| 1. |
- Munch, Henrik K, et al.
(författare)
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Construction of Insulin 18-mer Nanoassemblies Driven by Coordination to Iron(II) and Zinc(II) Ions at Distinct Sites.
- 2016
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Ingår i: Angewandte Chemie (International edition). - : Wiley. - 1521-3773. ; 55:7, s. 2378-2381
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Tidskriftsartikel (refereegranskat)abstract
- Controlled self-assembly (SA) of proteins offers the possibility to tune their properties or to create new materials. Herein, we present the synthesis of a modified human insulin (HI) with two distinct metal-ion binding sites, one native, the other abiotic, enabling hierarchical SA through coordination with two different metal ions. Selective attachment of an abiotic 2,2'-bipyridine (bipy) ligand to HI, yielding HI-bipy, enabled Zn(II) -binding hexamers to SA into trimers of hexamers, [[HI-bipy]6 ]3 , driven by octahedral coordination to a Fe(II) ion. The structures were studied in solution by small-angle X-ray scattering and on surfaces with AFM. The abiotic metal ligand had a higher affinity for Fe(II) than Zn(II) ions, enabling control of the hexamer formation with Zn(II) and the formation of trimers of hexamers with Fe(II) ions. This precise control of protein SA to give oligomers of oligomers provides nanoscale structures with potential applications in nanomedicine.
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| 2. |
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| 3. |
- Nygaard, Jesper, et al.
(författare)
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Metal Ion Controlled Self-Assembly of a Chemically Reengineered Protein Drug Studied by Small-Angle X-ray Scattering
- 2012
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Ingår i: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 28:33, s. 12159-12170
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Tidskriftsartikel (refereegranskat)abstract
- Precise control of the oligomeric state of proteins is of central importance for biological function and for the properties of biopharmaceutical drugs. Here, the self-assembly of 2,2'-bipyridine conjugated monomeric insulin analogues, induced through coordination to divalent metal ions, was studied. This protein drug system was designed to form non-native homo-oligomers through selective coordination of two divalent metal ions, Fe(II) and Zn(II), respectively. The insulin type chosen for this study is a variant designed for a reduced tendency toward native dimer formation at physiological concentrations. A small-angle X-ray scattering analysis of the bipyridine-modified insulin system confirmed an organization into a novel well-ordered structure based on insulin trimers, as induced by the addition of Fe(II). In contrast, unmodified monomeric insulin formed larger and more randomly structured assemblies upon addition of Fe(II). The addition of Zn(II), on the other hand, led to the formation of small quantities of insulin hexamers for both the bipyridine-modified and the unmodified monomeric insulin. Interestingly, the location of the bipyridine-modification significantly affects the tendency to hexamer formation as compared to the unmodified insulin. Our study shows how combining a structural study and chemical design can be used to obtain molecular understanding and control of the self-assembly of a protein drug. This knowledge may eventually be employed to develop an optimized in vivo drug release profile.
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| 4. |
- Alme, Tomas Nordheim, et al.
(författare)
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Chronic fatigue syndromes: real illnesses that people can recover from
- 2023
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Ingår i: Scandinavian Journal of Primary Health Care. - : TAYLOR & FRANCIS LTD. - 0281-3432 .- 1502-7724. ; 41:4, s. 372-376
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Tidskriftsartikel (refereegranskat)abstract
- The Oslo Chronic Fatigue Consortium consists of researchers and clinicians who question the current narrative that chronic fatigue syndromes, including post-covid conditions, are incurable diseases. Instead, we propose an alternative view, based on research, which offers more hope to patients. Whilst we regard the symptoms of these conditions as real, we propose that they are more likely to reflect the brains response to a range of biological, psychological, and social factors, rather than a specific disease process. Possible causes include persistent activation of the neurobiological stress response, accompanied by associated changes in immunological, hormonal, cognitive and behavioural domains. We further propose that the symptoms are more likely to persist if they are perceived as threatening, and all activities that are perceived to worsen them are avoided. We also question the idea that the best way to cope with the illness is by prolonged rest, social isolation, and sensory deprivation.Instead, we propose that recovery is often possible if patients are helped to adopt a less threatening understanding of their symptoms and are supported in a gradual return to normal activities. Finally, we call for a much more open and constructive dialogue about these conditions. This dialogue should include a wider range of views, including those of patients who have recovered from them.
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| 5. |
- Barrie, William, et al.
(författare)
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Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations
- 2024
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Ingår i: NATURE. - 0028-0836 .- 1476-4687. ; 625:7994
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that is most prevalent in Northern Europe. Although it is known that inherited risk for MS is located within or in close proximity to immune-related genes, it is unknown when, where and how this genetic risk originated1. Here, by using a large ancient genome dataset from the Mesolithic period to the Bronze Age2, along with new Medieval and post-Medieval genomes, we show that the genetic risk for MS rose among pastoralists from the Pontic steppe and was brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the steppe population and later in Europe, probably driven by pathogenic challenges coinciding with changes in diet, lifestyle and population density. This study highlights the critical importance of the Neolithic period and Bronze Age as determinants of modern immune responses and their subsequent effect on the risk of developing MS in a changing environment. Analysis of a large ancient genome dataset shows that genetic risk for multiple sclerosis rose in steppe pastoralists, providing insight into how genetic ancestry from the Neolithic and Bronze Age has shaped modern immune responses.
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| 6. |
- Bousquet, Jean, et al.
(författare)
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ARIA digital anamorphosis : Digital transformation of health and care in airway diseases from research to practice
- 2021
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Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : John Wiley & Sons. - 0105-4538 .- 1398-9995. ; 76:1, s. 168-190
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Forskningsöversikt (refereegranskat)abstract
- Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.
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| 7. |
- Bousquet, J. Jean, et al.
(författare)
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Next-generation ARIA care pathways for rhinitis and asthma : a model for multimorbid chronic diseases
- 2019
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Ingår i: Clinical and Translational Allergy. - : BMC. - 2045-7022. ; 9
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Forskningsöversikt (refereegranskat)abstract
- Background: In all societies, the burden and cost of allergic and chronic respiratory diseases are increasing rapidly. Most economies are struggling to deliver modern health care effectively. There is a need to support the transformation of the health care system into integrated care with organizational health literacy.Main body: As an example for chronic disease care, MASK (Mobile Airways Sentinel NetworK), a new project of the ARIA (Allergic Rhinitis and its Impact on Asthma) initiative, and POLLAR (Impact of Air POLLution on Asthma and Rhinitis, EIT Health), in collaboration with professional and patient organizations in the field of allergy and airway diseases, are proposing real-life ICPs centred around the patient with rhinitis, and using mHealth to monitor environmental exposure. Three aspects of care pathways are being developed: (i) Patient participation, health literacy and self-care through technology-assisted "patient activation", (ii) Implementation of care pathways by pharmacists and (iii) Next-generation guidelines assessing the recommendations of GRADE guidelines in rhinitis and asthma using real-world evidence (RWE) obtained through mobile technology. The EU and global political agendas are of great importance in supporting the digital transformation of health and care, and MASK has been recognized by DG Sante as a Good Practice in the field of digitally-enabled, integrated, person-centred care.Conclusion: In 20 years, ARIA has considerably evolved from the first multimorbidity guideline in respiratory diseases to the digital transformation of health and care with a strong political involvement.
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| 8. |
- Christensen, Lise, et al.
(författare)
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Gravitationally lensed galaxies at 2 < z < 3.5 : direct abundance measurements of Ly alpha emitters
- 2012
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 427:3, s. 1973-1982
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Tidskriftsartikel (refereegranskat)abstract
- Strong gravitational lensing magnifies the flux from distant galaxies, allowing us to detect emission lines that would otherwise fall below the detection threshold for medium-resolution spectroscopy. Here we present the detection of temperature-sensitive oxygen emission lines from three galaxies at 2 ? z ? 3.5, which enables us to directly determine the oxygen abundances and thereby double the number of galaxies at z > 2 for which this has been possible. The three galaxies have similar to 10?per?cent solar oxygen abundances in agreement with strong emission-line diagnostics. Carbon and nitrogen ratios relative to oxygen are subsolar as expected for young metal-poor galaxies. Two of the galaxies are Lyman a (Lya) emitters with rest-frame equivalent widths of 20 and 40 angstrom, respectively, and their high magnification factors allow us for the first time to gain insight into the physical characteristics of high-redshift Lya emitters. Using constraints from the physical properties of the galaxies, we accurately reproduce their line profiles with radiative transfer models. The models show a relatively small outflow in agreement with the observed small velocity offsets between nebular emission and interstellar absorption lines.
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| 9. |
- Christensen, Lise, et al.
(författare)
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The low-mass end of the fundamental relation for gravitationally lensed star-forming galaxies at 1 < z < 6
- 2012
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 427:3, s. 1953-1972
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Forskningsöversikt (refereegranskat)abstract
- We present Very Large Telescope/X-shooter spectra of 13 galaxies in the redshift range 1 ? z ? 6, which are strongly lensed by massive galaxy clusters. Spectroscopic redshifts are measured for nine galaxies, while three sources have redshifts determined from continuum breaks in their spectra. The stellar masses of the galaxies span four orders of magnitude between 107 and 1011?M? and have luminosities at 1500 angstrom rest frame between 0.004 and 9L* after correcting for the magnification. This allows us to probe a variety of galaxy types from young, low-mass starburst galaxies to massive evolved galaxies. The lensed galaxies with stellar masses less than 1010?M? have a large scatter compared to the fundamental relation between stellar mass, star formation rates and oxygen abundances. We provide a modified fit to the fundamental relation for low-mass, low-metallicity galaxies with a weaker dependence of the metallicity on either the star formation rate or stellar mass compared to low-redshift, high-mass and high-metallicity Sloan Digital Sky Survey galaxies.
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| 10. |
- Ekdahl, Bertil, et al.
(författare)
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A general architecture for autonomous agents
- 2003
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Ingår i: Proceedings IEEE/WIC International Conference on Intelligent Agent Technology (IAT 2003). - 0769519318 ; , s. 419-423
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Konferensbidrag (refereegranskat)abstract
- Being autonomous (or being an agent) does not describe an effective process and even if we succeeded in characterizing the conditions for being autonomous it would be of no use. Instead, it is the conditions of acting autonomously that should be of concern and the interest should be directed towards systems in which we can find, and possibly define, such acting processes. It turns out that anticipatory systems are the only systems where autonomy is a determining factor. The anticipatory systems are further categorized into two disjoint classes: true anticipatory which systems have a model of their surroundings and semi-anticipatory which systems possess only a description of their surroundings. Here model is used in its semantic sense. It is argued that the only way to catch is to define them as semi-anticipatory. Defining software agent in this way gives a precise characterization of the concept
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| 11. |
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| 12. |
- Jensen, Benjamin A H, et al.
(författare)
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Lysates of Methylococcus capsulatus Bath induce a lean-like microbiota, intestinal FoxP3+RORγt+IL-17+ Tregs and improve metabolism
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Interactions between host and gut microbial communities are modulated by diets and play pivotal roles in immunological homeostasis and health. We show that exchanging the protein source in a high fat, high sugar, westernized diet from casein to whole-cell lysates of the non-commensal bacterium Methylococcus capsulatus Bath is sufficient to reverse western diet-induced changes in the gut microbiota to a state resembling that of lean, low fat diet-fed mice, both under mild thermal stress (T22 °C) and at thermoneutrality (T30 °C). Concomitant with microbiota changes, mice fed the Methylococcus-based western diet exhibit improved glucose regulation, reduced body and liver fat, and diminished hepatic immune infiltration. Intake of the Methylococcu-based diet markedly boosts Parabacteroides abundances in a manner depending on adaptive immunity, and upregulates triple positive (Foxp3+RORγt+IL-17+) regulatory T cells in the small and large intestine. Collectively, these data point to the potential for leveraging the use of McB lysates to improve immunometabolic homeostasis.
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| 13. |
- Jensen, Christian Fuglesang S., et al.
(författare)
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Microdissection Testicular Sperm Extraction Versus Multiple Needle-pass Percutaneous Testicular Sperm Aspiration in Men with Nonobstructive Azoospermia : A Randomized Clinical Trial
- 2022
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838. ; 82:4, s. 377-384
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Tidskriftsartikel (refereegranskat)abstract
- Background: Surgical extraction of testicular spermatozoa is needed in men with nonobstructive azoospermia (NOA) who wish to become biological fathers. Based on available uncontrolled studies with unspecific patient selection, microdissection testicular sperm extraction (mTESE), having a sperm retrieval rate (SRR) of 50%, is considered the most efficient sperm retrieval procedure. However, no randomized clinical trials for comparison of different sperm retrieval procedures exist. Testicular sperm aspiration (TESA) is simple and commonly used, and we hypothesized that this technique using multiple needle passes would give similar SRRs to mTESE. Objective: To compare mTESE and multiple needle-pass TESA in men with NOA. Design, setting, and participants: A randomized clinical trial was performed between June 2017 and April 2021, with inclusion of 100 men with NOA from four centers in Denmark and Sweden. All participants received treatment at the same institution. Intervention: Participants were randomized to mTESE (n = 49) or multiple needle-pass TESA (n = 51). Patients with failed multiple needle-pass TESA proceeded directly to salvage mTESE. Outcome measurements and statistical analysis: The primary outcome was SRR. Secondary outcomes included complications and changes in reproductive hormones after surgery. Results and limitations: Spermatozoa were retrieved in 21/49 (43%) men after mTESE and in 11/51 (22%) men after multiple needle-pass TESA (rate difference –0.21; 95% confidence interval –0.39 to –0.03; p = 0.02). The combined SRR for multiple needle-pass TESA + salvage mTESE was 15/51 (29%). No complications occurred after multiple needle-pass TESA only, while 5/89 (6%) men having mTESE experienced a complication requiring surgical intervention. Overall, no statistically significant differences in reproductive hormones were observed between groups after 6 mo. Limitations include the low number of patients in secondary outcome data. Conclusions: In direct comparison, SRR was higher in mTESE than in multiple needle-pass TESA. Patient summary: Men with azoospermia need surgical extraction of spermatozoa to become biological fathers. In this randomized trial, we compared two surgeries (microdissection testicular sperm extraction [mTESE] and testicular sperm aspiration [TESA]) and found that mTESE gives a higher sperm retrieval rate than multiple needle-pass TESA.
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| 14. |
- Jensen, Esben Skov, et al.
(författare)
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Effect of Sleep Disturbance Symptoms on Treatment Outcome in Blended Cognitive Behavioral Therapy for Depression (E-COMPARED Study): Secondary Analysis
- 2022
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Ingår i: Journal of Medical Internet Research. - : JMIR Publications Inc. - 1438-8871. ; 24:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sleep disturbance symptoms are common in major depressive disorder (MDD) and have been found to hamper the treatment effect of conventional face-to-face psychological treatments such as cognitive behavioral therapy. To increase the dissemination of evidence-based treatment, blended cognitive behavioral therapy (bCBT) consisting of web-based and face-to-face treatment is on the rise for patients with MDD. To date, no study has examined whether sleep disturbance symptoms have an impact on bCBT treatment outcomes and whether it affects bCBT and treatment-as-usual (TAU) equally. Objective: The objectives of this study are to investigate whether baseline sleep disturbance symptoms have an impact on treatment outcomes independent of treatment modality and whether sleep disturbance symptoms impact bCBT and TAU in routine care equally. Methods: The study was based on data from the E-COMPARED (European Comparative Effectiveness Research on Blended Depression Treatment Versus Treatment-as-Usual) study, a 2-arm, multisite, parallel randomized controlled, noninferiority trial. A total of 943 outpatients with MDD were randomized to either bCBT (476/943, 50.5%) or TAU consisting of routine clinical MDD treatment (467/943, 49.5%). The primary outcome of this study was the change in depression symptom severity at the 12-month follow-up. The secondary outcomes were the change in depression symptom severity at the 3- and 6-month follow-up and MDD diagnoses at the 12-month follow-up, assessed using the Patient Health Questionnaire-9 and Mini-International Neuropsychiatric Interview, respectively. Mixed effects models were used to examine the association of sleep disturbance symptoms with treatment outcome and treatment modality over time. Results: Of the 943 patients recruited for the study, 558 (59.2%) completed the 12-month follow-up assessment. In the total sample, baseline sleep disturbance symptoms did not significantly affect change in depressive symptom severity at the 12-month follow-up (beta=.16, 95% CI -0.04 to 0.36). However, baseline sleep disturbance symptoms were negatively associated with treatment outcome for bCBT (beta=.49, 95% CI 0.22-0.76) but not for TAU (beta=-.23, 95% CI -0.50 to 0.05) at the 12-month follow-up, even when adjusting for baseline depression symptom severity. The same result was seen for the effect of sleep disturbance symptoms on the presence of depression measured with Mini-International Neuropsychiatric Interview at the 12-month follow-up. However, for both treatment formats, baseline sleep disturbance symptoms were not associated with depression symptom severity at either the 3- (beta=.06, 95% CI -0.11 to 0.23) or 6-month (beta=.09, 95% CI -0.10 to 0.28) follow-up. Conclusions: Baseline sleep disturbance symptoms may have a negative impact on long-term treatment outcomes in bCBT for MDD. This effect was not observed for TAU. These findings suggest that special attention to sleep disturbance symptoms might be warranted when MDD is treated with bCBT. Future studies should investigate the effect of implementing modules specifically targeting sleep disturbance symptoms in bCBT for MDD to improve long-term prognosis.
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| 15. |
- Jensen, Jimmy, et al.
(författare)
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Neurocognitive and psychopathological correlates of self-monitoring ability in schizophrenia.
- 2004
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Ingår i: European Archives of Psychiatry and Clinical Neuroscience. - : Springer. - 0940-1334 .- 1433-8491. ; 254:5, s. 312-317
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Tidskriftsartikel (refereegranskat)abstract
- In a previous study reported by our group one salient finding was that many patients with schizophrenia appeared to be unable to judge their own quality of life (QoL) and that this inability was associated with negative symptoms. The association between negative symptoms, poor self-monitoring capacity and lack of insight might be explained by a common underlying factor, i.e. neurocognitive impairment. Fifty schizophrenic patients were examined by symptom ratings and a comprehensive neuropsychological test battery. The cognitive performance of the patients was very poor. The major findings of the present study were the association between clinically rated Lack of judgement (PANSS G12) and 1) a set of standard performance and executive indices of the computerised tests, and 2) difference scores between objective performance/strategies and self-ratings of the same attributes. There appears to be a substantial contribution of cognitive and executive problems to the poor judgement and lack of insight of schizophrenic patients, and these problems can to some extent be assessed objectively.
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| 16. |
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| 17. |
- Jensen, Lise, et al.
(författare)
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Seeing through the eyes of a teacher : differences in perceptions of HE teaching in face-to-face and digital contexts
- 2020
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Ingår i: Studies in Higher Education. - : Informa UK Limited. - 0307-5079 .- 1470-174X. ; 45:6, s. 1149-1159
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Tidskriftsartikel (refereegranskat)abstract
- Studies of how contextual factors influence teachers’ approaches to teaching have chiefly focused on face-to-face teaching in physical campus contexts. This study advances understanding of how applicable this knowledge is in digital contexts. The study explores how university teachers perceive the differences between teaching in physical campus contexts and the digital teaching contexts found in online courses. Interview data were collected from 15 university teachers and analysed using thematic analysis. The results show that respondents perceived digital teaching contexts to be changeable. Changes were attributed to technology development and influences from students and teachers. The respondents varied in how close or anonymous they perceived their online students to be compared to their campus students. The variation was related to the type of teaching-learning activities prioritised by the respondents. However, no relationships were found between respondents’ perceptions of their student-teacher relationship and class size, time invested, or type of communication.
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| 18. |
- Jensen, Lise, et al.
(författare)
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The Blurred Line Between Failure and Success in Student–Industry Projects
- 2011
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Ingår i: Third International Symposium on Project Appr oaches in Engineering Education (PAEE’2011): Aligning Engineering Education with Engineering Challenges. - 9789898525055 ; , s. 43-50
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Konferensbidrag (refereegranskat)abstract
- Student–industry activities are often heralded as win–win–win activities in which students gain knowledge of their future professional fields, companies access student knowledge, and universities both offer students stimulating learning opportunities and strengthen ties with industry. Student–industry projects can be defined as an active learning methodology characterized by pedagogical values such as improving student understanding of the concepts, motivation, interest in the subject, and work efficiency (Barak, 2009). Biggs and Tang (2009) find that a stimulating learning environment relies on three main components: 1. an open environment, 2. worthwhile tasks, and 3. demands that students can realistically hope to meet. In the same vein, Perkins (1991) stresses the importance of learners’ attitudes towards the learning situation and of students’ “buying in” to the instruction agenda, factors that are much more easily stimulated when students are confronted with real problems by stakeholders than when presented with constructed problems in simulated situations. Leenders and Maufette-Leenders (2010) argue that a fictitious scenario will not appear credible and not engage students the way an authentic situation does. Authentic learning “focuses on real-world, complex problems and their solutions” (Lombardi, 2007, p. 2), and introduction into a professional environment helps students become “enculturated” into the discipline, a crucial concept according to Lave and Wenger, as “a training program that consists of instructional settings separated from actual performance would tend to split the learner’s ability to manage the learning situation apart from his ability to perform the skill” (1991). University representatives generally agree that student–industry activities make students more employable after graduation (Dawson et al., 1997). Seen in this light, one may wonder why so many student–industry activities are established, only to survive a few iterations. Student–industry activities are by no means homogenous, and include a wide variety of collaboration models ranging from short undemanding meetings between students and industry representatives to long complex relationships demanding considerable effort from universities, companies, and students alike. We have no reason to believe that the success factors for these widely divergent collaboration models are identical. In approaching the concept of “success”, we find it desirable to distinguish between various student–industry activities in a defined framework. In the project management field, critical success factors are often discussed and identified (Pinto and Prescott, 1988; Westerveld, 2003); to better the odds of survival of student–industry activities, the same needs to be done in the field of university–industry collaboration to create more stable student–industry activities.
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| 19. |
- Jensen, Lise, et al.
(författare)
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University–Industry–Student: A volatile triangle
- 2011
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Ingår i: Proceedings of the ICETI 2011, International Conference on Education, Training and Informatics. - 9781936338184
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Konferensbidrag (refereegranskat)abstract
- Collaboration involving student–industry activities entails a complex interaction between university, students, and industry. The university–student–industry triangle identified here is neither static nor balanced, and each of the three intertwined relationships displays distinguishing characteristics. Each has its own structure; the activity phases of the relationships are not synchronous, and each of the three parties enters into collaboration guided by different motives and expectations of the outcome. Though the reasons for engaging in collaboration differ dramatically from party to party, they all relate to one of three aspects, i.e., a strategic/tactical, an operational, and an individual/emotional aspect, which together form the “motivation prism”. To ensure enterprise longevity, university representatives should concentrate on the realistic set-up of student–industry activities, on calibrating company expectations, and on personal relationships with company representatives.
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| 20. |
- Jønsson, Rie, et al.
(författare)
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Aggregative adherence fimbriae form compact structures as seen by SAXS
- 2023
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Ingår i: Scientific Reports. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Bacterial colonization is mediated by fimbriae, which are thin hair-like appendages dispersed from the bacterial surface. The aggregative adherence fimbriae from enteroaggregative E. coli are secreted through the outer membrane and consist of polymerized minor and major pilin subunits. Currently, the understanding of the structural morphology and the role of the minor pilin subunit in the polymerized fimbriae are limited. In this study we use small-angle X-ray scattering to reveal the structural morphology of purified fimbriae in solution. We show that the aggregative fimbriae are compact arrangements of subunit proteins Agg5A + Agg3B which are assembled pairwise on a flexible string rather than extended in relatively straight filaments. Absence of the minor subunit leads to less compact fimbriae, but did not affect the length. The study provides novel insights into the structural morphology and assembly of the aggregative adherence fimbriae. Our study suggests that the minor subunit is not located at the tip of the fimbriae as previously speculated but has a higher importance for the assembled fimbriae by affecting the global structure.
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| 21. |
- Kidholm, Kristian, et al.
(författare)
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Telemedicine and the assessment of clinician time. A scoping review
- 2023
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Ingår i: International Journal of Technology Assessment in Health Care. - 0266-4623 .- 1471-6348. ; 40:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Telemedicine may improve healthcare access and efficiency if demanding less clinician time than usual care. We sought to describe the degree to which telemedicine trials assess the effect of telemedicine on clinicians' time and to discuss how including the Time Needed to Treat (TNT) in HTA of telemedicine could affect 33 the design of telemedicine services and studies. Methods: We conducted a scoping review by searching clinicaltrials.gov using the search term "telemedicine"and limiting results to randomized trials or observational studies with a comparison group registered between January 2012 and October 2023. We then reviewed trial registration data to determine if any of the outcomes assessed in the trials measured effect on clinicians' time. Results: We found 113 studies and of these 78 studies of telemedicine met the inclusion criteria and were included. Nine (12 percent) of the 78 studies had some measure of clinician time as a primary outcome, and 11 (14 percent) as secondary outcome. Four studies compared direct measures of TNT with telemedicine vs. usual care, but no statistically significant difference was found. Of the sixteen studies including indirect measures of clinician time, thirteen found no significant effects, two found a statistically significant reduction and one found a statistically significant increase. Discussion: This scoping review found that clinician time is not commonly measured in studies of telemedicine interventions. Attention to telemedicine's TNT in clinical studies and HTAs of telemedicine in practice may bring 48 attention to the organization of workflows and increase the value of telemedicine.
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| 22. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 23. |
- Lindholm, Christin, et al.
(författare)
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Student–industry collaboration models: challenges and risks
- 2011
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Ingår i: Proceedings of Annual Conference: SEFI 2011. ; , s. 765-772
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Konferensbidrag (refereegranskat)abstract
- Many student–industry activities have emerged in recent years, and universities have invested considerable time and energy in designing and implementing such collaboration models. However, as models differ significantly, student–industry activities should not all be bundled together. This paper examines student–industry activities conducted as integral parts of engineering study programmes. These activities allow students and industry representatives to meet. The results are based on four major components: an interview study, a case study of the Meet with industry guest lecture series, a case study of the Industry link project course, and a risk analysis of two student–industry collaboration models. Two very well-known, but markedly different, types of collaboration models have been chosen, one collaboration model, delivering real results to industry (e.g., project) and one collaboration model, not delivering real results to industry (e.g., guest lectures). Both collaboration models have been subjected to risk analysis, leading to the identification of strategic areas specific to the particular collaboration model. Based on the findings we suggest that, before choosing a specific model of student–industry collaboration, a risk analysis should be conducted focusing on the three key areas, i.e., Resources, Framework, and Pedagogic considerations, perhaps not primarily to identify specific risks, but to identify the typical risk areas for the activities to be offered
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| 24. |
- Malik, Leila, et al.
(författare)
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Self-assembly of designed coiled coil peptides studied by small-angle X-ray scattering and analytical ultracentrifugation
- 2013
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Ingår i: Journal of Peptide Science. - : Wiley. - 1099-1387 .- 1075-2617. ; 19:5, s. 283-292
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Tidskriftsartikel (refereegranskat)abstract
- alpha-Helical coiled coil structures, which are noncovalently associated heptad repeat peptide sequences, are ubiquitous in nature. Similar amphipathic repeat sequences have also been found in helix-containing proteins and have played a central role in de novo design of proteins. In addition, they are promising tools for the construction of nanomaterials. Small-angle X-ray scattering (SAXS) has emerged as a new biophysical technique for elucidation of protein topology. Here, we describe a systematic study of the self-assembly of a small ensemble of coiled coil sequences using SAXS and analytical ultracentrifugation (AUC), which was correlated with molecular dynamics simulations. Our results show that even minor sequence changes have an effect on the folding topology and the self-assembly and that these differences can be observed by a combination of AUC, SAXS, and circular dichroism spectroscopy. A small difference in these methods was observed, as SAXS for one peptide and revealed the presence of a population of longer aggregates, which was not observed by AUC. Copyright (c) 2013 European Peptide Society and John Wiley & Sons, Ltd.
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| 25. |
- Motte, Damien, et al.
(författare)
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Användning av CEQ:s TM-skala för projektbaserade kurser
- 2021
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Ingår i: LTHs 11:e Pedagogiska inspirationskonferens. - 2003-3761 .- 2003-377X. ; , s. 9-12
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Konferensbidrag (refereegranskat)abstract
- Skalan Tydliga mål (TM) i Course Evaluation Questionnaire (CEQ, en kursutvärderingsenkät som ges vid Lunds Tekniska Högskola), mäter hur väl lärarna kommunicerar kursens lärandemål och vad de förväntar sig att studenterna ska prestera för att uppfylla lärandemålen. Projektbaserade kurser har en form av examination – pro- jektet – som inte är vanlig för studenterna och där tydlighet har en särskild vikt. Projektbaserade kurser har ofta ett sämre betyg för TM-skalan än andra kurser, vilket indikerar att stu- denterna oftare känner sig osäkra på vad de förväntas leverera och hur deras projekt kommer att bedömas.Flera orsaker till dessa osäkerheter har tidigare identifierats och i denna studie har sambandet mellan dessa orsaker och omdömena på TM-skalan undersökt. För detta syfte byggdes en ”osäkerhetsskala” (OS); ett aggregerat mått av osäkerheten studenterna upplever p.g.a. dessa orsaker. Resultaten visar att det finns en stark korrelation mellan OS och TM-skalan för de tre kurser som ingick i studien.I studien undersöktes även om studenternas individuella at tityd mot och hantering av osäkerhet påverkar deras svar till TM-skalan. För detta användes en kort version av instrumen- tet Uncertainty Response Scale (URS). Ingen korrelation mel- lan URS och TM-skalan och mellan URS och OS hittades.
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| 26. |
- Motte, Damien, et al.
(författare)
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Tydligare mål och förväntningar i projektbaserade kurser
- 2018
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Ingår i: LTHs 10:e Pedagogiska inspirationskonferens. - 2003-3761 .- 2003-377X. ; , s. 52-55
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Konferensbidrag (refereegranskat)abstract
- CEQ-resultaten för en del projektbaserade kurser visar att studenterna upplever att kursens mål inte är tydliga (skalan "Tydliga mål", TM, i CEQ). Studenterna verkar således vara ganska osäkra på vad lärarna förväntar sig av dem. Detta är ett problem som kräver uppmärksamhet, eftersom otydliga mål och förväntningar kan vara en anledning till frustration, oro och onödig stress hos studenterna, även om de är i övrigt ganska nöjda med projektkurser i efterhand.En intervjuundersökning med studenter från olika projektbaserade LTH-kurser har genomförts och en orsak-verkanmodell som förtydligar osäkerheterna som studenterna känner kring projektarbete har utvecklats.Några lärare har redan lyckats förbättra sina kurser så att studenterna upplever att de vet vad som förväntas av dem, vilket speglas i resultatet som kurserna får i skalan TM i CEQenkäten. Baserat på dessa kurser och orsak-verkan-modellen presenteras ett angreppssätt och tre exempel.
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| 27. |
- Nguyen, Quynh T., et al.
(författare)
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Seasonal variation of atmospheric particle number concentrations, new particle formation and atmospheric oxidation capacity at the high Arctic site Villum Research Station, Station Nord
- 2016
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Ingår i: Atmospheric Chemistry and Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 16:17, s. 11319-11336
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Tidskriftsartikel (refereegranskat)abstract
- This work presents an analysis of the physical properties of sub-micrometer aerosol particles measured at the high Arctic site Villum Research Station, Station Nord (VRS), northeast Greenland, between July 2010 and February 2013. The study focuses on particle number concentrations, particle number size distributions and the occurrence of new particle formation (NPF) events and their seasonality in the high Arctic, where observations and characterization of such aerosol particle properties and corresponding events are rare and understanding of related processes is lacking. A clear accumulation mode was observed during the darker months from October until mid-May, which became considerably more pronounced during the prominent Arctic haze months from March to mid-May. In contrast, nucleation- and Aitken-mode particles were predominantly observed during the summer months. Analysis of wind direction and wind speed indicated possible contributions of marine sources from the easterly side of the station to the observed summertime particle number concentrations, while southwesterly to westerly winds dominated during the darker months. NPF events lasting from hours to days were mostly observed from June until August, with fewer events observed during the months with less sunlight, i.e., March, April, September and October. The results tend to indicate that ozone (O3) might be weakly anti-correlated with particle number concentrations of the nucleation-mode range (10-30ĝ€nm) in almost half of the NPF events, while no positive correlation was observed. Calculations of air mass back trajectories using the Hybrid Single Particle Lagrangian Integrated Trajectory (HYSPLIT) model for the NPF event days suggested that the onset or interruption of events could possibly be explained by changes in air mass origin. A map of event occurrence probability was computed, indicating that southerly air masses from over the Greenland Sea were more likely linked to those events.
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| 28. |
- Nielsen, Birgitte Lund, et al.
(författare)
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Social, emotional and intercultural competencies: a literature review with a particular focus on the school staff
- 2019
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Ingår i: European Journal of Teacher Education. - : Informa UK Limited. - 0261-9768 .- 1469-5928. ; 42:3, s. 410-428
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Tidskriftsartikel (refereegranskat)abstract
- Framed by the EU-project Hand in Hand focusing on Social, Emotional and Intercultural (SEI) competencies among students and school staff the paper discusses implementation and professional competencies based on a literature review. Five themes were identified: 1) Intercultural/transcultural competency is not often referred to in the same research as social-emotional learning, though socio-emotional aspects appear to be `in the core ', 2) it is crucial to be aware of agency among school staff in a SEI-implementation, 3) successful implementation is about more than the activities in the specific program, it is rather about elements in synergy and professional learning over time, 4) the subtle balance between adaptation and fidelity might best be addressed in an adaptive curriculum emphasizing active ingredients, and 5) this is a field with many intervention studies, but it is urgent to consider if the psychometric measures are sufficiently sensitive to catch the subtle changes related to SEI-competencies.
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| 29. |
- Pennells, Lisa, et al.
(författare)
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Equalization of four cardiovascular risk algorithms after systematic recalibration : individual-participant meta-analysis of 86 prospective studies
- 2019
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 40:7, s. 621-
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Tidskriftsartikel (refereegranskat)abstract
- Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after ‘recalibration’, a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at ‘high’ 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29–39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22–24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44–51 such individuals using original algorithms, in contrast to 37–39 individuals with recalibrated algorithms.Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.
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| 30. |
- Persson, Mia, et al.
(författare)
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Sociality genes are associated with human-directed social behaviour in golden and Labrador retriever dogs
- 2018
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Ingår i: PeerJ. - : PEERJ INC. - 2167-8359. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Dogs have human-directed social skills that allow them to communicate and cooperate with humans. We have previously identified two loci on chromosome 26 associated with human contact-seeking behaviors during an unsolvable problem task in laboratory beagles (Persson et A, 2016). The aim of the present study was to verify the single nucleotide polymorphisms (SNPs) in additional dog breeds. We also studied how the allele frequencies have changed during domestication and recent selection. Methods: Dogs of two breeds, 61 golden retrievers and 100 Labrador retrievers, were phenotyped and genotyped, and 19 wolves were genotyped. The Labrador retrievers were divided into common and field type by pedigree data to make it possible to study the effects of recent selection. All dogs were tested in an unsolvable problem task where human-directed social behaviors were scored. DNA from dogs (buccal swabs) and wolves (blood or brain tissue) was analyzed for genotype on two of the previously identified SNP markers, BICF2G630798942 (SNP1) and BICF2S23712114 (SNP2), by pyrosequencing. Results: There was genetic variation for SNP1 in both dog breeds whereas the wolves were fixed for this polymorphism, and for SNP2 there was variation in both dogs and wolves. For both SNPs, Labrador retriever types differed significantly in allele frequencies. We found associations between SNPs and human-directed social behavior in both dog breeds. In golden retrievers, SNP I was associated with physical contact variables, for example, with the duration of physical contact with the owner (F-2,F-56 = 4.389, p = 0.017). SNP2 was associated with several behavioral variables in both breeds, among others owner gazing frequency in both golden retrievers (F-2,F-55 = 6.330, p = 0.003) and Labradors (F-1,F-93 = 5.209, p = 0.025). Discussion: Our results verify the association between the previously identified SNPs and human-directed social behavior scored in an unsolvable problem task. Differences in allele frequencies suggest that these loci have been affected by selection. The results indicate that these genomic regions are involved in human-directed social behavior in not only beagles but in other dog breeds as well. We hypothesize that they may have been important during dog domestication.
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| 31. |
- Reverté, Sara, et al.
(författare)
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National records of 3000 European bee and hoverfly species : A contribution to pollinator conservation
- 2023
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Ingår i: Insect Conservation and Diversity. - 1752-458X. ; 16:6, s. 758-775
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Tidskriftsartikel (refereegranskat)abstract
- Pollinators play a crucial role in ecosystems globally, ensuring the seed production of most flowering plants. They are threatened by global changes and knowledge of their distribution at the national and continental levels is needed to implement efficient conservation actions, but this knowledge is still fragmented and/or difficult to access. As a step forward, we provide an updated list of around 3000 European bee and hoverfly species, reflecting their current distributional status at the national level (in the form of present, absent, regionally extinct, possibly extinct or non-native). This work was attainable by incorporating both published and unpublished data, as well as knowledge from a large set of taxonomists and ecologists in both groups. After providing the first National species lists for bees and hoverflies for many countries, we examine the current distributional patterns of these species and designate the countries with highest levels of species richness. We also show that many species are recorded in a single European country, highlighting the importance of articulating European and national conservation strategies. Finally, we discuss how the data provided here can be combined with future trait and Red List data to implement research that will further advance pollinator conservation.
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| 32. |
- Saldert, Charlotta, 1966, et al.
(författare)
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Complexity in measuring outcomes after communication partner training: Alignment between goals of intervention and methods of evaluation
- 2018
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Ingår i: Aphasiology. - : Informa UK Limited. - 0268-7038 .- 1464-5041. ; 32:10, s. 1167-1193
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Tidskriftsartikel (refereegranskat)abstract
- Background: Researchers are currently discussing the need for consensus on a core set of outcome measures to assess interventions in aphasia. For indirect, environmental approaches to aphasia intervention, such as communication partner training (CPT), the roadmap to obtaining consensus on core outcome measures seems especially complex. While the purpose of CPT is to improve communication for people with communication disorders, the intervention is aimed at the communication partner. There is also a variety of goals, activities, and possible settings for CPT. This complexity increases the risk of a mismatch between the goals and content of the intervention and measures used to evaluate the outcome.Aims: The purpose of this paper is to describe the complexity of measuring outcomes from CPT. The aim is to enable clinicians and researchers to reflect on the outcomes to be measured and also on how different types of measures may or may not be aligned with the goals and content of a specific CPT intervention.Main contribution: The current proliferation of outcome measures used in CPT is considered in the light of a survey of general factors to be considered in evaluating intervention outcomes. The complexity of measuring outcomes in CPT is illustrated and the importance of alignment of main objectives, intervention tasks, and projected outcomes is exemplified by referencing two common types of CPT approaches. Objectives relating to knowledge of aphasia, interactional behaviour, and feelings and attitudes are considered in relation to specific outcome measurements. It is suggested that both study-specific and more general measures are needed for capturing and comparing outcomes. The measurement of relevant outcome in CPT is discussed along with implications for future research and clinical practice.Conclusions: Different CPT approaches share the same purpose of facilitating communication in aphasia, but their application in research studies or in the clinic, is specific to the particular context. Special care must thus be taken in both clinical practice and research to safeguard the alignment between objectives, tasks, and projected intervention outcomes and the actual measures used. Further, it is concluded that there is a need for the development of new measures based on a consensus on key outcomes to be measured in CPT.
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| 33. |
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| 34. |
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| 35. |
- Sundman, Ann-Sofie, et al.
(författare)
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Understanding of human referential gestures is not correlated to human-directed social behaviour in Labrador retrievers and German shepherd dogs
- 2018
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Ingår i: Applied Animal Behaviour Science. - : Elsevier. - 0168-1591 .- 1872-9045. ; 201, s. 46-53
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Tidskriftsartikel (refereegranskat)abstract
- Dogs are known to excel in interspecific communication with humans and both communicate with humans and follow human communicative cues. Two tests commonly used to test these skills are, firstly, the problem-solving paradigm, and, secondly, following human referential signals, for example pointing. The aim of the present study was to investigate whether dogs that seek more human contact in an unsolvable problem-solving paradigm also better understand human communicative cues in a pointing test. We also assessed between- and within-breed variation in both tests. 167 dogs were tested and were of the breeds German shepherd dog and Labrador retriever. The Labradors were separated into the two selection lines: common type (bred for show and pet) and field type (bred for hunting). A principal component analysis of behaviours during the problem solving revealed four components: Passivity, Experimenter Contact, Owner Contact and Eye Contact. We analysed the effect of these components on success rate in the pointing test and we found no effect for three of them, while a negative correlation was found for Owner Contact (F(1,147) = 6.892; P = 0.010). This was only present in common-typed Labradors. We conclude that the ability to follow a pointing cue does not predict the propensity for human-directed social behaviour in a problem-solving situation and suggest that the two tests measure different aspects of human-directed social behaviour in dogs.
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| 36. |
- Surendran, Praveen, et al.
(författare)
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Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:10, s. 1151-1161
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Tidskriftsartikel (refereegranskat)abstract
- High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used -1/4155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.
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| 37. |
- Thomassen, Mads, et al.
(författare)
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Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants : Application of a points-based ACMG/AMP approach
- 2022
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 43:12, s. 1921-1944
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Tidskriftsartikel (refereegranskat)abstract
- Skipping of BRCA2 exon 3 (∆E3) is a naturally occurring splicing event, complicating clinical classification of variants that may alter ∆E3 expression. This study used multiple evidence types to assess pathogenicity of 85 variants in/near BRCA2 exon 3. Bioinformatically predicted spliceogenic variants underwent mRNA splicing analysis using minigenes and/or patient samples. ∆E3 was measured using quantitative analysis. A mouse embryonic stem cell (mESC) based assay was used to determine the impact of 18 variants on mRNA splicing and protein function. For each variant, population frequency, bioinformatic predictions, clinical data, and existing mRNA splicing and functional results were collated. Variant class was assigned using a gene-specific adaptation of ACMG/AMP guidelines, following a recently proposed points-based system. mRNA and mESC analysis combined identified six variants with transcript and/or functional profiles interpreted as loss of function. Cryptic splice site use for acceptor site variants generated a transcript encoding a shorter protein that retains activity. Overall, 69/85 (81%) variants were classified using the points-based approach. Our analysis shows the value of applying gene-specific ACMG/AMP guidelines using a points-based approach and highlights the consideration of cryptic splice site usage to appropriately assign PVS1 code strength.
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| 38. |
- Zeng, Chenjie, et al.
(författare)
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Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus
- 2016
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 x 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 x 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 x 10(-4)) identified in the general populations, and rs113824616 (P = 7 x 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.
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