| 1. |
- Abbott, Benjamin W., et al.
(author)
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Biomass offsets little or none of permafrost carbon release from soils, streams, and wildfire : an expert assessment
- 2016
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In: Environmental Research Letters. - : IOP Publishing. - 1748-9326. ; 11:3
-
Journal article (peer-reviewed)abstract
- As the permafrost region warms, its large organic carbon pool will be increasingly vulnerable to decomposition, combustion, and hydrologic export. Models predict that some portion of this release will be offset by increased production of Arctic and boreal biomass; however, the lack of robust estimates of net carbon balance increases the risk of further overshooting international emissions targets. Precise empirical or model-based assessments of the critical factors driving carbon balance are unlikely in the near future, so to address this gap, we present estimates from 98 permafrost-region experts of the response of biomass, wildfire, and hydrologic carbon flux to climate change. Results suggest that contrary to model projections, total permafrost-region biomass could decrease due to water stress and disturbance, factors that are not adequately incorporated in current models. Assessments indicate that end-of-the-century organic carbon release from Arctic rivers and collapsing coastlines could increase by 75% while carbon loss via burning could increase four-fold. Experts identified water balance, shifts in vegetation community, and permafrost degradation as the key sources of uncertainty in predicting future system response. In combination with previous findings, results suggest the permafrost region will become a carbon source to the atmosphere by 2100 regardless of warming scenario but that 65%-85% of permafrost carbon release can still be avoided if human emissions are actively reduced.
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| 2. |
- Antel, C., et al.
(author)
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Feebly-interacting particles : FIPs 2022 Workshop Report
- 2023
-
In: European Physical Journal C. - : Springer. - 1434-6044 .- 1434-6052. ; 83:12
-
Research review (peer-reviewed)abstract
- Particle physics today faces the challenge of explaining the mystery of dark matter, the origin of matter over anti-matter in the Universe, the origin of the neutrino masses, the apparent fine-tuning of the electro-weak scale, and many other aspects of fundamental physics. Perhaps the most striking frontier to emerge in the search for answers involves new physics at mass scales comparable to familiar matter, below the GeV-scale, or even radically below, down to sub-eV scales, and with very feeble interaction strength. New theoretical ideas to address dark matter and other fundamental questions predict such feebly interacting particles (FIPs) at these scales, and indeed, existing data provide numerous hints for such possibility. A vibrant experimental program to discover such physics is under way, guided by a systematic theoretical approach firmly grounded on the underlying principles of the Standard Model. This document represents the report of the FIPs 2022 workshop, held at CERN between the 17 and 21 October 2022 and aims to give an overview of these efforts, their motivations, and the decadal goals that animate the community involved in the search for FIPs.
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| 3. |
- Weinstein, John N., et al.
(author)
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The cancer genome atlas pan-cancer analysis project
- 2013
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:10, s. 1113-1120
-
Research review (peer-reviewed)abstract
- The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. © 2013 Nature America, Inc. All rights reserved.
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| 4. |
- Sansone, G., et al.
(author)
-
Electron localization following attosecond molecular photoionization
- 2010
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 465:7299, s. 3-763
-
Journal article (peer-reviewed)abstract
- For the past several decades, we have been able to directly probe the motion of atoms that is associated with chemical transformations and which occurs on the femtosecond (10(-15)-s) timescale. However, studying the inner workings of atoms and molecules on the electronic timescale(1-4) has become possible only with the recent development of isolated attosecond (10(-18)-s) laser pulses(5). Such pulses have been used to investigate atomic photoexcitation and photoionization(6,7) and electron dynamics in solids(8), and in molecules could help explore the prompt charge redistribution and localization that accompany photoexcitation processes. In recent work, the dissociative ionization of H-2 and D-2 was monitored on femtosecond timescales(9) and controlled using few-cycle near-infrared laser pulses(10). Here we report a molecular attosecond pump-probe experiment based on that work: H-2 and D-2 are dissociatively ionized by a sequence comprising an isolated attosecond ultraviolet pulse and an intense few-cycle infrared pulse, and a localization of the electronic charge distribution within the molecule is measured that depends-with attosecond time resolution-on the delay between the pump and probe pulses. The localization occurs by means of two mechanisms, where the infrared laser influences the photoionization or the dissociation of the molecular ion. In the first case, charge localization arises from quantum mechanical interference involving autoionizing states and the laser-altered wavefunction of the departing electron. In the second case, charge localization arises owing to laser-driven population transfer between different electronic states of the molecular ion. These results establish attosecond pump-probe strategies as a powerful tool for investigating the complex molecular dynamics that result from the coupling between electronic and nuclear motions beyond the usual Born-Oppenheimer approximation.
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| 5. |
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| 6. |
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| 7. |
- Sansone, G., et al.
(author)
-
Attosecond excitation of electron wavepackets
- 2008
-
In: Quantum Electronics and Laser Science Conference, QELS 2008. - 9781557528599
-
Conference paper (peer-reviewed)abstract
- We present experiments, supported by time-dependent Schrödinger simulations, on the dynamics of Helium bound states after an attosecond excitation in the presence of a strong infrared laser field.
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| 8. |
- Kelkensberg, F., et al.
(author)
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Molecular Dissociative Ionization and Wave-Packet Dynamics Studied Using Two-Color XUV and IR Pump-Probe Spectroscopy
- 2009
-
In: Physical Review Letters. - 1079-7114. ; 103:12
-
Journal article (peer-reviewed)abstract
- We present a combined theoretical and experimental study of ultrafast wave-packet dynamics in the dissociative ionization of H-2 molecules as a result of irradiation with an extreme-ultraviolet (XUV) pulse followed by an infrared (IR) pulse. In experiments where the duration of both the XUV and IR pulses are shorter than the vibrational period of H-2+, dephasing and rephasing of the vibrational wave packet that is formed in H-2+ upon ionization of the neutral molecule by the XUV pulse is observed. In experiments where the duration of the IR pulse exceeds the vibrational period of H-2+ (15 fs), a pronounced dependence of the H+ kinetic energy distribution on XUV-IR delay is observed that can be explained in terms of the adiabatic propagation of the H-2+ wave packet on field-dressed potential energy curves.
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| 9. |
- Mauritsson, Johan, et al.
(author)
-
Attosecond Electron Spectroscopy Using a Novel Interferometric Pump-Probe Technique
- 2010
-
In: Physical Review Letters. - 1079-7114. ; 105:5
-
Journal article (peer-reviewed)abstract
- We present an interferometric pump-probe technique for the characterization of attosecond electron wave packets (WPs) that uses a free WP as a reference to measure a bound WP. We demonstrate our method by exciting helium atoms using an attosecond pulse (AP) with a bandwidth centered near the ionization threshold, thus creating both a bound and a free WP simultaneously. After a variable delay, the bound WP is ionized by a few-cycle infrared laser precisely synchronized to the original AP. By measuring the delay-dependent photoelectron spectrum we obtain an interferogram that contains both quantum beats as well as multipath interference. Analysis of the interferogram allows us to determine the bound WP components with a spectral resolution much better than the inverse of the AP duration.
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| 10. |
- Papadopoulos, N G, et al.
(author)
-
International consensus on (ICON) pediatric asthma.
- 2012
-
In: Allergy. - : Wiley. - 1398-9995 .- 0105-4538. ; 67:8, s. 976-97
-
Journal article (peer-reviewed)abstract
- Asthma is the most common chronic lower respiratory disease in childhood throughout the world. Several guidelines and/or consensus documents are available to support medical decisions on pediatric asthma. Although there is no doubt that the use of common systematic approaches for management can considerably improve outcomes, dissemination and implementation of these are still major challenges. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), recently formed by the EAACI, AAAAI, ACAAI, and WAO, has decided to propose an International Consensus on (ICON) Pediatric Asthma. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences, thus providing a concise reference. The principles of pediatric asthma management are generally accepted. Overall, the treatment goal is disease control. To achieve this, patients and their parents should be educated to optimally manage the disease, in collaboration with healthcare professionals. Identification and avoidance of triggers is also of significant importance. Assessment and monitoring should be performed regularly to re-evaluate and fine-tune treatment. Pharmacotherapy is the cornerstone of treatment. The optimal use of medication can, in most cases, help patients control symptoms and reduce the risk for future morbidity. The management of exacerbations is a major consideration, independent of chronic treatment. There is a trend toward considering phenotype-specific treatment choices; however, this goal has not yet been achieved.
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| 11. |
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| 12. |
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| 13. |
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| 14. |
- Lepine, F., et al.
(author)
-
Short XUV pulses to characterize field-free molecular alignment
- 2007
-
In: Journal of Modern Optics. - : Informa UK Limited. - 0950-0340 .- 1362-3044. ; 54:7, s. 953-966
-
Journal article (peer-reviewed)abstract
- We present experiments on field-free molecular alignment of N-2 and CO2 probed with short XUV pulses that are obtained via high-harmonic generation. The XUV pulses induce a dissociative ionization or a Coulomb explosion of the molecule, where the fragment ion recoil (measured using the velocity map imaging technique) provides information on the alignment of the parent molecule at the time of ionization. We discuss how photoelectron detection may in future allow the determination of molecular-frame photoelectron angular distributions and molecular structure.
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| 15. |
- Alimena, Juliette, et al.
(author)
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Searching for long-lived particles beyond the Standard Model at the Large Hadron Collider
- 2020
-
In: Journal of Physics G. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 47:9
-
Journal article (peer-reviewed)abstract
- Particles beyond the Standard Model (SM) can generically have lifetimes that are long compared to SM particles at the weak scale. When produced at experiments such as the Large Hadron Collider (LHC) at CERN, these long-lived particles (LLPs) can decay far from the interaction vertex of the primary proton-proton collision. Such LLP signatures are distinct from those of promptly decaying particles that are targeted by the majority of searches for new physics at the LHC, often requiring customized techniques to identify, for example, significantly displaced decay vertices, tracks with atypical properties, and short track segments. Given their non-standard nature, a comprehensive overview of LLP signatures at the LHC is beneficial to ensure that possible avenues of the discovery of new physics are not overlooked. Here we report on the joint work of a community of theorists and experimentalists with the ATLAS, CMS, and LHCb experiments-as well as those working on dedicated experiments such as MoEDAL, milliQan, MATHUSLA, CODEX-b, and FASER-to survey the current state of LLP searches at the LHC, and to chart a path for the development of LLP searches into the future, both in the upcoming Run 3 and at the high-luminosity LHC. The work is organized around the current and future potential capabilities of LHC experiments to generally discover new LLPs, and takes a signature-based approach to surveying classes of models that give rise to LLPs rather than emphasizing any particular theory motivation. We develop a set of simplified models; assess the coverage of current searches; document known, often unexpected backgrounds; explore the capabilities of proposed detector upgrades; provide recommendations for the presentation of search results; and look towards the newest frontiers, namely high-multiplicity 'dark showers', highlighting opportunities for expanding the LHC reach for these signals.
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| 16. |
- Ballantyne, Kaye N., et al.
(author)
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Toward Male Individualization with Rapidly Mutating Y-Chromosomal Short Tandem Repeats
- 2014
-
In: Human Mutation. - : John Wiley & Sons. - 1059-7794 .- 1098-1004. ; 35:8, s. 1021-1032
-
Journal article (peer-reviewed)abstract
- Relevant for various areas of human genetics, Y-chromosomal short tandem repeats (Y-STRs) are commonly used for testing close paternal relationships among individuals and populations, and for male lineage identification. However, even the widely used 17-loci Yfiler set cannot resolve individuals and populations completely. Here, 52 centers generated quality-controlled data of 13 rapidly mutating (RM) Y-STRs in 14,644 related and unrelated males from 111 worldwide populations. Strikingly, greater than99% of the 12,272 unrelated males were completely individualized. Haplotype diversity was extremely high (global: 0.9999985, regional: 0.99836-0.9999988). Haplotype sharing between populations was almost absent except for six (0.05%) of the 12,156 haplotypes. Haplotype sharing within populations was generally rare (0.8% nonunique haplotypes), significantly lower in urban (0.9%) than rural (2.1%) and highest in endogamous groups (14.3%). Analysis of molecular variance revealed 99.98% of variation within populations, 0.018% among populations within groups, and 0.002% among groups. Of the 2,372 newly and 156 previously typed male relative pairs, 29% were differentiated including 27% of the 2,378 father-son pairs. Relative to Yfiler, haplotype diversity was increased in 86% of the populations tested and overall male relative differentiation was raised by 23.5%. Our study demonstrates the value of RMY-STRs in identifying and separating unrelated and related males and provides a reference database.
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| 17. |
- Bock, B.B., et al.
(author)
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Farmers' Relationship with Different Animals: The Importance of Getting Close to the Animals - Case Studies of French, Swedish and Dutch Cattle, Pig and Poultry Farmers.
- 2007
-
In: International Journal of Sociology of Agriculture and Food.. - 0798-1759. ; 15:3, s. 108-125
-
Journal article (peer-reviewed)abstract
- The article analyses how cattle and poultry farmers in the Netherlands described their relationship with their farm animals and explores the factors that influence their level of attachment to them. The analysis draws upon Willkie’s (2005) framework of farmer-animal relationship, which distinguishes between different levels of attachment and detachment. This framework was useful for explaining why farmers developed different levels of attachment to animals, with the species, farm sector and housing system all playing roles in influencing this. Farmers tended to be more attached to cows than to chickens and felt more attachment towards breeding, as opposed to fattening, animals. Breeding, especially of cows, linked the animal to the personal histories of farmers, since their ancestors had often established the bloodlines of dairy cows. Farmers’ relationships with their animals were also influenced by the organization of production at the farm: the number of animals, their length of stay on the farm and the housing system. These factors all influenced the visibility of the animal as an individual and as a ‘real’ animal and not a living tool of production. The species and function of an animal and the organization of production largely defined the frequency, intensity and intimacy of farmers’ contact with individual animals. Practically all farmers (across sectors) perceived taking good care of animals and avoidance of suffering as a core element of their job and caring about animals as central to their definition of a ‘good farmer’. Beyond this, different groups of farmers showed clear differences in their level of attachment to their animals. In general dairy farmers felt more strongly attached to their dairy cows than farmers to their beef cattle or veal, whereas most poultry farmers felt rather detached from their chicken, and tended to perceive them as part of a flock and ‘living production tools’. These animals were not only de-individualized; at times and when seen solely as part of a meat and egg production system they were almost de-animalized.
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| 18. |
- Cardenas, D. E., et al.
(author)
-
Sub-cycle dynamics in relativistic nanoplasma acceleration
- 2019
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9
-
Journal article (peer-reviewed)abstract
- The interaction of light with nanometer-sized solids provides the means of focusing optical radiation to sub-wavelength spatial scales with associated electric field enhancements offering new opportunities for multifaceted applications. We utilize collective effects in nanoplasmas with sub-two-cycle light pulses of extreme intensity to extend the waveform-dependent electron acceleration regime into the relativistic realm, by using 106 times higher intensity than previous works to date. Through irradiation of nanometric tungsten needles, we obtain multi-MeV energy electron bunches, whose energy and direction can be steered by the combined effect of the induced near-field and the laser field. We identified a two-step mechanism for the electron acceleration: (i) ejection within a sub-half-optical-cycle into the near-field from the target at >TVm−1 acceleration fields, and (ii) subsequent acceleration in vacuum by the intense laser field. Our observations raise the prospect of isolating and controlling relativistic attosecond electron bunches, and pave the way for next generation electron and photon sources.
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| 19. |
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| 20. |
- L'Huillier, A., et al.
(author)
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Atomic physics with attosecond pulses
- 2006
-
In: International Conference on Ultrafast Phenomena, UP 2006. - 1557528101 - 9781557528100
-
Conference paper (peer-reviewed)
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| 21. |
- Montandon, A. J., et al.
(author)
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Direct estimate of the haemophilia B (factor IX deficiency) mutation rate and of the ratio of the sex-specific mutation rates in Sweden
- 1992
-
In: Human Genetics. - 0340-6717. ; 89:3, s. 319-322
-
Journal article (peer-reviewed)abstract
- Mutation rates for X-linked recessive diseases have so far been estimated indirectly by postulating an equilibrium between the loss of defective genes caused by the low reproductive fitness of affected males and the gain resulting from new mutations. Here, for the first time, we directly estimate both the overall and sex-specific mutation rates for haemophilia B by detecting the gene defect of the families registered at the Malmö Haemophilia Centre. These represent a complete sample of the Swedish haemophilia B population (45 out of 77 pedigrees) and contain 23 families with a single affected male. Fifteen of these males had mothers available for study, and of these mothers, 13 had parents available for study. We show that 3 of the above patients and 10 of their mothers carry new mutations, and by extrapolation calculate that 8 males and 98 females should carry new haemophilia B mutations in the Swedish population (8.52 × 106 individuals). This leads to the following estimate of the mutation rates: overall μ = 4.1 × 10-6; male specific v = 2.1 × 10-5; and female specific u = 1.9 × 10-6. The ratio of such male to female specific mutation rates is thus v/u = 11.
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| 22. |
- O'Bryant, S. E., et al.
(author)
-
Comparing biological markers of Alzheimer's disease across blood fraction and platforms: Comparing apples to oranges
- 2016
-
In: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 3, s. 27-34
-
Journal article (peer-reviewed)abstract
- Introduction: This study investigated the comparability of potential Alzheimer's disease (AD) biomarkers across blood fractions and assay platforms. Methods: Nonfasting serum and plasma samples from 300 participants (150 AD patients and 150 controls) were analyzed. Proteomic markers were obtained via electrochemiluminescence or Luminex technology. Comparisons were conducted via Pearson correlations. The relative importance of proteins within an AD diagnostic profile was examined using random forest importance plots. Results: On the Meso Scale Discovery multiplex platform, 10 of the 21 markers shared >50% of the variance across blood fractions (serum amyloid A R2 = 0.99, interleukin (IL)10 R2 = 0.95, fatty acid-binding protein (FABP) R2 = 0.94, I309 R2 = 0.94, IL-5 R2 = 0.94, IL-6 R2 = 0.94, eotaxin3 R2 = 0.91, IL-18 R2 = 0.87, soluble tumor necrosis factor receptor 1 R2 = 0.85, and pancreatic polypeptide R2 = 0.81). When examining protein concentrations across platforms, only five markers shared >50% of the variance (beta 2 microglobulin R2 = 0.92, IL-18 R2 = 0.80, factor VII R2 = 0.78, CRP R2 = 0.74, and FABP R2 = 0.70). Discussion: The current findings highlight the importance of considering blood fractions and assay platforms when searching for AD relevant biomarkers. © 2016 The Authors.
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| 23. |
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| 24. |
- Varju, Katalin, et al.
(author)
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Angularly resolved electron wave packet interferences
- 2006
-
In: Journal of Physics B: Atomic, Molecular and Optical Physics. - : IOP Publishing. - 0953-4075 .- 1361-6455. ; 39:18, s. 3983-3991
-
Journal article (peer-reviewed)abstract
- We study experimentally the ionization of argon atoms by a train of attosecond pulses in the presence of a strong infrared laser field, using a velocity map imaging technique. The recorded momentum distribution strongly depends on the delay between the attosecond pulses and the laser field. We interpret the interference patterns observed for different delays using numerical and analytical calculations within the strong field approximation.
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| 25. |
- Green, P. M., et al.
(author)
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Haemophilia B mutations in a complete Swedish population sample : a test of new strategy for the genetic counselling of diseases with high mutational heterogeneity
- 1991
-
In: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 78:3, s. 390-397
-
Journal article (peer-reviewed)abstract
- Carrier and prenatal diagnosis based on the identification of the gene defect (direct diagnosis) increases the proportion of haemophilia B families that can be offered precise genetic counselling from the 50-60% attainable by DNA markers, to 100%, and they also provide information on the molecular biology of the disease. We propose that in order to maximize the practical and scientific benefits of direct diagnosis the gene defect of complete (possibly national) populations of patients should be characterized and the information stored in appropriate confidential databases. We demonstrate the feasibility of such a strategy by characterizing the mutations of all the patients registered with the Malmo haemophilia centre. These patients (44♂ and 1♀) are from 45 unrelated families and 24 (53%) have negative family history. The 25 patients with similar reduction of factor IX:C and factor IX:Ag (24♂ + 1♀) have: two gross deletions, three frameshifts, four translation stops, six mutations expected to affect pre-mRNA splicing and 10 amino acid substitutions. The six patients with greater reduction of factor IX:C than factor IX:Ag and the seven with reduced IX:C and normal IX:Ag have only amino acid substitutions. Patients with inhibitors have: one complete deletion, one frameshift and three translation stops. One patient has both a translation stop and a functionally neutral amino acid substitution (His257→Tyr). Characterization of the factor IX mutation was successful in every case, usually entailed 4 person-days work, and has led to the identification of 12 amino acid residues essential for the factor IX structure and function.
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| 26. |
- Kling, Teresia, 1985, et al.
(author)
-
Integrative Modeling Reveals Annexin A2-mediated Epigenetic Control of Mesenchymal Glioblastoma
- 2016
-
In: Ebiomedicine. - : Elsevier BV. - 2352-3964. ; 12, s. 72-85
-
Journal article (peer-reviewed)abstract
- Glioblastomas are characterized by transcriptionally distinct subtypes, but despite possible clinical relevance, their regulation remains poorly understood. The commonly used molecular classification systems for GBM all identify a subtype with high expression of mesenchymal marker transcripts, strongly associated with invasive growth. We used a comprehensive data-driven network modeling technique (augmented sparse inverse covariance selection, aSICS) to define separate genomic, epigenetic, and transcriptional regulators of glioblastoma subtypes. Our model identified Annexin A2 (ANXA2) as a novel methylation-controlled positive regulator of the mesenchymal subtype. Subsequent evaluation in two independent cohorts established ANXA2 expression as a prognostic factor that is dependent on ANXA2 promoter methylation. ANXA2 knockdown in primary glioblastoma stem cell-like cultures suppressed known mesenchymal master regulators, and abrogated cell proliferation and invasion. Our results place ANXA2 at the apex of a regulatory cascade that determines glioblastoma mesenchymal transformation and validate aSICS as a general methodology to uncover regulators of cancer subtypes. (C) 2016 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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| 27. |
- Remetter, Thomas, et al.
(author)
-
Attosecond electron wave packet interferometry
- 2006
-
In: Nature Physics. - : Springer Science and Business Media LLC. - 1745-2473 .- 1745-2481. ; 2:5, s. 323-326
-
Journal article (peer-reviewed)abstract
- A complete quantum-mechanical description of matter and its interaction with the environment requires detailed knowledge of a number of complex parameters. In particular, information about the phase of wavefunctions is important for predicting the behaviour of atoms, molecules or larger systems. In optics, information about the evolution of the phase of light in time(1) and space(2) is obtained by interferometry. To obtain similar information for atoms and molecules, it is vital to develop analogous techniques. Here we present an interferometric method for determining the phase variation of electronic wave packets in momentum space, and demonstrate its applicability to the fundamental process of single-photon ionization. We use a sequence of extreme-ultraviolet attosecond pulses(3,4) to ionize argon atoms and an infrared laser field, which induces a momentum shear(5) between consecutive electron wave packets. The interferograms that result from the interaction of these wave packets provide useful information about their phase. This technique opens a promising new avenue for reconstructing the wavefunctions(6,7) of atoms and molecules and for following the ultrafast dynamics of electronic wave packets.
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| 28. |
- Tran, Thao Thanh, et al.
(author)
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Inhibition of the master regulator of Listeria monocytogenes virulence enables bacterial clearance from spacious replication vacuoles in infected macrophages
- 2022
-
In: PLoS Pathogens. - : Public Library Science. - 1553-7366 .- 1553-7374. ; 18:1
-
Journal article (peer-reviewed)abstract
- A hallmark of Listeria (L.) monocytogenes pathogenesis is bacterial escape from maturing entry vacuoles, which is required for rapid bacterial replication in the host cell cytoplasm and cell-to-cell spread. The bacterial transcriptional activator PrfA controls expression of key virulence factors that enable exploitation of this intracellular niche. The transcriptional activity of PrfA within infected host cells is controlled by allosteric coactivation. Inhibitory occupation of the coactivator site has been shown to impair PrfA functions, but consequences of PrfA inhibition for L. monocytogenes infection and pathogenesis are unknown. Here we report the crystal structure of PrfA with a small molecule inhibitor occupying the coactivator site at 2.0 Å resolution. Using molecular imaging and infection studies in macrophages, we demonstrate that PrfA inhibition prevents the vacuolar escape of L. monocytogenes and enables extensive bacterial replication inside spacious vacuoles. In contrast to previously described spacious Listeria-containing vacuoles, which have been implicated in supporting chronic infection, PrfA inhibition facilitated progressive clearance of intracellular L. monocytogenes from spacious vacuoles through lysosomal degradation. Thus, inhibitory occupation of the PrfA coactivator site facilitates formation of a transient intravacuolar L. monocytogenes replication niche that licenses macrophages to effectively eliminate intracellular bacteria. Our findings encourage further exploration of PrfA as a potential target for antimicrobials and highlight that intra-vacuolar residence of L. monocytogenes in macrophages is not inevitably tied to bacterial persistence.
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| 29. |
- Veisz, Laszlo, et al.
(author)
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Sub-5-fs laser-driven nanophotonics in the relativistic intensity regime
- 2018
-
In: Optics InfoBase Conference Papers. - : Optica Publishing Group. - 9781557528209
-
Conference paper (peer-reviewed)abstract
- We investigated the interaction of nanometric tungsten targets with ultra-relativisticintensity sub-5-fs laser pulses. Electrons accelerated to multi-MeV energy with electric fields exceeding the TV/m range and dependence on the laser waveform (carrier-envelope phase) were observed.
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