| 1. |
- Chen, Zhishan, et al.
(författare)
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Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
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| 2. |
- Fernandez-Rozadilla, Ceres, et al.
(författare)
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Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
- 2023
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 55, s. 89-99
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
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| 3. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 4. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 5. |
- Allam, Venkata, et al.
(författare)
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Macrophage migration inhibitory factor promotes glucocorticoid resistance of neutrophilic inflammation in a murine model of severe asthma
- 2023
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Ingår i: Thorax. - : BMJ Publishing Group Ltd. - 0040-6376 .- 1468-3296. ; 78:7, s. 661-673
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Tidskriftsartikel (refereegranskat)abstract
- Background: Severe neutrophilic asthma is resistant to treatment with glucocorticoids. The immunomodulatory protein macrophage migration inhibitory factor (MIF) promotes neutrophil recruitment to the lung and antagonises responses to glucocorticoids. We hypothesised that MIF promotes glucocorticoid resistance of neutrophilic inflammation in severe asthma.Methods: We examined whether sputum MIF protein correlated with clinical and molecular characteristics of severe neutrophilic asthma in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. We also investigated whether MIF regulates neutrophilic inflammation and glucocorticoid responsiveness in a murine model of severe asthma in vivo.Results: MIF protein levels positively correlated with the number of exacerbations in the previous year, sputum neutrophils and oral corticosteroid use across all U-BIOPRED subjects. Further analysis of MIF protein expression according to U-BIOPRED-defined transcriptomic-associated clusters (TACs) revealed increased MIF protein and a corresponding decrease in annexin-A1 protein in TAC2, which is most closely associated with airway neutrophilia and NLRP3 inflammasome activation. In a murine model of severe asthma, treatment with the MIF antagonist ISO-1 significantly inhibited neutrophilic inflammation and increased glucocorticoid responsiveness. Coimmunoprecipitation studies using lung tissue lysates demonstrated that MIF directly interacts with and cleaves annexin-A1, potentially reducing its biological activity.Conclusion: Our data suggest that MIF promotes glucocorticoid-resistance of neutrophilic inflammation by reducing the biological activity of annexin-A1, a potent glucocorticoid-regulated protein that inhibits neutrophil accumulation at sites of inflammation. This represents a previously unrecognised role for MIF in the regulation of inflammation and points to MIF as a potential therapeutic target for the management of severe neutrophilic asthma.
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| 6. |
- Craig, Wendy, et al.
(författare)
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Social Media Use and Cyber-Bullying: A Cross-National Analysis of Young People in 42 Countries
- 2020
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Ingår i: Journal of Adolescent Health. - : ELSEVIER SCIENCE INC. - 1054-139X .- 1879-1972. ; 66:6, s. S100-S108
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Social media use (SMU) has become an intrinsic part of adolescent life. Negative consequences of SMU for adolescent health could include exposures to online forms of aggression. We explored age, gender, and cross-national differences in adolescents engagement in SMU, then relationships between SMU and victimization and the perpetration of cyber-bullying. Methods: We used data on young people aged 11-15 years (weighted n = 180,919 in 42 countries) who participated in the 2017-2018 Health Behaviour in School-aged Children study to describe engagement in the three types of SMU (intense, problematic, and talking with strangers online) by age and gender and then in the perpetration and victimization of cyber-bullying. Relationships between SMU and cyber-bullying outcomes were estimated using Poisson regression (weighted n = 166,647 from 42 countries). Results: Variations in SMU and cyber-bullying follow developmental and gender-based patterns across countries. In pooled analyses, engagement in SMU related to cyber-bullying victimization (adjusted relative risks = 1.14 [95% confidence interval (CI): 1.10-1.19] to 1.48 [95% CI: 1.42-1.55]) and perpetration (adjusted relative risk = 1.31 [95% CI: 1.26-1.36] to 1.84 [95% CI: 1.74-1.95]). These associations were stronger for cyber-perpetration versus cyber-victimization and for girls versus boys. Problematic SMU was most strongly and consistently associated with cyber-bullying, both for victimization and perpetration. Stratified analyses showed that SMU related to cyber-victimization in 19%-45% of countries and to cyber-perpetration in 38%-86% of countries. Conclusions: Accessibility to social media and its pervasive use has led to new opportunities for online aggression. The time adolescents spend on social media, engage in problematic use, and talk to strangers online each relate to cyber-bullying and merit public health intervention. Problematic use of social media poses the strongest and most consistent risk. (C) 2020 Published by Elsevier Inc. on behalf of Society for Adolescent Health and Medicine.
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| 7. |
- Craig, Wendy, et al.
(författare)
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Social Media Use and Cyber-Bullying: A Cross-National Analysis of Young People in 42 Countries
- 2020
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Ingår i: Journal of Adolescent Health. - : Elsevier BV. - 1054-139X .- 1879-1972. ; 66:6
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Social media use (SMU) has become an intrinsic part of adolescent life. Negative consequences of SMU for adolescent health could include exposures to online forms of aggression. We explored age, gender, and cross-national differences in adolescents' engagement in SMU, then relationships between SMU and victimization and the perpetration of cyber-bullying. Methods: We used data on young people aged 11–15 years (weighted n = 180,919 in 42 countries) who participated in the 2017–2018 Health Behaviour in School-aged Children study to describe engagement in the three types of SMU (intense, problematic, and talking with strangers online) by age and gender and then in the perpetration and victimization of cyber-bullying. Relationships between SMU and cyber-bullying outcomes were estimated using Poisson regression (weighted n = 166,647 from 42 countries). Results: Variations in SMU and cyber-bullying follow developmental and gender-based patterns across countries. In pooled analyses, engagement in SMU related to cyber-bullying victimization (adjusted relative risks = 1.14 [95% confidence interval (CI): 1.10–1.19] to 1.48 [95% CI: 1.42–1.55]) and perpetration (adjusted relative risk = 1.31 [95% CI: 1.26–1.36] to 1.84 [95% CI: 1.74–1.95]). These associations were stronger for cyber-perpetration versus cyber-victimization and for girls versus boys. Problematic SMU was most strongly and consistently associated with cyber-bullying, both for victimization and perpetration. Stratified analyses showed that SMU related to cyber-victimization in 19%–45% of countries and to cyber-perpetration in 38%–86% of countries. Conclusions: Accessibility to social media and its pervasive use has led to new opportunities for online aggression. The time adolescents spend on social media, engage in problematic use, and talk to strangers online each relate to cyber-bullying and merit public health intervention. Problematic use of social media poses the strongest and most consistent risk.
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| 8. |
- Forchini, Giovanni, et al.
(författare)
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Report 28 : Excess non-COVID-19 deaths in England and Wales between 29th February and 5th June 2020
- 2020
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- There were 189,403 deaths from any cause reported in England from 29th February to 5th June 2020 inclusive, and 11,278 all-cause deaths in Wales over the same period. Of those deaths, 44,736 (23.6%) registered COVID-19 on the death certificate in England, and 2,294 (20.3%) in Wales, while 144,667 (76.4%) were not recorded as having been due to COVID-19 in England, and 8,984 (79.7%) in Wales. However, it could be that some of the ‘non-COVID-19’ deaths have in fact also been caused by COVID-19, either as the direct cause of death, or indirectly through provisions for the pandemic impeding access to care for other conditions. There is uncertainty in how many of the non-COVID-19 deaths were directly or indirectly caused by the pandemic. We estimated the excess deaths that were not recorded as associated with COVID-19 in the death certificate (excess non-COVID-19 deaths) as the deaths for which COVID-19 was not reported as the cause, compared to those we would have expected to occur had the pandemic not happened. Expected deaths were forecast with an analysis of historic trends in deaths between 2010 and April 2020 using data by the Office of National Statistics and a statistical time series model.According to the model, we expected 136,294 (95% CI 133,882 - 138,696) deaths in England, and 8,983 (CI 8,051 - 9,904) in Wales over this period, significantly fewer than the number of deaths reported. This means that there were 8,983 (95% CI 5,971 - 10,785) total excess non-COVID-19 deaths in England. For every 100 COVID-19 deaths during the period from 29th February to 5th June 2020 there were 19 (95% CI 13 – 24) cumulative excess non-COVID-19 deaths. The proportion of cumulative excess non-COVID-19 deaths of all reported deaths during this period was 4.4% (95% CI 3.2% - 5.7%) in England, with small regional variations. Excess deaths were highest in the South East at 2,213 (95% CI 327 - 4,047) and in London at 1,937 (95% CI 896 - 3,010), respectively. There is no evidence of non-COVID-19 excess deaths in Wales. Excess non-COVID-19 deaths are occurring in individuals aged 85+ and 75-84, and those aged 45-64. For those aged 85+, excess non-COVID-19 deaths are driven by females, with 6,115 (95% CI 206 – 11,795) deaths in total but no significant findings for males of those ages. For ages 75-84, excess non-COVID-19 deaths are nearly double for females at 2,070 (95% CI 393 – 3,887) than for males at 1,336 (95% CI 938 – 1,710), while for ages 45-64, excess non-COVID-19 deaths for females are at 347 (95% CI 90 – 603), almost half those of males at 681 (95% CI 282 – 1,091). There is no evidence of excess non-COVID-19 deaths for ages 65-74, and those below 45.Excess non-COVID-19 deaths could be due to non-reporting of COVID-19 on the death certificate or an increase in mortality for non-COVID-19 conditions. Severely ill patients may have been unable to access life-saving emergency treatment because of constraints in healthcare provision, or because they avoided seeking care due to concern over hospital-acquired infection, or to avoid burdening healthcare providers. Further research into reasons for excess non-COVID-19 deaths is warranted.This report accompanies the weekly update of excess death estimates on the Github website of the Abdul Latif Jameel Institute of Disease and Emergency Analytics (J-IDEA) (https://j-idea.github.io/ONSdeaths/) which has been set up to be regularly updated until June 2022.
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| 9. |
- Kimel, Alexey, et al.
(författare)
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The 2022 magneto-optics roadmap
- 2022
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Ingår i: Journal of Physics D. - : Institute of Physics (IOP). - 0022-3727 .- 1361-6463. ; 55:46
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Tidskriftsartikel (refereegranskat)abstract
- Magneto-optical (MO) effects, viz. magnetically induced changes in light intensity or polarization upon reflection from or transmission through a magnetic sample, were discovered over a century and a half ago. Initially they played a crucially relevant role in unveiling the fundamentals of electromagnetism and quantum mechanics. A more broad-based relevance and wide-spread use of MO methods, however, remained quite limited until the 1960s due to a lack of suitable, reliable and easy-to-operate light sources. The advent of Laser technology and the availability of other novel light sources led to an enormous expansion of MO measurement techniques and applications that continues to this day (see section 1). The here-assembled roadmap article is intended to provide a meaningful survey over many of the most relevant recent developments, advances, and emerging research directions in a rather condensed form, so that readers can easily access a significant overview about this very dynamic research field. While light source technology and other experimental developments were crucial in the establishment of today's magneto-optics, progress also relies on an ever-increasing theoretical understanding of MO effects from a quantum mechanical perspective (see section 2), as well as using electromagnetic theory and modelling approaches (see section 3) to enable quantitatively reliable predictions for ever more complex materials, metamaterials, and device geometries. The latest advances in established MO methodologies and especially the utilization of the MO Kerr effect (MOKE) are presented in sections 4 (MOKE spectroscopy), 5 (higher order MOKE effects), 6 (MOKE microscopy), 8 (high sensitivity MOKE), 9 (generalized MO ellipsometry), and 20 (Cotton–Mouton effect in two-dimensional materials). In addition, MO effects are now being investigated and utilized in spectral ranges, to which they originally seemed completely foreign, as those of synchrotron radiation x-rays (see section 14 on three-dimensional magnetic characterization and section 16 on light beams carrying orbital angular momentum) and, very recently, the terahertz (THz) regime (see section 18 on THz MOKE and section 19 on THz ellipsometry for electron paramagnetic resonance detection). Magneto-optics also demonstrates its strength in a unique way when combined with femtosecond laser pulses (see section 10 on ultrafast MOKE and section 15 on magneto-optics using x-ray free electron lasers), facilitating the very active field of time-resolved MO spectroscopy that enables investigations of phenomena like spin relaxation of non-equilibrium photoexcited carriers, transient modifications of ferromagnetic order, and photo-induced dynamic phase transitions, to name a few. Recent progress in nanoscience and nanotechnology, which is intimately linked to the achieved impressive ability to reliably fabricate materials and functional structures at the nanoscale, now enables the exploitation of strongly enhanced MO effects induced by light–matter interaction at the nanoscale (see section 12 on magnetoplasmonics and section 13 on MO metasurfaces). MO effects are also at the very heart of powerful magnetic characterization techniques like Brillouin light scattering and time-resolved pump-probe measurements for the study of spin waves (see section 7), their interactions with acoustic waves (see section 11), and ultra-sensitive magnetic field sensing applications based on nitrogen-vacancy centres in diamond (see section 17). Despite our best attempt to represent the field of magneto-optics accurately and do justice to all its novel developments and its diversity, the research area is so extensive and active that there remains great latitude in deciding what to include in an article of this sort, which in turn means that some areas might not be adequately represented here. However, we feel that the 20 sections that form this 2022 magneto-optics roadmap article, each written by experts in the field and addressing a specific subject on only two pages, provide an accurate snapshot of where this research field stands today. Correspondingly, it should act as a valuable reference point and guideline for emerging research directions in modern magneto-optics, as well as illustrate the directions this research field might take in the foreseeable future.
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| 10. |
- Slieker, Roderick C, et al.
(författare)
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Distinct Molecular Signatures of Clinical Clusters in People with Type 2 Diabetes : an IMIRHAPSODY Study
- 2021
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 70:11, s. 2683-2693
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes is a multifactorial disease with multiple underlying aetiologies. To address this heterogeneity a previous study clustered people with diabetes into five diabetes subtypes. The aim of the current study is to investigate the aetiology of these clusters by comparing their molecular signatures. In three independent cohorts, in total 15,940 individuals were clustered based on five clinical characteristics. In a subset, genetic- (N=12828), metabolomic- (N=2945), lipidomic- (N=2593) and proteomic (N=1170) data were obtained in plasma. In each datatype each cluster was compared with the other four clusters as the reference. The insulin resistant cluster showed the most distinct molecular signature, with higher BCAAs, DAG and TAG levels and aberrant protein levels in plasma enriched for proteins in the intracellular PI3K/Akt pathway. The obese cluster showed higher cytokines. A subset of the mild diabetes cluster with high HDL showed the most beneficial molecular profile with opposite effects to those seen in the insulin resistant cluster. This study showed that clustering people with type 2 diabetes can identify underlying molecular mechanisms related to pancreatic islets, liver, and adipose tissue metabolism. This provides novel biological insights into the diverse aetiological processes that would not be evident when type 2 diabetes is viewed as a homogeneous disease.
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