| 1. |
- Hess, Timo, et al.
(författare)
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Dissecting the genetic heterogeneity of gastric cancer
- 2023
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 92
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Tidskriftsartikel (refereegranskat)abstract
- Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture.Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO.Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level.Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO.
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| 2. |
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| 3. |
- Arndt, D. S., et al.
(författare)
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STATE OF THE CLIMATE IN 2017
- 2018
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Ingår i: Bulletin of The American Meteorological Society - (BAMS). - : American Meteorological Society. - 0003-0007 .- 1520-0477. ; 99:8, s. S1-S310
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Forskningsöversikt (refereegranskat)
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| 4. |
- Galván, Ignacio Fdez., et al.
(författare)
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OpenMolcas : From Source Code to Insight
- 2019
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 15:11, s. 5925-5964
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Tidskriftsartikel (refereegranskat)abstract
- In this Article we describe the OpenMolcas environment and invite the computational chemistry community to collaborate. The open-source project already includes a large number of new developments realized during the transition from the commercial MOLCAS product to the open-source platform. The paper initially describes the technical details of the new software development platform. This is followed by brief presentations of many new methods, implementations, and features of the OpenMolcas program suite. These developments include novel wave function methods such as stochastic complete active space self-consistent field, density matrix renormalization group (DMRG) methods, and hybrid multiconfigurational wave function and density functional theory models. Some of these implementations include an array of additional options and functionalities. The paper proceeds and describes developments related to explorations of potential energy surfaces. Here we present methods for the optimization of conical intersections, the simulation of adiabatic and nonadiabatic molecular dynamics, and interfaces to tools for semiclassical and quantum mechanical nuclear dynamics. Furthermore, the Article describes features unique to simulations of spectroscopic and magnetic phenomena such as the exact semiclassical description of the interaction between light and matter, various X-ray processes, magnetic circular dichroism, and properties. Finally, the paper describes a number of built-in and add-on features to support the OpenMolcas platform with postcalculation analysis and visualization, a multiscale simulation option using frozen-density embedding theory, and new electronic and muonic basis sets.
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| 5. |
- Arndt, D. S., et al.
(författare)
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State of the Climate in 2016
- 2017
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Ingår i: Bulletin of The American Meteorological Society - (BAMS). - 0003-0007 .- 1520-0477. ; 98:8, s. S1-S280
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Tidskriftsartikel (refereegranskat)abstract
- In 2016, the dominant greenhouse gases released into Earth's atmosphere-carbon dioxide, methane, and nitrous oxide-continued to increase and reach new record highs. The 3.5 +/- 0.1 ppm rise in global annual mean carbon dioxide from 2015 to 2016 was the largest annual increase observed in the 58-year measurement record. The annual global average carbon dioxide concentration at Earth's surface surpassed 400 ppm (402.9 +/- 0.1 ppm) for the first time in the modern atmospheric measurement record and in ice core records dating back as far as 800000 years. One of the strongest El Nino events since at least 1950 dissipated in spring, and a weak La Nina evolved later in the year. Owing at least in part to the combination of El Nino conditions early in the year and a long-term upward trend, Earth's surface observed record warmth for a third consecutive year, albeit by a much slimmer margin than by which that record was set in 2015. Above Earth's surface, the annual lower troposphere temperature was record high according to all datasets analyzed, while the lower stratospheric temperature was record low according to most of the in situ and satellite datasets. Several countries, including Mexico and India, reported record high annual temperatures while many others observed near-record highs. A week-long heat wave at the end of April over the northern and eastern Indian peninsula, with temperatures surpassing 44 degrees C, contributed to a water crisis for 330 million people and to 300 fatalities. In the Arctic the 2016 land surface temperature was 2.0 degrees C above the 1981-2010 average, breaking the previous record of 2007, 2011, and 2015 by 0.8 degrees C, representing a 3.5 degrees C increase since the record began in 1900. The increasing temperatures have led to decreasing Arctic sea ice extent and thickness. On 24 March, the sea ice extent at the end of the growth season saw its lowest maximum in the 37-year satellite record, tying with 2015 at 7.2% below the 1981-2010 average. The September 2016 Arctic sea ice minimum extent tied with 2007 for the second lowest value on record, 33% lower than the 1981-2010 average. Arctic sea ice cover remains relatively young and thin, making it vulnerable to continued extensive melt. The mass of the Greenland Ice Sheet, which has the capacity to contribute similar to 7 m to sea level rise, reached a record low value. The onset of its surface melt was the second earliest, after 2012, in the 37-year satellite record. Sea surface temperature was record high at the global scale, surpassing the previous record of 2015 by about 0.01 degrees C. The global sea surface temperature trend for the 21st century-to-date of +0.162 degrees C decade(-1) is much higher than the longer term 1950-2016 trend of +0.100 degrees C decade(-1). Global annual mean sea level also reached a new record high, marking the sixth consecutive year of increase. Global annual ocean heat content saw a slight drop compared to the record high in 2015. Alpine glacier retreat continued around the globe, and preliminary data indicate that 2016 is the 37th consecutive year of negative annual mass balance. Across the Northern Hemisphere, snow cover for each month from February to June was among its four least extensive in the 47-year satellite record. Continuing a pattern below the surface, record high temperatures at 20-m depth were measured at all permafrost observatories on the North Slope of Alaska and at the Canadian observatory on northernmost Ellesmere Island. In the Antarctic, record low monthly surface pressures were broken at many stations, with the southern annular mode setting record high index values in March and June. Monthly high surface pressure records for August and November were set at several stations. During this period, record low daily and monthly sea ice extents were observed, with the November mean sea ice extent more than 5 standard deviations below the 1981-2010 average. These record low sea ice values contrast sharply with the record high values observed during 2012-14. Over the region, springtime Antarctic stratospheric ozone depletion was less severe relative to the 1991-2006 average, but ozone levels were still low compared to pre-1990 levels. Closer to the equator, 93 named tropical storms were observed during 2016, above the 1981-2010 average of 82, but fewer than the 101 storms recorded in 2015. Three basins-the North Atlantic, and eastern and western North Pacific-experienced above-normal activity in 2016. The Australian basin recorded its least active season since the beginning of the satellite era in 1970. Overall, four tropical cyclones reached the Saffir-Simpson category 5 intensity level. The strong El Nino at the beginning of the year that transitioned to a weak La Nina contributed to enhanced precipitation variability around the world. Wet conditions were observed throughout the year across southern South America, causing repeated heavy flooding in Argentina, Paraguay, and Uruguay. Wetter-than-usual conditions were also observed for eastern Europe and central Asia, alleviating the drought conditions of 2014 and 2015 in southern Russia. In the United States, California had its first wetter-than-average year since 2012, after being plagued by drought for several years. Even so, the area covered by drought in 2016 at the global scale was among the largest in the post-1950 record. For each month, at least 12% of land surfaces experienced severe drought conditions or worse, the longest such stretch in the record. In northeastern Brazil, drought conditions were observed for the fifth consecutive year, making this the longest drought on record in the region. Dry conditions were also observed in western Bolivia and Peru; it was Bolivia's worst drought in the past 25 years. In May, with abnormally warm and dry conditions already prevailing over western Canada for about a year, the human-induced Fort McMurray wildfire burned nearly 590000 hectares and became the costliest disaster in Canadian history, with $3 billion (U.S. dollars) in insured losses.
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| 6. |
- Carlomagno, Brunella, et al.
(författare)
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End-to-end simulations of the E-ELT/METIS coronagraphs
- 2016
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Ingår i: Adaptive Optics Systems V. - : SPIE - International Society for Optical Engineering. ; , s. 1-10
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Konferensbidrag (refereegranskat)abstract
- The direct detection of low-mass planets in the habitable zone of nearby stars is an important science case for future E-ELT instruments such as the mid-infrared imager and spectrograph METIS, which features vortex phase masks and apodizing phase plates (APP) in its baseline design. In this work, we present end-to-end performance simulations, using Fourier propagation, of several METIS coronagraphic modes, including focal-plane vortex phase masks and pupil-plane apodizing phase plates, for the centrally obscured, segmented E-ELT pupil. The atmosphere and the AO contributions are taken into account. Hybrid coronagraphs combining the advantages of vortex phase masks and APPs are considered to improve the METIS coronagraphic performance.
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| 7. |
- Chen, Cong, et al.
(författare)
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Distinguishing attosecond electron-electron scattering and screening in transition metals
- 2017
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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. ; 114:27, s. E5300-E5307
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Tidskriftsartikel (refereegranskat)abstract
- Electron-electron interactions are the fastest processes in materials, occurring on femtosecond to attosecond timescales, depending on the electronic band structure of the material and the excitation energy. Such interactions can play a dominant role in light-induced processes such as nano-enhanced plasmonics and catalysis, light harvesting, or phase transitions. However, to date it has not been possible to experimentally distinguish fundamental electron interactions such as scattering and screening. Here, we use sequences of attosecond pulses to directly measure electron-electron interactions in different bands of different materials with both simple and complex Fermi surfaces. By extracting the time delays associated with photoemission we show that the lifetime of photoelectrons from the d band of Cu are longer by similar to 100 as compared with those from the same band of Ni. We attribute this to the enhanced electron-electron scattering in the unfilled d band of Ni. Using theoretical modeling, we can extract the contributions of electron-electron scattering and screening in different bands of different materials with both simple and complex Fermi surfaces. Our results also show that screening influences high-energy photoelectrons (approximate to 20 eV) significantly less than low-energy photoelectrons. As a result, high-energy photoelectrons can serve as a direct probe of spin-dependent electron-electron scattering by neglecting screening. This can then be applied to quantifying the contribution of electron interactions and screening to low-energy excitations near the Fermi level. The information derived here provides valuable and unique information for a host of quantum materials.
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| 8. |
- de Boer, J., et al.
(författare)
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Multiple rings in the transition disk and companion candidates around RX J1615.3-3255 High contrast imaging with VLT/SPHERE
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 595
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Tidskriftsartikel (refereegranskat)abstract
- Context. The effects of a planet sculpting the disk from which it formed are most likely to be found in disks that are in transition between being classical protoplanetary and debris disks. Recent direct imaging of transition disks has revealed structures such as dust rings, gaps, and spiral arms, but an unambiguous link between these structures and sculpting planets is yet to be found. Aims. We aim to find signs of ongoing planet-disk interaction and study the distribution of small grains at the surface of the transition disk around RXJ1615.3-3255 (RX J1615). Methods. We observed RXJ1615 with VLT/SPHERE. From these observations, we obtained polarimetric imaging with ZIMPOL (R'-band) and IRDIS (J), and IRDIS (H2H3) dual-band imaging with simultaneous spatially resolved spectra with the IFS (YJ). Results. We image the disk for the first time in scattered light and detect two arcs, two rings, a gap and an inner disk with marginal evidence for an inner cavity. The shapes of the arcs suggest that they are probably segments of full rings. Ellipse fitting for the two rings and inner disk yield a disk inclination i = 47 +/- 2 degrees and find semi-major axes of 1.50 +/- 0.01 '' (278 au), 1.06 +/- 0.01 '' (196 au) and 0.30 +/- 0.01 '' (56 au), respectively. We determine the scattering surface height above the midplane, based on the projected ring center offsets. Nine point sources are detected between 2.1 '' and 8.0 '' separation and considered as companion candidates. With NACO data we recover four of the nine point sources, which we determine to be not co-moving, and therefore unbound to the system. Conclusions. We present the first detection of the transition disk of RXJ1615 in scattered light. The height of the rings indicate limited flaring of the disk surface, which enables partial self-shadowing in the disk. The outermost arc either traces the bottom of the disk or it is another ring with semi-major axis greater than or similar to 2.35 '' (435 au). We explore both scenarios, extrapolating the complete shape of the feature, which will allow us to distinguish between the two in future observations. The most attractive scenario, where the arc traces the bottom of the outer ring, requires the disk to be truncated at r approximate to 360 au. If the closest companion candidate is indeed orbiting the disk at 540 au, then it would be the most likely cause for such truncation. This companion candidate, as well as the remaining four, all require follow up observations to determine if they are bound to the system.
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| 9. |
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| 10. |
- Ellinghaus, David, et al.
(författare)
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Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies
- 2013
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 145:2, s. 339-347
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies.METHODS: We sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems.RESULTS: We identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 x 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 x 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor kappa B activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways.CONCLUSIONS: We have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.
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| 11. |
- Escott-Price, Valentina, et al.
(författare)
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Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e94661-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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| 12. |
- Freitag, Daniel F., et al.
(författare)
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Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis
- 2015
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Ingår i: The Lancet Diabetes & Endocrinology. - 2213-8595. ; 3:4, s. 243-253
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Tidskriftsartikel (refereegranskat)abstract
- Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.
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| 13. |
- Freitag, Leon, et al.
(författare)
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Orbital entanglement and CASSCF analysis of the Ru-NO bond in a Ruthenium nitrosyl complex
- 2015
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 17:22, s. 14383-14392
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Tidskriftsartikel (refereegranskat)abstract
- Complete active space self-consistent field (CASSCF) wavefunctions and an orbital entanglement analysis obtained from a density-matrix renormalisation group (DMRG) calculation are used to understand the electronic structure, and, in particular, the Ru-NO bond of a Ru nitrosyl complex. Based on the configurations and orbital occupation numbers obtained for the CASSCF wavefunction and on the orbital entropy measurements evaluated for the DMRG wavefunction, we unravel electron correlation effects in the Ru coordination sphere of the complex. It is shown that Ru-NO pi bonds show static and dynamic correlation, while other Ru-ligand bonds feature predominantly dynamic correlation. The presence of static correlation requires the use of multiconfigurational methods to describe the Ru-NO bond. Subsequently, the CASSCF wavefunction is analysed in terms of configuration state functions based on localised orbitals. The analysis of the wavefunctions in the electronic singlet ground state and the first triplet state provides a picture of the Ru-NO moiety beyond the standard representation based on formal oxidation states. A distinct description of the Ru and NO fragments is advocated. The electron configuration of Ru is an equally weighted superposition of Ru-II and Ru-III configurations, with the Ru-III configuration originating from charge donation mostly from Cl ligands. However, and contrary to what is typically assumed, the electronic configuration of the NO ligand is best described as electroneutral.
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| 14. |
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| 15. |
- He, Liqun, et al.
(författare)
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Single-cell RNA sequencing of mouse brain and lung vascular and vessel-associated cell types
- 2018
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Ingår i: Scientific Data. - : NATURE PUBLISHING GROUP. - 2052-4463. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Vascular diseases are major causes of death, yet our understanding of the cellular constituents of blood vessels, including how differences in their gene expression profiles create diversity in vascular structure and function, is limited. In this paper, we describe a single-cell RNA sequencing (scRNA-seq) dataset that defines vascular and vessel-associated cell types and subtypes in mouse brain and lung. The dataset contains 3,436 single cell transcriptomes from mouse brain, which formed 15 distinct clusters corresponding to cell (sub) types, and another 1,504 single cell transcriptomes from mouse lung, which formed 17 cell clusters. In order to allow user-friendly access to our data, we constructed a searchable database (http://betsholtzlab.org/VascularSingleCells/database.html). Our dataset constitutes a comprehensive molecular atlas of vascular and vessel-associated cell types in the mouse brain and lung, and as such provides a strong foundation for future studies of vascular development and diseases.
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| 16. |
- Jones, Lesley, et al.
(författare)
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Convergent genetic and expression data implicate immunity in Alzheimer's disease
- 2015
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671
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Tidskriftsartikel (refereegranskat)abstract
- Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
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| 17. |
- Keller, Maria, et al.
(författare)
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Genetically programmed changes in transcription of the novel progranulin regulator
- 2020
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Ingår i: Journal of Molecular Medicine. - : Springer Science and Business Media LLC. - 0946-2716 .- 1432-1440. ; 98:8, s. 1139-1148
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: Progranulin is a glycoprotein marking chronic inflammation in obesity and type 2 diabetes. Previous studies suggested PSRC1 (proline and serine rich coiled-coil 1) to be a target of genetic variants associated with serum progranulin levels. We aimed to identify potentially functional variants and characterize their role in regulation of PSRC1. Phylogenetic module complexity analysis (PMCA) prioritized four polymorphisms (rs12740374, rs629301, rs660240, rs7528419) altering transcription factor binding sites with an overall score for potential regulatory function of Sall > 7.0. The effects of these variants on transcriptional activity and binding of transcription factors were tested by luciferase reporter and electrophoretic mobility shift assays (EMSA). In parallel, blood DNA promoter methylation of two regions was tested in subjects with a very high (N = 100) or a very low (N = 100) serum progranulin. Luciferase assays revealed lower activities in vectors carrying the rs629301-A compared with the C allele. Moreover, EMSA indicated a different binding pattern for the two rs629301 alleles, with an additional prominent band for the A allele, which was finally confirmed with the supershift for the Yin Yang 1 transcription factor (YY1). Subjects with high progranulin levels manifested a significantly higher mean DNA methylation (P < 1 × 10−7) in one promoter region, which was in line with a significantly lower PSRC1 mRNA expression levels in blood (P = 1 × 10−3). Consistently, rs629301-A allele was associated with lower PSRC1 mRNA expression (P < 1 × 10−7). Our data suggest that the progranulin-associated variant rs629301 modifies the transcription of PSRC1 through alteration of YY1 binding capacity. DNA methylation studies further support the role of PSRC1 in regulation of progranulin serum levels. Key messages: PSRC1 (proline and serine rich coiled-coil 1) SNPs are associated with serum progranulin levels.rs629301 regulates PSRC1 expression by affecting Yin Yang 1 transcription factor (YY1) binding.PSRC1 is also epigenetically regulated in subjects with high progranulin levels.
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| 18. |
- Ledinek, Dorothea, et al.
(författare)
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Effect of different Na supply methods on thin Cu(In,Ga)Se2 solar cells with Al2O3 rear passivation layers
- 2018
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Ingår i: Solar Energy Materials and Solar Cells. - : Elsevier BV. - 0927-0248 .- 1879-3398. ; 187:1, s. 160-169
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Tidskriftsartikel (refereegranskat)abstract
- In this work, rear-contact passivated Cu(In,Ga)Se2 (CIGS) solar cells were fabricated without any intentional contact openings between the CIGS and Mo layers. The investigated samples were either Na free or one of two Na supply methods was used, i) a NaF precursor on top of the Al2O3 rear passivation layer or ii) an in situ post- deposition treatment with NaF after co-evaporation of the CIGS layer. The thickness of the ALD-Al2O3 passi- vation layer was also varied in order to find an optimal combination of Na supply and passivation layer thickness. Our results from electrical characterization show remarkably different solar cell behavior for different Na supplies. For up to 1nm thick Al2O3 layers an electronically good contact could be confirmed independently of Na deposition method and content. When the Al2O3 thickness exceeded 1 nm, the current was blocked on all samples except on the samples with the NaF precursor. On these samples the current was not blocked up to an Al2O3 layer thickness of about 6 nm, the maximum thickness we could achieve without the CIGS peeling off the Al2O3 layer. Transmission electron microscopy reveals a porous passivation layer for the samples with a NaF precursor. An analysis of the dependence of the open circuit voltage on temperature (JVT) indicates that a thicker NaF precursor layer lowers the height of the hole barrier at the rear contact for the passivated cells. This energy barrier is also lower for the passivated sample, compared to an unpassivated sample, when both samples have been post-deposition treated.
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| 19. |
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| 20. |
- Marini, S., et al.
(författare)
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Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity A Meta-analysis
- 2019
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Ingår i: Jama Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 76:4, s. 480-491
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Genetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations. OBJECTIVE To evaluate associations between established differences in ICH risk by race/ethnicity and the variability in the risks of apolipoprotein E (APOE) epsilon 4 alleles, the most potent genetic risk factor for ICH. DESIGN, SETTING, AND PARTICIPANTS This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study. MAIN OUTCOMES AND MEASURES Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies. RESULTS In total, 13 124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE epsilon 2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P < .001) and APOE epsilon 4 (OR, 1.51; 95% CI, 1.23-1.85; P < .001) were associated with lobar ICH risk; however, within self-identified Hispanic and black participants, no associations were found. After propensity score matching for hypertension burden, APOE epsilon 4 was associated with lobar ICH risk among Hispanic (OR, 1.14; 95% CI, 1.03-1.28; P = .01) but not in black (OR, 1.02; 95% CI, 0.98-1.07; P = .25) participants. APOE epsilon 2 and epsilon 4 did not show an association with nonlobar ICH risk in any race/ethnicity. CONCLUSIONS AND RELEVANCE APOE epsilon 4 and epsilon 2 alleles appear to affect lobar ICH risk variably by race/ethnicity, associations that are confirmed in white individuals but can be shown in Hispanic individuals only when the excess burden of hypertension is propensity score-matched; further studies are needed to explore the interactions between APOE alleles and environmental exposures that vary by race/ethnicity in representative populations at risk for ICH.
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| 21. |
- Mittler, Eva, et al.
(författare)
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Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses
- 2022
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science. - 1946-6234 .- 1946-6242. ; 14:636
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Tidskriftsartikel (refereegranskat)abstract
- The rodent-borne hantavirus Puumala virus (PUUV) and related agents cause hemorrhagic fever with renal syndrome (HFRS) in humans. Other hantaviruses, including Andes virus (ANDV) and Sin Nombre virus, cause a distinct zoonotic disease, hantavirus cardiopulmonary syndrome (HCPS). Although these infections are severe and have substantial case fatality rates, no FDA-approved hantavirus countermeasures are available. Recent work suggests that monoclonal antibodies may have therapeutic utility. We describe here the isolation of human neutralizing antibodies (nAbs) against tetrameric Gn/Gc glycoprotein spikes from PUUV-experienced donors. We define a dominant class of nAbs recognizing the "capping loop" of Gn that masks the hydrophobic fusion loops in Gc. A subset of nAbs in this class, including ADI-42898, bound Gn/Gc complexes but not Gn alone, strongly suggesting that they recognize a quaternary epitope encompassing both Gn and Gc. ADI-42898 blocked the cell entry of seven HCPS- and HFRS-associated hantaviruses, and single doses of this nAb could protect Syrian hamsters and bank voles challenged with the highly virulent HCPS-causing ANDV and HFRS-causing PUUV, respectively. ADI-42898 is a promising candidate for clinical development as a countermeasure for both HCPS and HFRS, and its mode of Gn/Gc recognition informs the development of broadly protective hantavirus vaccines.
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| 22. |
- Mittler, Eva, et al.
(författare)
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Structural and mechanistic basis of neutralization by a pan-hantavirus protective antibody
- 2023
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 15:700
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Tidskriftsartikel (refereegranskat)abstract
- Emerging rodent-borne hantaviruses cause severe diseases in humans with no approved vaccines or therapeutics. We recently isolated a monoclonal broadly neutralizing antibody (nAb) from a Puumala virus-experienced human donor. Here, we report its structure bound to its target, the Gn/Gc glycoprotein heterodimer comprising the viral fusion complex. The structure explains the broad activity of the nAb: It recognizes conserved Gc fusion loop sequences and the main chain of variable Gn sequences, thereby straddling the Gn/Gc heterodimer and locking it in its prefusion conformation. We show that the nAb's accelerated dissociation from the divergent Andes virus Gn/Gc at endosomal acidic pH limits its potency against this highly lethal virus and correct this liability by engineering an optimized variant that sets a benchmark as a candidate pan-hantavirus therapeutic.
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| 23. |
- Mäe, Maarja Andaloussi, et al.
(författare)
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Single-Cell Analysis of Blood-Brain Barrier Response to Pericyte Loss
- 2021
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Ingår i: Circulation Research. - : Lippincott Williams & Wilkins. - 0009-7330 .- 1524-4571. ; 128:4, s. E46-E62
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Pericytes are capillary mural cells playing a role in stabilizing newly formed blood vessels during development and tissue repair. Loss of pericytes has been described in several brain disorders, and genetically induced pericyte deficiency in the brain leads to increased macromolecular leakage across the blood-brain barrier (BBB). However, the molecular details of the endothelial response to pericyte deficiency remain elusive.Objective: To map the transcriptional changes in brain endothelial cells resulting from lack of pericyte contact at single-cell level and to correlate them with regional heterogeneities in BBB function and vascular phenotype.Methods and Results: We reveal transcriptional, morphological, and functional consequences of pericyte absence for brain endothelial cells using a combination of methodologies, including single-cell RNA sequencing, tracer analyses, and immunofluorescent detection of protein expression in pericyte-deficient adult Pdgfb(ret/ret) mice. We find that endothelial cells without pericyte contact retain a general BBB-specific gene expression profile, however, they acquire a venous-shifted molecular pattern and become transformed regarding the expression of numerous growth factors and regulatory proteins. Adult Pdgfb(ret/ret) brains display ongoing angiogenic sprouting without concomitant cell proliferation providing unique insights into the endothelial tip cell transcriptome. We also reveal heterogeneous modes of pericyte-deficient BBB impairment, where hotspot leakage sites display arteriolar-shifted identity and pinpoint putative BBB regulators. By testing the causal involvement of some of these using reverse genetics, we uncover a reinforcing role for angiopoietin 2 at the BBB.Conclusions: By elucidating the complexity of endothelial response to pericyte deficiency at cellular resolution, our study provides insight into the importance of brain pericytes for endothelial arterio-venous zonation, angiogenic quiescence, and a limited set of BBB functions. The BBB-reinforcing role of ANGPT2 (angiopoietin 2) is paradoxical given its wider role as TIE2 (TEK receptor tyrosine kinase) receptor antagonist and may suggest a unique and context-dependent function of ANGPT2 in the brain.
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| 24. |
- Parke, Harry
(författare)
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Applications of motional control in trapped Rydberg ion experiments
- 2022
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Trapped ion systems are one of the leading technologies for the development of various novel quantum devices, including computers, simulators and enhanced sensors. Ion traps offer a high level of control in terms of both the electronic and motional states of individual quantum systems. This enables information to be efficiently encoded and transferred, often via interaction with highly controlled laser fields. In particular, the use of collective motional excitation to generate entanglement is a principle that underlies the majority of gate operations that have thus far been implemented in trapped ion systems. Another method, originally devised to circumvent the need for collective motional excitation in entangling operations, is to use Rydberg states which can be engineered to produce strong, direct and state-dependent interactions between ions. Due to their sensitivity to electric fields, trapped Rydberg ions have also opened the possibility for the development of entirely new gate schemes and for use in quantum metrology. In this work we employ the high level of motional control available to trapped ion systems in order to perform three experiments, involving quantum simulation, computation and metrology respectively. In the first we make use of a single ion and couple its electronic and motional states to simulate sub- and superradiant emission for an atom confined in a 2D cavity. The results obtained showed that technical limitations in our experimental system currently inhibit the formation of such states. In the second experiment we introduce a novel gate scheme for quantum computation using trapped Rydberg ions, initial results demonstrating the feasibility of the gate scheme are presented and future plans for this work are summarised. For the final experiment we investigate the effects of an electric quadrupole field interacting with a single ion to second and higher orders. We observe resonance shifts for the Rydberg excitation and the presence of sidebands due to the interaction when performing spectral scans. These observations show good agreement when compared with theoretical models. Finally a new technique for performing coherent spectroscopy of Ryberg states is demonstrated.
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| 25. |
- Pulit, S. L., et al.
(författare)
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Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes
- 2018
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Ingår i: Neurology-Genetics. - : Ovid Technologies (Wolters Kluwer Health). - 2376-7839. ; 4:6
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Tidskriftsartikel (refereegranskat)abstract
- Objective We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 x 10(-4) in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 x 10(-48)), explaining similar to 20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07,p = 0.004), but no other primary stroke subtypes (all p > 0.1). Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.
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