| 1. |
- Kanai, M, et al.
(author)
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- 2023
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swepub:Mat__t
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| 2. |
- Niemi, MEK, et al.
(author)
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- 2021
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swepub:Mat__t
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| 10. |
- Dalton, A. S., et al.
(author)
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An updated radiocarbon-based ice margin chronology for the last deglaciation of the North American Ice Sheet Complex
- 2020
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In: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791. ; 234
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Journal article (peer-reviewed)abstract
- The North American Ice Sheet Complex (NAISC; consisting of the Laurentide, Cordilleran and Innuitian ice sheets) was the largest ice mass to repeatedly grow and decay in the Northern Hemisphere during the Quaternary. Understanding its pattern of retreat following the Last Glacial Maximum is critical for studying many facets of the Late Quaternary, including ice sheet behaviour, the evolution of Holocene landscapes, sea level, atmospheric circulation, and the peopling of the Americas. Currently, the most up-to-date and authoritative margin chronology for the entire ice sheet complex is featured in two publications (Geological Survey of Canada Open File 1574 [Dyke et al., 2003]; 'Quaternary Glaciations - Extent and Chronology, Part II' [Dyke, 2004]). These often-cited datasets track ice margin recession in 36 time slices spanning 18 ka to 1 ka (all ages in uncalibrated radiocarbon years) using a combination of geomorphology, stratigraphy and radiocarbon dating. However, by virtue of being over 15 years old, the ice margin chronology requires updating to reflect new work and important revisions. This paper updates the aforementioned 36 ice margin maps to reflect new data from regional studies. We also update the original radiocarbon dataset from the 2003/2004 papers with 1541 new ages to reflect work up to and including 2018. A major revision is made to the 18 ka ice margin, where Banks and Eglinton islands (once considered to be glacial refugia) are now shown to be fully glaciated. Our updated 18 ka ice sheet increased in areal extent from 17.81 to 18.37 million km(2), which is an increase of 3.1% in spatial coverage of the NAISC at that time. Elsewhere, we also summarize, region-by-region, significant changes to the deglaciation sequence. This paper integrates new information provided by regional experts and radiocarbon data into the deglaciation sequence while maintaining consistency with the original ice margin positions of Dyke et al. (2003) and Dyke (2004) where new information is lacking; this is a pragmatic solution to satisfy the needs of a Quaternary research community that requires up-to-date knowledge of the pattern of ice margin recession of what was once the world's largest ice mass. The 36 updated isochrones are available in PDF and shapefile format, together with a spreadsheet of the expanded radiocarbon dataset (n = 5195 ages) and estimates of uncertainty for each interval. (C) 2020 Elsevier Ltd. All rights reserved.
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| 11. |
- Augustin, Livia S. A., et al.
(author)
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Dietary Fibre Consensus from the International Carbohydrate Quality Consortium (ICQC)
- 2020
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In: Nutrients. - : MDPI. - 2072-6643. ; 12:9
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Journal article (peer-reviewed)abstract
- Dietary fibre is a generic term describing non-absorbed plant carbohydrates and small amounts of associated non-carbohydrate components. The main contributors of fibre to the diet are the cell walls of plant tissues, which are supramolecular polymer networks containing variable proportions of cellulose, hemicelluloses, pectic substances, and non-carbohydrate components, such as lignin. Other contributors of fibre are the intracellular storage oligosaccharides, such as fructans. A distinction needs to be made between intrinsic sources of dietary fibre and purified forms of fibre, given that the three-dimensional matrix of the plant cell wall confers benefits beyond fibre isolates. Movement through the digestive tract modifies the cell wall structure and may affect the interactions with the colonic microbes (e.g., small intestinally non-absorbed carbohydrates are broken down by bacteria to short-chain fatty acids, absorbed by colonocytes). These aspects, combined with the fibre associated components (e.g., micronutrients, polyphenols, phytosterols, and phytoestrogens), may contribute to the health outcomes seen with the consumption of dietary fibre. Therefore, where possible, processing should minimise the degradation of the plant cell wall structures to preserve some of its benefits. Food labelling should include dietary fibre values and distinguish between intrinsic and added fibre. Labelling may also help achieve the recommended intake of 14 g/1000 kcal/day.
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| 12. |
- Buch, S., et al.
(author)
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Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study
- 2023
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In: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 72:2, s. 381-391
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Journal article (peer-reviewed)abstract
- Objective Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. Design Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case-control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). Results Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41x10(-9), OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94x10(-5), OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12x10(-44)). Conclusion This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis.
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| 13. |
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| 14. |
- Hebborn, C., et al.
(author)
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Optical potentials for the rare-isotope beam era
- 2023
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In: Journal of Physics G: Nuclear and Particle Physics. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 50:6
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Journal article (peer-reviewed)abstract
- We review recent progress and motivate the need for further developments in nuclear optical potentials that are widely used in the theoretical analysis of nucleon elastic scattering and reaction cross sections. In regions of the nuclear chart away from stability, which represent a frontier in nuclear science over the coming decade and which will be probed at new rare-isotope beam facilities worldwide, there is a targeted need to quantify and reduce theoretical reaction model uncertainties, especially with respect to nuclear optical potentials. We first describe the primary physics motivations for an improved description of nuclear reactions involving short-lived isotopes, focusing on its benefits for fundamental science discoveries and applications to medicine, energy, and security. We then outline the various methods in use today to build optical potentials starting from phenomenological, microscopic, and ab initio methods, highlighting in particular, the strengths and weaknesses of each approach. We then discuss publicly-available tools and resources facilitating the propagation of recent progresses in the field to practitioners. Finally, we provide a set of open challenges and recommendations for the field to advance the fundamental science goals of nuclear reaction studies in the rare-isotope beam era. This paper is the outcome of the Facility for Rare Isotope Beams Theory Alliance (FRIB-TA) topical program ‘Optical Potentials in Nuclear Physics’ held in March 2022 at FRIB. Its content is non-exhaustive, was chosen by the participants and reflects their efforts related to optical potentials.
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| 15. |
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| 16. |
- Falster, Daniel, et al.
(author)
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AusTraits, a curated plant trait database for the Australian flora
- 2021
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In: Scientific Data. - : Nature Portfolio. - 2052-4463. ; 8:1
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Journal article (peer-reviewed)abstract
- We introduce the AusTraits database - a compilation of values of plant traits for taxa in the Australian flora (hereafter AusTraits). AusTraits synthesises data on 448 traits across 28,640 taxa from field campaigns, published literature, taxonomic monographs, and individual taxon descriptions. Traits vary in scope from physiological measures of performance (e.g. photosynthetic gas exchange, water-use efficiency) to morphological attributes (e.g. leaf area, seed mass, plant height) which link to aspects of ecological variation. AusTraits contains curated and harmonised individual- and species-level measurements coupled to, where available, contextual information on site properties and experimental conditions. This article provides information on version 3.0.2 of AusTraits which contains data for 997,808 trait-by-taxon combinations. We envision AusTraits as an ongoing collaborative initiative for easily archiving and sharing trait data, which also provides a template for other national or regional initiatives globally to fill persistent gaps in trait knowledge.
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| 17. |
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| 18. |
- Olsson, MIT, et al.
(author)
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Gender Gap in Parental Leave Intentions : Evidence from 37 Countries
- 2023
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In: Political Psychology. - : Wiley-Blackwell Publishing Ltd. - 0162-895X .- 1467-9221. ; 44:6, s. 1163-1192
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Journal article (peer-reviewed)abstract
- Despite global commitments and efforts, a gender-based division of paid and unpaid work persists. To identify how psychological factors, national policies, and the broader sociocultural context contribute to this inequality, we assessed parental-leave intentions in young adults (18–30 years old) planning to have children (N = 13,942; 8,880 identified as women; 5,062 identified as men) across 37 countries that varied in parental-leave policies and societal gender equality. In all countries, women intended to take longer leave than men. National parental-leave policies and women's political representation partially explained cross-national variations in the gender gap. Gender gaps in leave intentions were paradoxically larger in countries with more gender-egalitarian parental-leave policies (i.e., longer leave available to both fathers and mothers). Interestingly, this cross-national variation in the gender gap was driven by cross-national variations in women's (rather than men's) leave intentions. Financially generous leave and gender-egalitarian policies (linked to men's higher uptake in prior research) were not associated with leave intentions in men. Rather, men's leave intentions were related to their individual gender attitudes. Leave intentions were inversely related to career ambitions. The potential for existing policies to foster gender equality in paid and unpaid work is discussed.
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| 19. |
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| 20. |
- Aleksandrova, Elena V, et al.
(author)
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Structural basis of Cfr-mediated antimicrobial resistance and mechanisms for its evasion
- 2023
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Other publication (other academic/artistic)abstract
- The ribosome is an essential drug target as many classes of clinically important antibiotics bind and inhibit its functional centers. The catalytic peptidyl transferase center (PTC) is targeted by the broadest array of inhibitors belonging to several chemical classes. One of the most abundant and clinically prevalent mechanisms of resistance to PTC-acting drugs is C8-methylation of the universally conserved adenine residue 2503 (A2503) of the 23S rRNA by the methyltransferase Cfr. Despite its clinical significance, a sufficient understanding of the molecular mechanisms underlying Cfr-mediated resistance is currently lacking. In this work, we developed a method to express a functionally-active Cfr-methyltransferase in the thermophilic bacterium Thermus thermophilus and report a set of high-resolution structures of the Cfr-modified 70S ribosome containing aminoacyl- and peptidyl-tRNAs. Our structures reveal that an allosteric rearrangement of nucleotide A2062 upon Cfr-methylation of A2503 is likely responsible for the inability of some PTC inhibitors to bind to the ribosome, providing additional insights into the Cfr resistance mechanism. Lastly, by determining the structures of the Cfr-methylated ribosome in complex with the antibiotics iboxamycin and tylosin, we provide the structural bases behind two distinct mechanisms of evading Cfr-mediated resistance.
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| 21. |
- Aleksandrova, Elena V., et al.
(author)
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Structural basis of Cfr-mediated antimicrobial resistance and mechanisms to evade it
- 2024
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In: Nature Chemical Biology. - : Springer Nature. - 1552-4450 .- 1552-4469. ; 20:7, s. 867-876
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Journal article (peer-reviewed)abstract
- The bacterial ribosome is an essential drug target as many clinically important antibiotics bind and inhibit its functional centers. The catalytic peptidyl transferase center (PTC) is targeted by the broadest array of inhibitors belonging to several chemical classes. One of the most abundant and clinically prevalent resistance mechanisms to PTC-acting drugs in Gram-positive bacteria is C8-methylation of the universally conserved A2503 nucleobase by Cfr methylase in 23S ribosomal RNA. Despite its clinical importance, a sufficient understanding of the molecular mechanisms underlying Cfr-mediated resistance is currently lacking. Here, we report a set of high-resolution structures of the Cfr-modified 70S ribosome containing aminoacyl- and peptidyl-transfer RNAs. These structures reveal an allosteric rearrangement of nucleotide A2062 upon Cfr-mediated methylation of A2503 that likely contributes to the reduced potency of some PTC inhibitors. Additionally, we provide the structural bases behind two distinct mechanisms of engaging the Cfr-methylated ribosome by the antibiotics iboxamycin and tylosin.
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| 22. |
- Baldwin, H, et al.
(author)
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Neuroanatomical heterogeneity and homogeneity in individuals at clinical high risk for psychosis
- 2022
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In: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 12:1, s. 297-
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Journal article (peer-reviewed)abstract
- Individuals at Clinical High Risk for Psychosis (CHR-P) demonstrate heterogeneity in clinical profiles and outcome features. However, the extent of neuroanatomical heterogeneity in the CHR-P state is largely undetermined. We aimed to quantify the neuroanatomical heterogeneity in structural magnetic resonance imaging measures of cortical surface area (SA), cortical thickness (CT), subcortical volume (SV), and intracranial volume (ICV) in CHR-P individuals compared with healthy controls (HC), and in relation to subsequent transition to a first episode of psychosis. The ENIGMA CHR-P consortium applied a harmonised analysis to neuroimaging data across 29 international sites, including 1579 CHR-P individuals and 1243 HC, offering the largest pooled CHR-P neuroimaging dataset to date. Regional heterogeneity was indexed with the Variability Ratio (VR) and Coefficient of Variation (CV) ratio applied at the group level. Personalised estimates of heterogeneity of SA, CT and SV brain profiles were indexed with the novel Person-Based Similarity Index (PBSI), with two complementary applications. First, to assess the extent of within-diagnosis similarity or divergence of neuroanatomical profiles between individuals. Second, using a normative modelling approach, to assess the ‘normativeness’ of neuroanatomical profiles in individuals at CHR-P. CHR-P individuals demonstrated no greater regional heterogeneity after applying FDR corrections. However, PBSI scores indicated significantly greater neuroanatomical divergence in global SA, CT and SV profiles in CHR-P individuals compared with HC. Normative PBSI analysis identified 11 CHR-P individuals (0.70%) with marked deviation (>1.5 SD) in SA, 118 (7.47%) in CT and 161 (10.20%) in SV. Psychosis transition was not significantly associated with any measure of heterogeneity. Overall, our examination of neuroanatomical heterogeneity within the CHR-P state indicated greater divergence in neuroanatomical profiles at an individual level, irrespective of psychosis conversion. Further large-scale investigations are required of those who demonstrate marked deviation.
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| 23. |
- Battaglia, Manuela, et al.
(author)
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Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes
- 2020
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In: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 43:1, s. 5-12
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Journal article (peer-reviewed)abstract
- The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the "single disease" approach appears untenable, as does the notion of individualizing each single patient's care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.
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| 24. |
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| 27. |
- Gong, Yilun, et al.
(author)
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Assessment of corrosive attack of Fe9Cr1Mo alloys in pressurised CO2 for prediction of breakaway oxidation
- 2023
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In: Corrosion Science. - : Elsevier BV. - 0010-938X .- 1879-0496. ; 222
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Journal article (peer-reviewed)abstract
- To provide clarity on the poorly-understood mechanism of breakaway oxidation, corrosion of Fe9Cr1Mo steel in pressurised CO2 is quantified and modelled. The temperature range 400-640 degrees C, relevant to nuclear power plants, is emphasised. Attack is in the form of combined oxide scale growth and internal carburisation of the metal. Carbon activity in the metal at its surface exhibits a strong time dependence consistent with the kinetically-limited transport of carbon due to the slow Boudouard reaction. Breakaway is associated with the approach to saturation of the steel with respect to carbon. Diffusion modelling agrees well with steel carbide precipitation observations.
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| 28. |
- Hartmann, A, et al.
(author)
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Tourette syndrome research highlights from 2021
- 2022
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In: F1000Research. - : F1000 Research Ltd. - 2046-1402. ; 11, s. 716-
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Journal article (peer-reviewed)abstract
- We summarize selected research reports from 2021 relevant to Tourette syndrome that the authors consider most important or interesting. The authors welcome article suggestions and thoughtful feedback from readers.
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| 29. |
- Obana, Nozomu, et al.
(author)
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Genome-encoded ABCF factors implicated in intrinsic antibiotic resistance in Gram-positive bacteria : VmlR2, Ard1 and CplR
- 2023
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In: Nucleic Acids Research. - : Oxford University Press (OUP). - 1362-4962 .- 0305-1048. ; 51:9, s. 4536-4554
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Journal article (peer-reviewed)abstract
- Genome-encoded antibiotic resistance (ARE) ATP-binding cassette (ABC) proteins of the F subfamily (ARE-ABCFs) mediate intrinsic resistance in diverse Gram-positive bacteria. The diversity of chromosomally-encoded ARE-ABCFs is far from being fully experimentally explored. Here we characterise phylogenetically diverse genome-encoded ABCFs from Actinomycetia (Ard1 from Streptomyces capreolus, producer of the nucleoside antibiotic A201A), Bacilli (VmlR2 from soil bacterium Neobacillus vireti) and Clostridia (CplR from Clostridium perfringens, Clostridium sporogenes and Clostridioides difficile). We demonstrate that Ard1 is a narrow spectrum ARE-ABCF that specifically mediates self-resistance against nucleoside antibiotics. The single-particle cryo-EM structure of a VmlR2-ribosome complex allows us to rationalise the resistance spectrum of this ARE-ABCF that is equipped with an unusually long antibiotic resistance determinant (ARD) subdomain. We show that CplR contributes to intrinsic pleuromutilin, lincosamide and streptogramin A resistance in Clostridioides, and demonstrate that C. difficile CplR (CDIF630_02847) synergises with the transposon-encoded 23S ribosomal RNA methyltransferase Erm to grant high levels of antibiotic resistance to the C. difficile 630 clinical isolate. Finally, assisted by uORF4u, our novel tool for detection of upstream open reading frames, we dissect the translational attenuation mechanism that controls the induction of cplR expression upon an antibiotic challenge.
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| 30. |
- Rodriguez-Sanchez, J. L., et al.
(author)
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Systematic study of Δ (1232) resonance excitations using single isobaric charge-exchange reactions induced by medium-mass projectiles of Sn
- 2022
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In: Physical Review C. - 2469-9993 .- 2469-9985. ; 106:1
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Journal article (peer-reviewed)abstract
- The fragment separator FRS has been used for the first time to measure the (n,p)- and (p,n)-type isobaric charge-exchange cross sections of stable Sn112,124 isotopes accelerated at 1A GeV with an uncertainty of 3% and to separate quasielastic and inelastic components in the missing-energy spectra of the ejectiles. The inelastic contribution can be associated to the excitation of isobar Δ(1232) resonances and to the pion emission in s wave, in both the target and projectile nuclei, while the quasielastic contribution is associated with the nuclear spin-isospin response of nucleon-hole excitations. The data lead to interesting results, where we observe a clear quenching of the quasielastic component, and their comparisons to theoretical calculations demonstrate that the baryonic resonances can be excited in the target and projectile nuclei. To go further in this investigation, we propose to study the excitation of baryonic resonances, taking advantage of the combination of high-resolving power magnetic spectrometers with the Wide Angle Shower Apparatus (WASA) calorimeter. These new measurements will allow us to determine the momenta of the ejectiles and pions emitted in coincidence after the single isobaric charge-exchange collisions, providing us unique opportunities to study the evolution of the baryonic resonance dynamics with the neutron-proton asymmetry through the use of exotic radioactive ion beams.
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| 31. |
- Samplonius, Jelmer M., et al.
(author)
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Strengthening the evidence base for temperature-mediated phenological asynchrony and its impacts
- 2021
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In: Nature Ecology and Evolution. - : Springer Science and Business Media LLC. - 2397-334X. ; 5:2, s. 155-164
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Research review (peer-reviewed)abstract
- Climate warming has caused the seasonal timing of many components of ecological food chains to advance. In the context of trophic interactions, the match–mismatch hypothesis postulates that differential shifts can lead to phenological asynchrony with negative impacts for consumers. However, at present there has been no consistent analysis of the links between temperature change, phenological asynchrony and individual-to-population-level impacts across taxa, trophic levels and biomes at a global scale. Here, we propose five criteria that all need to be met to demonstrate that temperature-mediated trophic asynchrony poses a growing risk to consumers. We conduct a literature review of 109 papers studying 129 taxa, and find that all five criteria are assessed for only two taxa, with the majority of taxa only having one or two criteria assessed. Crucially, nearly every study was conducted in Europe or North America, and most studies were on terrestrial secondary consumers. We thus lack a robust evidence base from which to draw general conclusions about the risk that climate-mediated trophic asynchrony may pose to populations worldwide.
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| 32. |
- Ainelo, Andres, et al.
(author)
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The structure of DarB in complex with RelNTD reveals nonribosomal activation of Rel stringent factors
- 2023
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In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 9:3, s. 1-14
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Journal article (peer-reviewed)abstract
- Rel stringent factors are bifunctional ribosome-associated enzymes that catalyze both synthesis and hydrolysis of the alarmones (p)ppGpp. Besides the allosteric control by starved ribosomes and (p)ppGpp, Rel is regulated by various protein factors depending on specific stress conditions, including the c-di-AMP-binding protein DarB. However, how these effector proteins control Rel remains unknown. We have determined the crystal structure of the DarB2:RelNTD2 complex, uncovering that DarB directly engages the SYNTH domain of Rel to stimulate (p)ppGpp synthesis. This association with DarB promotes a SYNTH-primed conformation of the N-terminal domain region, markedly increasing the affinity of Rel for ATP while switching off the hydrolase activity of the enzyme. Binding to c-di-AMP rigidifies DarB, imposing an entropic penalty that precludes DarB-mediated control of Rel during normal growth. Our experiments provide the basis for understanding a previously unknown mechanism of allosteric regulation of Rel stringent factors independent of amino acid starvation.
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| 33. |
- Arance, Ana, et al.
(author)
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Phase II LEAP-004 Study of Lenvatinib Plus Pembrolizumab for Melanoma With Confirmed Progression on a Programmed Cell Death Protein-1 or Programmed Death Ligand 1 Inhibitor Given as Monotherapy or in Combination.
- 2023
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In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 1527-7755. ; 41:1, s. 75-85
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Journal article (peer-reviewed)abstract
- Effective treatments are needed for melanoma that progresses on inhibitors of programmed cell death protein-1 (PD-1) or its ligand (PD-L1). We conducted the phase II LEAP-004 study to evaluate the combination of the multikinase inhibitor lenvatinib and the PD-1 inhibitor pembrolizumab in this population (ClinicalTrials.gov identifier: NCT03776136).Eligible patients with unresectable stage III-IV melanoma with confirmed progressive disease (PD) within 12 weeks of the last dose of a PD-1/L1 inhibitor given alone or with other therapies, including cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4) inhibitors, received lenvatinib 20 mg orally once daily plus ≤ 35 doses of pembrolizumab 200 mg intravenously once every 3 weeks until PD or unacceptable toxicity. The primary end point was objective response rate (ORR) per RECIST, version 1.1, by independent central review.A total of 103 patients were enrolled and treated. The median study follow-up was 15.3 months. ORR in the total population was 21.4% (95% CI, 13.9 to 30.5), with three (2.9%) complete responses and 19 (18.4%) partial responses. The median duration of response was 8.3 months (range, 3.2-15.9+). ORR was 33.3% in the 30 patients with PD on prior anti-PD-1 plus anti-CTLA-4 therapy. The median progression-free survival and overall survival in the total population were 4.2 months (95% CI, 3.8 to 7.1) and 14.0 months (95% CI, 10.8 to not reached), respectively. Grade 3-5 treatment-related adverse events occurred in 47 (45.6%) patients, most commonly hypertension (21.4%); one patient died from a treatment-related event (decreased platelet count).Lenvatinib plus pembrolizumab provides clinically meaningful, durable responses in patients with advanced melanoma with confirmed PD on prior PD-1/L1 inhibitor-based therapy, including those with PD on anti-PD-1 plus anti-CTLA-4 therapy. The safety profile was as expected. These data support lenvatinib plus pembrolizumab as a potential regimen for this population of high unmet need.
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| 34. |
- Austria, M. D., et al.
(author)
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Sexual and Gender Minority Persons' Perception of the Female Sexual Function Index
- 2021
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In: Journal of Sexual Medicine. - : Oxford University Press (OUP). - 1743-6095. ; 18:12, s. 2020-2027
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Journal article (peer-reviewed)abstract
- Background: Patient-reported outcome instruments to assess sexual functioning typically assume that patients are heterosexual and have a single sexual partner, thus they may have limited applicability for sexual and gender minority (SGM) populations as well as for nonpartnered individuals or those with multiple partners. Aim: To explore the perceptions of SGM persons regarding the Female Sexual Function Index (FSFI), a commonly used sexual functioning questionnaire. Methods: We conducted 2 rounds of cognitive interviews with 27 SGM persons with and without a cancer diagnosis. Interviews were audio-recorded and transcribed. Two researchers independently coded the transcripts using inductive thematic analysis to identify major themes. Outcomes: Themes identified via qualitative analysis. Results: Cognitive debriefing with the participants provided critical insights about the way we ask questions about sexual functioning in the oncology clinic. Three overarching themes arose from the data: (i) Certain aspects of the questionnaire were felt to unnecessarily medicalize sexuality; (ii) FSFI domains were perceived to represent a narrow and heteronormative experience of sexuality focused on penile-vaginal intercourse; (iii) Questionnaire domains emphasizing sexual "performance" were perceived as male-oriented. Clinical implications: Questionnaires such as the FSFI that were developed in research studies with specific eligibility criteria need to be adapted to the broader population seen in clinical practice. Strengths & Limitations: Strengths of the study include purposive sampling of SGM persons through LGBTQ networks. Our sample included individuals of different sexual orientations, gender identities, marital status, and cancer histories. However, a limitation is that the the majority of the sample was white and college-educated. Other limitations of the study include the potential sampling bias of self-selected participants with a particular interest in the study questions. Conclusion: The findings provide important evidence for the development of a more inclusive sexual function measure, moving away from the traditional heteronormative, cisnormative approach to measuring sexual function. Copyright (C) 2021, International Society of Sexual Medicine. Published by Elsevier Inc. All rights reserved.
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| 35. |
- Austria, M., et al.
(author)
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Patient Perceptions of a Decision Support Tool for Men with Localized Prostate Cancer
- 2023
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In: Medical Decision Making Policy & Practice. - : SAGE Publications. - 2381-4683. ; 8:1
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Journal article (peer-reviewed)abstract
- Purpose. To evaluate patient perceptions of a Web-based decision aid for the treatment of localized prostate cancer. Methods. We assessed patient perceptions of a multicomponent, Web-based decision aid with a preference elicitation/values clarification exercise using adaptive conjoint analysis, the generation of a summary report, and provision of information about localized prostate cancer treatment options. Using a think-aloud approach, we conducted 21 cognitive interviews with prostate cancer patients presented with the decision aid prior to seeing their urologist. Thematic content analysis was used to examine patient perceptions of the tool's components and content prior to engaging in shared decision making with their clinician. Results. Five themes were identified: 1) patients had some negative emotional reactions to the tool, pointing out what they perceived to be unnecessarily negative framing and language used; 2) patients were forced to stop and think about preferences while going through the tool and found this deliberation to be useful; 3) patients were confused by the tool; 4) patients tried to discern the intent of the conjoint analysis questions; and 5) there was a disconnect between patients' negative reactions while using the tool and a contrasting general satisfaction with the final "values profile" created by the tool. Conclusions. Studies are needed to explore the disconnect between patients' expressing negative reactions while going through some components of decision aids but satisfaction with the final output. In particular, we hypothesize that this effect might be explained by cognitive biases such as choice-supportive bias, hindsight bias, and the "IKEA effect." This is one of the first projects to elicit patient reactions while they were completing a decision aid, and we recommend further similar, qualitative postprocess evaluation studies.
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| 39. |
- Bures, M., et al.
(author)
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Interoperability and Integration Testing Methods for IoT Systems : A Systematic Mapping Study
- 2020
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In: Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics). - Cham : Springer Science+Business Media B.V.. - 9783030587673 ; , s. 93-112
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Conference paper (peer-reviewed)abstract
- The recent active development of Internet of Things (IoT) solutions in various domains has led to an increased demand for security, safety, and reliability of these systems. Security and data privacy are currently the most frequently discussed topics; however, other reliability aspects also need to be focused on to maintain smooth and safe operation of IoT systems. Until now, there has been no systematic mapping study dedicated to the topic of interoperability and integration testing of IoT systems specifically; therefore, we present such an overview in this study. We analyze 803 papers from four major primary databases and perform detailed assessment and quality check to find 115 relevant papers. In addition, recently published testing techniques and approaches are analyzed and classified; the challenges and limitations in the field are also identified and discussed. Research trends related to publication time, active researchers, and publication media are presented in this study. The results suggest that studies mainly focus only on general testing methods, which can be applied to integration and interoperability testing of IoT systems; thus, there are research opportunities to develop additional testing methods focused specifically on IoT systems, so that they are more effective in the IoT context.
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| 40. |
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| 41. |
- Coyle, S, et al.
(author)
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Targeting the NLRP3 Inflammasome in Glaucoma
- 2021
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In: Biomolecules. - : MDPI AG. - 2218-273X. ; 11:8
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Journal article (peer-reviewed)abstract
- Glaucoma is a group of optic neuropathies characterised by the degeneration of retinal ganglion cells, resulting in damage to the optic nerve head (ONH) and loss of vision in one or both eyes. Increased intraocular pressure (IOP) is one of the major aetiological risk factors in glaucoma, and is currently the only modifiable risk factor. However, 30–40% of glaucoma patients do not present with elevated IOP and still proceed to lose vision. The pathophysiology of glaucoma is therefore not completely understood, and there is a need for the development of IOP-independent neuroprotective therapies to preserve vision. Neuroinflammation has been shown to play a key role in glaucoma and, specifically, the NLRP3 inflammasome, a key driver of inflammation, has recently been implicated. The NLRP3 inflammasome is expressed in the eye and its activation is reported in pre-clinical studies of glaucoma. Activation of the NLRP3 inflammasome results in IL-1β processing. This pro inflammatory cytokine is elevated in the blood of glaucoma patients and is believed to drive neurotoxic inflammation, resulting in axon degeneration and the death of retinal ganglion cells (RGCs). This review discusses glaucoma as an inflammatory disease and evaluates targeting the NLRP3 inflammasome as a therapeutic strategy. A hypothetical mechanism for the action of the NLRP3 inflammasome in glaucoma is presented.
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| 42. |
- Crowe-McAuliffe, Caillan, et al.
(author)
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Structural Basis for Bacterial Ribosome-Associated Quality Control by RqcH and RqcP
- 2021
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In: Molecular Cell. - : Cell Press. - 1097-2765 .- 1097-4164. ; 81:1, s. 115-126.e7
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Journal article (peer-reviewed)abstract
- In all branches of life, stalled translation intermediates are recognized and processed by ribosome-associated quality control (RQC) pathways. RQC begins with the splitting of stalled ribosomes, leaving an unfinished polypeptide still attached to the large subunit. Ancient and conserved NEMF family RQC proteins target these incomplete proteins for degradation by the addition of C-terminal "tails.'' How such tailing can occur without the regular suite of translational components is, however, unclear. Using single-particle cryo-electron microscopy (EM) of native complexes, we show that C-terminal tailing in Bacillus subtilis is mediated by NEMF protein RqcH in concert with RqcP, an Hsp15 family protein. Our structures reveal how these factors mediate tRNA movement across the ribosomal 50S subunit to synthesize polypeptides in the absence of mRNA or the small subunit.
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| 43. |
- Crowe-McAuliffe, Caillan, et al.
(author)
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Structural basis for PoxtA-mediated resistance to phenicol and oxazolidinone antibiotics
- 2022
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13
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Journal article (peer-reviewed)abstract
- PoxtA and OptrA are ATP binding cassette (ABC) proteins of the F subtype (ABCF). They confer resistance to oxazolidinone and phenicol antibiotics, such as linezolid and chloramphenicol, which stall translating ribosomes when certain amino acids are present at a defined position in the nascent polypeptide chain. These proteins are often encoded on mobile genetic elements, facilitating their rapid spread amongst Gram-positive bacteria, and are thought to confer resistance by binding to the ribosome and dislodging the bound antibiotic. However, the mechanistic basis of this resistance remains unclear. Here we refine the PoxtA spectrum of action, demonstrate alleviation of linezolid-induced context-dependent translational stalling, and present cryo-electron microscopy structures of PoxtA in complex with the Enterococcus faecalis 70S ribosome. PoxtA perturbs the CCA-end of the P-site tRNA, causing it to shift by ∼4 Å out of the ribosome, corresponding to a register shift of approximately one amino acid for an attached nascent polypeptide chain. We postulate that the perturbation of the P-site tRNA by PoxtA thereby alters the conformation of the attached nascent chain to disrupt the drug binding site.
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| 44. |
- Crowe-McAuliffe, Caillan, et al.
(author)
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Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens
- 2021
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Journal article (peer-reviewed)abstract
- Target protection proteins confer resistance to the host organism by directly binding to the antibiotic target. One class of such proteins are the antibiotic resistance (ARE) ATP-binding cassette (ABC) proteins of the F-subtype (ARE-ABCFs), which are widely distributed throughout Gram-positive bacteria and bind the ribosome to alleviate translational inhibition from antibiotics that target the large ribosomal subunit. Here, we present single-particle cryo-EM structures of ARE-ABCF-ribosome complexes from three Gram-positive pathogens: Enterococcus faecalis LsaA, Staphylococcus haemolyticus VgaALC and Listeria monocytogenes VgaL. Supported by extensive mutagenesis analysis, these structures enable a general model for antibiotic resistance mediated by these ARE-ABCFs to be proposed. In this model, ABCF binding to the antibiotic-stalled ribosome mediates antibiotic release via mechanistically diverse long-range conformational relays that converge on a few conserved ribosomal RNA nucleotides located at the peptidyltransferase center. These insights are important for the future development of antibiotics that overcome such target protection resistance mechanisms.
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| 45. |
- Egorov, Artyom A., et al.
(author)
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uORF4u : a tool for annotation of conserved upstream open reading frames
- 2023
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In: Bioinformatics. - 1367-4803. ; 39:5
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Journal article (peer-reviewed)abstract
- Summary: Upstream open reading frames (uORFs, often encoding so-called leader peptides) can regulate translation and transcription of downstream main ORFs (mORFs) in prokaryotes and eukaryotes. However, annotation of novel functional uORFs is challenging due to their short size of usually <100 codons. While transcription- and translation-level next-generation sequencing methods can be used for genome-wide functional uORF identification, this data are not available for the vast majority of species with sequenced genomes. At the same time, the exponentially increasing amount of genome assemblies gives us the opportunity to take advantage of evolutionary conservation in our predictions of functional ORFs. Here, we present a tool for conserved uORF annotation in 50 upstream sequences of a user-defined protein of interest or a set of protein homologs. It can also be used to find small conserved ORFs within a set of nucleotide sequences. The output includes publication-quality figures with multiple sequence alignments, sequence logos, and locus annotation of the predicted conserved uORFs in graphical vector format. Availability and implementation: uORF4u is written in Python3 and runs on Linux and MacOS. The command-line interface covers most practical use cases, while the provided Python API allows usage within a Python program and additional customization. Source code is available from the GitHub page: github.com/GCA-VH-lab/uorf4u. Detailed documentation that includes an example-driven guide available at the software home page: gca-vh-lab.github.io/uorf4u. A web version of uORF4u is available at server.atkinson-lab.com/uorf4u.
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| 46. |
- Ernits, Karin, et al.
(author)
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The structural basis of hyperpromiscuity in a core combinatorial network of type II toxin-antitoxin and related phage defense systems
- 2023
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In: Proceedings of the National Academy of Sciences of the United States of America. - 1091-6490 .- 0027-8424. ; 120:33, s. 1-12
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Journal article (peer-reviewed)abstract
- Toxin-antitoxin (TA) systems are a large group of small genetic modules found in prokaryotes and their mobile genetic elements. Type II TAs are encoded as bicistronic (two-gene) operons that encode two proteins: a toxin and a neutralizing antitoxin. Using our tool NetFlax (standing for Network-FlaGs for toxins and antitoxins), we have performed a large-scale bioinformatic analysis of proteinaceous TAs, revealing interconnected clusters constituting a core network of TA-like gene pairs. To understand the structural basis of toxin neutralization by antitoxins, we have predicted the structures of 3,419 complexes with AlphaFold2. Together with mutagenesis and functional assays, our structural predictions provide insights into the neutralizing mechanism of the hyperpromiscuous Panacea antitoxin domain. In antitoxins composed of standalone Panacea, the domain mediates direct toxin neutralization, while in multidomain antitoxins the neutralization is mediated by other domains, such as PAD1, Phd-C, and ZFD. We hypothesize that Panacea acts as a sensor that regulates TA activation. We have experimentally validated 16 NetFlax TA systems and used domain annotations and metabolic labeling assays to predict their potential mechanisms of toxicity (such as membrane disruption, and inhibition of cell division or protein synthesis) as well as biological functions (such as antiphage defense). We have validated the antiphage activity of a RosmerTA system encoded by Gordonia phage Kita, and used fluorescence microscopy to confirm its predicted membrane-depolarizing activity. The interactive version of the NetFlax TA network that includes structural predictions can be accessed at http://netflax.webflags.se/.
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| 47. |
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| 48. |
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| 49. |
- Jimmy, Steffi, et al.
(author)
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A widespread toxin-antitoxin system exploiting growth control via alarmone signaling
- 2020
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In: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 117:19, s. 10500-10510
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Journal article (peer-reviewed)abstract
- Under stressful conditions, bacterial RelA-SpoT Homolog (RSH) enzymes synthesize the alarmone (p)ppGpp, a nucleotide second messenger. (p)ppGpp rewires bacterial transcription and metabolism to cope with stress, and, at high concentrations, inhibits the process of protein synthesis and bacterial growth to save and redirect resources until conditions improve. Single-domain small alarmone synthetases (SASs) are RSH family members that contain the (p)ppGpp synthesis (SYNTH) domain, but lack the hydrolysis (HD) domain and regulatory C-terminal domains of the long RSHs such as Rel, RelA, and SpoT. We asked whether analysis of the genomic context of SASs can indicate possible functional roles. Indeed, multiple SAS subfamilies are encoded in widespread conserved bicistronic operon architectures that are reminiscent of those typically seen in toxin-antitoxin (TA) operons. We have validated five of these SASs as being toxic (toxSASs), with neutralization by the protein products of six neighboring antitoxin genes. The toxicity of Cellulomonas marina toxSAS FaRel is mediated by the accumulation of alarmones ppGpp and ppApp, and an associated depletion of cellular guanosine triphosphate and adenosine triphosphate pools, and is counteracted by its HD domain-containing antitoxin. Thus, the ToxSAS-antiToxSAS system with its multiple different antitoxins exemplifies how ancient nucleotide-based signaling mechanisms can be repurposed as TA modules during evolution, potentially multiple times independently.
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| 50. |
- Josephson, C. B., et al.
(author)
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Predicting postoperative epilepsy surgery satisfaction in adults using the 19-item Epilepsy Surgery Satisfaction Questionnaire and machine learning
- 2021
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In: Epilepsia. - : Wiley. - 0013-9580 .- 1528-1167. ; 62:9, s. 2103-2112
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Journal article (peer-reviewed)abstract
- Objective: The 19-item Epilepsy Surgery Satisfaction Questionnaire (ESSQ-19) is a validated and reliable post hoc means of assessing patient satisfaction with epilepsy surgery. Prediction models building on these data can be used to counsel patients. Methods: The ESSQ-19 was derived and validated on 229 patients recruited from Canada and Sweden. We isolated 201 (88%) patients with complete clinical data for this analysis. These patients were adults (≥18years old) who underwent epilepsy surgery 1year or more prior to answering the questionnaire. We extracted each patient’s ESSQ-19 score (scale is 0–100; 100 represents complete satisfaction) and relevant clinical variables that were standardized prior to the analysis. We used machine learning (linear kernel support vector regression [SVR]) to predict satisfaction and assessed performance using the R2 calculated following threefold cross-validation. Model parameters were ranked to infer the importance of each clinical variable to overall satisfaction with epilepsy surgery. Results: Median age was 41 years (interquartile range [IQR] = 32–53), and 116 (57%) were female. Median ESSQ-19 global score was 68 (IQR = 59–75), and median time from surgery was 5.4years (IQR = 2.0–8.9). Linear kernel SVR performed well following threefold cross-validation, with an R2 of.44 (95% confidence interval =.36–.52). Increasing satisfaction was associated with postoperative self-perceived quality of life, seizure freedom, and reductions in antiseizure medications. Self-perceived epilepsy disability, age, and increasing frequency of seizures that impair awareness were associated with reduced satisfaction. Significance: Machine learning applied postoperatively to the ESSQ-19 can be used to predict surgical satisfaction. This algorithm, once externally validated, can be used in clinical settings by fixing immutable clinical characteristics and adjusting hypothesized postoperative variables, to counsel patients at an individual level on how satisfied they will be with differing surgical outcomes. © 2021 International League Against Epilepsy
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