:3, s. 638-647
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Tidskriftsartikel (refereegranskat)abstract
- In this paper, we derive asymptotic distributions for linearity tests in time-varying smooth transition autoregressive models in the presence of a unit root. The limiting distributions are non-standard because of the unit root assumption, and it is shown that the linearity hypothesis is rejected far too often (up to 30.9% of the times at a 5% significance level) when using critical values from a chi-square distribution.
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| 48. |
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| 49. |
- Sandberg, Rickard
(författare)
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Least absolute deviation bases unit root tests in smooth transition type of models
- 2014
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Ingår i: Advances in non-linear economic modeling : theory and applications. - Berlin, Heidelberg : Springer Berlin Heidelberg. - 9783642420399 - 9783642420382 ; 17, s. 141-166
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Building on work by Phillips (Econ. Theory 7:450463, 1991), we derive LAD based unit root tests in a first-order ESTAR model with strong mixing innovations. Further theoretical results are derived and LAD based unit root tests in general nonlinear first-order dynamic models admitting a Taylor-series approximation are thereby easily obtained. Finite sample properties of the tests are explored using Monte Carlo experiments. The results show that the size properties of the tests are satisfactory, and the power against stationary ESTAR alternatives with innovational outliers is significantly higher than the power of the LS based unit root tests by Kapetanios et al. (J. Econ. 112:359379, 2003) and Rothe and Sibbertsen (Allg. Stat. Arch. 90:439456, 2006). In contrast, the LS based tests are more powerful than our tests in the case of stationary ESTAR models with Gaussian errors (no outliers). In an empirical application to eight real effective exchange rates (for major economies), evidence of the PPP hypothesis is supported for six of the countries using our tests. If LS based tests are instead used, the PPP hypothesis is supported for three countries only (countries for which the PPP hypothesis is also supported by our tests).
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| 50. |
- Sandberg, Rickard, et al.
(författare)
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Linearity testing for trending data with an application of the wild bootstrap
- 2013
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Ingår i: Essays on Nonlinear Time Series Econometrics. - : Oxford Scholarship. - 9780199679959 ; , s. 57-90
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- This chapter presents new linearity tests in smooth transition logistic time series models allowing for parameter instability. Building on work by Lundbergh and Teräsvirta (2003), Vogelsang (1998), and Harvey and Leybourne (2007), our linearity tests are constructed in such a way that they do not depend on the order of integration of the time series under consideration. As an important practical implication, this means that critical values from standard distributions can be used when testing for linearity, regardless of whether the process is linear I(0) or linear I(1). In fact, for many macroeconomic and financial time series, it is not evident whether a linear I(0) or linear I(1) process a priori should serve as the null hypothesis. Asymptotic properties of the tests are studied and consistency is shown. Monte Carlo simulations shed light on the tests’ empirical performance in finite samples. The tests, as well as its heteroskedasticity-robust wild bootstrap versions, are applied to 43 macroeconomic and financial US time series. Evidence of both nonlinearities and structural changes is found.
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