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| 5. |
- Choi, MY, et al.
(author)
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The prevalence and determinants of anti-DFS70 autoantibodies in an international inception cohort of systemic lupus erythematosus patients
- 2017
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In: Lupus. - : SAGE Publications. - 1477-0962 .- 0961-2033. ; 26:10, s. 1051-1059
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Journal article (peer-reviewed)abstract
- Autoantibodies to dense fine speckles 70 (DFS70) are purported to rule out the diagnosis of SLE when they occur in the absence of other SLE-related autoantibodies. This study is the first to report the prevalence of anti-DFS70 in an early, multinational inception SLE cohort and examine demographic, clinical, and autoantibody associations. Patients were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. The association between anti-DFS70 and multiple parameters in 1137 patients was assessed using univariate and multivariate logistic regression. The frequency of anti-DFS70 was 7.1% (95% CI: 5.7–8.8%), while only 1.1% (95% CI: 0.6–1.9%) were monospecific for anti-DFS70. In multivariate analysis, patients with musculoskeletal activity (Odds Ratio (OR) 1.24 [95% CI: 1.10, 1.41]) or with anti-β2 glycoprotein 1 (OR 2.17 [95% CI: 1.22, 3.87]) were more likely and patients with anti-dsDNA (OR 0.53 [95% CI: 0.31, 0.92]) or anti-SSB/La (OR 0.25 [95% CI: 0.08, 0.81]) were less likely to have anti-DFS70. In this study, the prevalence of anti-DFS70 was higher than the range previously published for adult SLE (7.1 versus 0–2.8%) and was associated with musculoskeletal activity and anti-β2 glycoprotein 1 autoantibodies. However, ‘monospecific’ anti-DFS70 autoantibodies were rare (1.1%) and therefore may be helpful to discriminate between ANA-positive healthy individuals and SLE.
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| 6. |
- Stinton, L. M., et al.
(author)
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PR3-ANCA: A Promising Biomarker in Primary Sclerosing Cholangitis (PSC)
- 2014
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In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:11
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Journal article (peer-reviewed)abstract
- Background and Aims: The only recognized biomarker for primary sclerosing cholangitis (PSC) is atypical anti-neutrophil cytoplasmic antibodies (aANCA), which, in addition to having low sensitivity and specificity, is an indirect immunofluorescence (IIF) test lacking the advantages of high throughput and objectivity. Recent reports have shown that antibodies to proteinase-3 (PR3-ANCA) might add diagnostic value in inflammatory bowel disease (IBD), specifically in ulcerative colitis (UC). As PSC is associated with IBD, the objective of this study was to evaluate the frequency and clinical significance of PR3-ANCA in a large cohort of patients. Methods: A total of 244 PSC and 254 control [autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), hepatitis C viral infection (HCV), hepatitis B viral infection (HBV), and healthy controls] sera and their clinical correlations were retrospectively analyzed for PR3-ANCA determined by ELISA and a new chemiluminescence immunoassay (CIA). Testing was also performed for aANCA by IIF. Results: When measured by CIA, PR3-ANCA was detected in 38.5% (94/244) of PSC patients compared to 10.6% (27/254) controls (p<0.0001). By ELISA, PR3-ANCA was detected in 23.4% (57/244) of PSC patients compared to 2.7% (6/254) controls (p<0.0001). PR3-ANCA in PSC patients was not associated with the presence or type of underlying IBD, and, in fact, it was more frequent in Crohn's disease (CD) patients with PSC than previously reported in CD alone. PR3-ANCA in PSC measured by CIA correlated with higher liver enzymes. Conclusion: PR3-ANCA is detected in a significant proportion of PSC patients compared to other liver diseases including PBC and AIH. PR3-ANCA is associated with higher liver enzyme levels in PSC, and is not solely related to underlying IBD.
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| 7. |
- Bentow, C., et al.
(author)
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International multi-center evaluation of a novel chemiluminescence assay for the detection of anti-dsDNA antibodies
- 2016
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In: Lupus. - : SAGE PUBLICATIONS LTD. - 0961-2033 .- 1477-0962. ; 25:8, s. 864-872
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Journal article (peer-reviewed)abstract
- Objective: Anti-double stranded desoxyribonucleic acid (anti-dsDNA) antibodies are considered fairly specific for systemic lupus erythematosus (SLE) and their quantification is useful for the clinical management of SLE patients. We assessed the diagnostic performance of the QUANTA Flash dsDNA chemiluminescent immunoassay (CIA) in comparison to an ELISA, using patients from five participating countries. The main focus was to evaluate the correlation between anti-dsDNA antibody results from the CIA and global SLE disease activity, as measured by the SLE Disease Activity Index 2000 (SLEDAI-2K). Patients and methods: A total of 1431 samples (SLE, n=843; disease controls, n=588) from five countries (Canada, USA, Portugal, Sweden and Spain) were tested with QUANTA Flash dsDNA (Inova Diagnostics, San Diego, CA, USA). Data obtained with the QUANTA Lite dsDNA SC ELISA (Inova Diagnostics) were available for samples from three sites (Canada, USA and Sweden, n=566). The SLEDAI-2K scores were available for 805 SLE patients and a cut-off ofamp;gt;4 was used to define active disease. Results: QUANTA Flash dsDNA had a sensitivity of 54.3% for the diagnosis of SLE, combined with 89.8% specificity. Anti-dsDNA antibody levels were significantly higher (pamp;lt;0.0001) in active SLE (SLEDAI-2Kamp;gt;4; n=232; median value 83.0IU/mL) versus the inactive patients (n=573; median value 22.3IU/mL), and the SLEDAI-2K scoring correlated with their dsDNA antibody levels (Spearmans rho=0.44, pamp;lt;0.0001). Similar but less pronounced findings were also found for the ELISA, in relation to disease activity. Conclusions: The QUANTA Flash dsDNA assay showed good clinical performance in a large international multi-center study. Additionally, the strong correlation between anti-dsDNA antibody results and SLEDAI-2K scores supported the potential utility of QUANTA Flash dsDNA for monitoring disease activity.
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| 10. |
- Hallek, M, et al.
(author)
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The HELIOS trial protocol: a phase III study of ibrutinib in combination with bendamustine and rituximab in relapsed/refractory chronic lymphocytic leukemia
- 2015
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In: Future oncology (London, England). - : Future Medicine Ltd. - 1744-8301 .- 1479-6694. ; 11:1, s. 51-59
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Journal article (peer-reviewed)abstract
- ABSTRACT Ibrutinib is an orally administered, covalent inhibitor of Bruton's tyrosine kinase with activity in B-cell malignancies based on Phase I/II studies. We describe the design and rationale for the Phase III HELIOS trial (trial registration: EudraCT No. 2012-000600-15; UTN No. U1111-1135-3745) investigating whether ibrutinib added to bendamustine and rituximab (BR) provides benefits over BR alone in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Eligible patients must have relapsed/refractory disease measurable on CT scan and meet ≥1 International Workshop on Chronic Lymphocytic Leukemia criterion for requiring treatment; patients with del(17p) are excluded. All patients receive BR (maximum six cycles) as background therapy and are randomized 1:1 to placebo or ibrutinib 420 mg/day. Treatment with ibrutinib or placebo will start concomitantly with BR and continue until disease progression or unacceptable toxicity. The primary end point is progression-free survival. Secondary end points include safety, objective response rate, overall survival, rate of minimal residual disease-negative remissions, and patient-reported outcomes. Tumor response will be assessed using the International Workshop on Chronic Lymphocytic Leukemia guidelines.
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| 11. |
- Khaleva, E, et al.
(author)
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Development of Core Outcome Measures sets for paediatric and adult Severe Asthma (COMSA)
- 2023
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In: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 61:4
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Journal article (peer-reviewed)abstract
- Effectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) working group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies.MethodsCOMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult, and paediatric clinicians, pharmaceutical representatives and health regulators from across Europe. Evidence included a systematic review of development, validity, and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients’ and carers’ views about outcome measures. It was discussed using a modified GRADE Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria.ResultsBoth adult and paediatric COM sets include forced expiratory volume in 1 s (FEV1) as z scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire, and Asthma Control Test (ACT) or Childhood-ACT while the adult COM includes the Severe Asthma Questionnaire and the Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately).ConclusionsThis patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma.
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| 12. |
- Khaleva, E, et al.
(author)
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Development of Core Outcome Measures sets for paediatric and adult Severe Asthma (COMSA)
- 2023
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In: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 61:4
-
Journal article (peer-reviewed)abstract
- Effectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) working group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies.MethodsCOMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult, and paediatric clinicians, pharmaceutical representatives and health regulators from across Europe. Evidence included a systematic review of development, validity, and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients’ and carers’ views about outcome measures. It was discussed using a modified GRADE Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria.ResultsBoth adult and paediatric COM sets include forced expiratory volume in 1 s (FEV1) as z scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire, and Asthma Control Test (ACT) or Childhood-ACT while the adult COM includes the Severe Asthma Questionnaire and the Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately).ConclusionsThis patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma.
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| 15. |
- Kollipost, F, et al.
(author)
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The effect of hydrogen bonding on torsional dynamics: A combined far-infrared jet and matrix isolation study of methanol dimer.
- 2014
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In: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 141:17
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Journal article (peer-reviewed)abstract
- The effect of strong intermolecular hydrogen bonding on torsional degrees of freedom is investigated by far-infrared absorption spectroscopy for different methanol dimer isotopologues isolated in supersonic jet expansions or embedded in inert neon matrices at low temperatures. For the vacuum-isolated and Ne-embedded methanol dimer, the hydrogen bond OH librational mode of the donor subunit is finally observed at ∼560 cm(-1), blue-shifted by more than 300 cm(-1) relative to the OH torsional fundamental of the free methanol monomer. The OH torsional mode of the acceptor embedded in neon is observed at ∼286 cm(-1). The experimental findings are held against harmonic predictions from local coupled-cluster methods with single and double excitations and a perturbative treatment of triple excitations [LCCSD(T)] and anharmonic. VPT2 corrections at canonical MP2 and density functional theory (DFT) levels in order to quantify the contribution of vibrational anharmonicity for this important class of intermolecular hydrogen bond vibrational motion.
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| 16. |
- Krege, JH, et al.
(author)
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Generation and reproductive phenotypes of mice lacking estrogen receptor beta
- 1998
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 95:26, s. 15677-15682
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Journal article (peer-reviewed)abstract
- Estrogens influence the differentiation and maintenance of reproductive tissues and affect lipid metabolism and bone remodeling. Two estrogen receptors (ERs) have been identified to date, ERα and ERβ. We previously generated and studied knockout mice lacking estrogen receptor α and reported severe reproductive and behavioral phenotypes including complete infertility of both male and female mice and absence of breast tissue development. Here we describe the generation of mice lacking estrogen receptor β (ERβ −/−) by insertion of a neomycin resistance gene into exon 3 of the coding gene by using homologous recombination in embryonic stem cells. Mice lacking this receptor develop normally and are indistinguishable grossly and histologically as young adults from their littermates. RNA analysis and immunocytochemistry show that tissues from ERβ −/− mice lack normal ERβ RNA and protein. Breeding experiments with young, sexually mature females show that they are fertile and exhibit normal sexual behavior, but have fewer and smaller litters than wild-type mice. Superovulation experiments indicate that this reduction in fertility is the result of reduced ovarian efficiency. The mutant females have normal breast development and lactate normally. Young, sexually mature male mice show no overt abnormalities and reproduce normally. Older mutant males display signs of prostate and bladder hyperplasia. Our results indicate that ERβ is essential for normal ovulation efficiency but is not essential for female or male sexual differentiation, fertility, or lactation. Future experiments are required to determine the role of ERβ in bone and cardiovascular homeostasis.
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| 17. |
- Mahler, Jasmin, et al.
(author)
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Endogenous murine A beta increases amyloid deposition in APP23 but not in APPPS1 transgenic mice
- 2015
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In: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 36:7, s. 2241-2247
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Journal article (peer-reviewed)abstract
- Endogenous murine amyloid-beta peptide (A beta) is expressed in most A beta precursor protein (APP) transgenic mouse models of Alzheimers disease but its contribution to beta-amyloidosis remains unclear. We demonstrate similar to 35% increased cerebral A beta load in APP23 transgenic mice compared with age-matched APP23 mice on an App-null background. No such difference was found for the much faster A beta-depositing APPPS1 transgenic mouse model between animals with or without the murine App gene. Nevertheless, both APP23 and APPPS1 mice codeposited murine A beta, and immunoelectron microscopy revealed a tight association of murine A beta with human A beta fibrils. Deposition of murine A beta was considerably less efficient compared with the deposition of human A beta indicating a lower amyloidogenic potential of murine A beta in vivo. The amyloid dyes Pittsburgh Compound-B and pentamer formyl thiophene acetic acid did not differentiate between amyloid deposits consisting of human A beta and deposits of mixed human-murine A beta. Our data demonstrate a differential effect of murine A beta on human A beta deposition in different APP transgenic mice. The mechanistically complex interaction of human and mouse A beta may affect pathogenesis of the models and should be considered when models are used for translational preclinical studies.
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| 18. |
- Beauchesne, Benjamin, et al.
(author)
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A new step forward in realistic cluster lens mass modelling : analysis of Hubble Frontier Field Cluster Abell S1063 from joint lensing, X-ray, and galaxy kinematics data
- 2023
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In: Monthly notices of the Royal Astronomical Society. - 0035-8711 .- 1365-2966. ; 527:2, s. 3246-3275
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Journal article (peer-reviewed)abstract
- We present a new method to simultaneously and self-consistently model the mass distribution of galaxy clusters that combines constraints from strong lensing features, X-ray emission, and galaxy kinematics measurements. We are able to successfully decompose clusters into their collisionless and collisional mass components thanks to the X-ray surface brightness, as well as use the dynamics of cluster members, to obtain more accurate masses exploiting the fundamental plane of elliptical galaxies. Knowledge from all observables is included through a consistent Bayesian approach in the likelihood or in physically motivated priors. We apply this method to the galaxy cluster Abell S1063 and produce a mass model that we publicly release with this paper. The resulting mass distribution presents different ellipticities for the intra-cluster gas and the other large-scale mass components as well as deviation from elliptical symmetry in the main halo. We assess the ability of our method to recover the masses of the different elements of the cluster using a mock cluster based on a simplified version of our Abell S1063 model. Thanks to the wealth of mutliwavelength information provided by the mass model and the detected X-ray emission, we also found evidence for an ongoing merger event with gas sloshing from a smaller infalling structure into the main cluster. In agreement with previous findings, the total mass, gas profile, and gas mass fraction are all consistent with small deviations from the hydrostatic equilibrium. This new mass model for Abell S1063 is publicly available, as the LENSTOOL extension used to construct it.
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| 19. |
- de La Vieuville, G., et al.
(author)
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Faint end of the z similar to 3-7 luminosity function of Lyman-alpha emitters behind lensing clusters observed with MUSE
- 2019
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 628
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Journal article (peer-reviewed)abstract
- Contact. This paper presents the results obtained with the Multi-Unit Spectroscopic Explorer (MUSE) at the ESOVery Large Telescope on the faint end of the Lyman-alpha luminosity function (LF) based on deep observations of four lensing clusters. The goal of our project is to set strong constraints on the relative contribution of the Lyman-alpha emitter (LAE) population to cosmic reionization.Aims. The precise aim of the present study is to further constrain the abundance of LAEs by taking advantage of the magnification provided by lensing clusters to build a blindly selected sample of galaxies which is less biased than current blank field samples in redshift and luminosity. By construction, this sample of LAEs is complementary to those built from deep blank fields, whether observed by MUSE or by other facilities, and makes it possible to determine the shape of the LF at fainter levels, as well as its evolution with redshift.Methods. We selected a sample of 156 LAEs with redshifts between 2.9 <= z <= 6.7 and magnification-corrected luminosities in the range 39 less than or similar to log L-Ly alpha [erg s(-1)] less than or similar to 43. To properly take into account the individual differences in detection conditions between the LAEs when computing the LF, including lensing configurations, and spatial and spectral morphologies, the non-parametric 1/V-max method was adopted. The price to pay to benefit from magnification is a reduction of the effective volume of the survey, together with a more complex analysis procedure to properly determine the effective volume V-max for each galaxy. In this paper we present a complete procedure for the determination of the LF based on IFU detections in lensing clusters. This procedure, including some new methods for masking, effective volume integration and (individual) completeness determinations, has been fully automated when possible, and it can be easily generalized to the analysis of IFU observations in blank fields.Results. As a result of this analysis, the Lyman-alpha LF has been obtained in four different redshift bins: 2.9 < z < 6; 7, 2.9 < z < 4.0, 4 : 0 < z < 5.0; and 5 : 0 < z < 6.7 with constraints down to log L-Ly alpha = 40.5. From our data only, no significant evolution of LF mean slope can be found. When performing a Schechter analysis also including data from the literature to complete the present sample towards the brightest luminosities, a steep faint end slope was measured varying from alpha = -1.69(-0.08)(+0.08) to alpha = -1.87(-0 .12)(+0.12) between the lowest and the highest redshift bins.Conclusions. The contribution of the LAE population to the star formation rate density at z similar to 6 is less than or similar to 50% depending on the luminosity limit considered, which is of the same order as the Lyman-break galaxy (LBG) contribution. The evolution of the LAE contribution with redshift depends on the assumed escape fraction of Lyman-alpha photons, and appears to slightly increase with increasing redshift when this fraction is conservatively set to one. Depending on the intersection between the LAE/LBG populations, the contribution of the observed galaxies to the ionizing flux may suffice to keep the universe ionized at z similar to 6.
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| 20. |
- Diepgen, TL, et al.
(author)
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Mercaptobenzothiazole or the mercapto-mix: which should be in the standard series?
- 2006
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In: Contact Dermatitis. - : Wiley. - 0105-1873 .- 1600-0536. ; 55:1, s. 36-38
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Journal article (peer-reviewed)abstract
- Mercaptobenzothiazole (MBT) compounds are well known contact allergens. To detect rubber allergic patients we use both MBT (2% in petrolatum) and a mercapto-mix with 4 constituents of 0.5% each in our standard series. In this article the EECDRG presents data of in total 32 475 consecutive tested patients attending the respective contact dermatitis clinics from 11 centres in Europe to determine if the mix and MBT detected the same allergic patients. We found 327 patients positive to the mix or MBT, or to both. 261 were positive to the mix and 254 to MBT. MBT was negative in 73 patients who were positive to the mix. If the mix had not been in the standard series, on average 22% of patients allergic to a mercapto-compound would have been missed, for MBT this would have been on average 20%. All clinics would have missed a significant number of positive reactions if both compounds had not been tested. We conclude, that both the mercapto mix and MBT are required in the standard series.
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| 21. |
- Dong, Yaa-Hui, et al.
(author)
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Use of Inhaled Corticosteroids in Patients With COPD and the Risk of TB and Influenza A Systematic Review and Meta-analysis of Randomized Controlled Trials
- 2014
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In: Chest. - : Elsevier BV. - 1931-3543 .- 0012-3692. ; 145:6, s. 1286-1297
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Journal article (peer-reviewed)abstract
- Background: The use of inhaled corticosteroids (ICSs) is associated with an increased risk of pneumonia in patients with COPD. However the risks of other respiratory infections such as TB and influenza remain unclear. Methods: Through a comprehensive literature search of MEDLINE EMBASE CINAHL Cochrane Library and ClinicalTrials.gov from inception to July 2013 we identified randomized controlled trials of ICS therapy lasting at least 6 months. We conducted meta-analyses by the Peto Mantel-Haenszel and Bayesian approaches to generate summary estimates comparing ICS with non-ICS treatment on the risk of TB and influenza. Results: Twenty-five trials (22,898 subjects) for TB and 26 trials (23,616 subjects) for influenza were included. Compared with non-ICS treatment ICS treatment was associated with a significantly higher risk of TB (Peto OR 2.29 95% CI 1.04-5.03) but not influenza (Peto OR 1.24 95% CI 0.94-1.63). Results were similar with each meta-analytic approach. Furthermore the number needed to harm to cause one additional TB event was lower for patients with COPD treated with ICSs in endemic areas than for those in nonendemic areas (909 vs 1,667 respectively). Conclusions: This study raises safety concerns about the risk of TB and influenza associated with ICS use in patients with COPD which deserve further investigation.
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| 22. |
- Drake, A. B., et al.
(author)
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The MUSE Hubble Ultra Deep Field Survey VI. The faint-end of the Lyα luminosity function at 2.91
- 2017
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 608
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Journal article (peer-reviewed)abstract
- We present the deepest study to date of the Ly alpha luminosity function in a blank field using blind integral field spectroscopy from MUSE. We constructed a sample of 604 Ly alpha emitters (LAEs) across the redshift range 2.91 < z < 6.64 using automatic detection software in the Hubble Ultra Deep Lield. The deep data cubes allowed us to calculate accurate total Ly alpha fluxes capturing low surface-brightness extended Ly alpha emission now known to be a generic property of high-redshift star-forming galaxies. We simulated realistic extended LAEs to fully characterise the selection function of our samples, and performed flux-recovery experiments to test and correct for bias in our determination of total Ly alpha fluxes. We find that an accurate completeness correction accounting for extended emission reveals a very steep faint-end slope of the luminosity function, alpha, down to luminosities of log(10) L erg s(-1) < 41.5, applying both the 1/V-max and maximum likelihood estimators. Splitting the sample into three broad redshift bins, we see the faint-end slope increasing from -2.03(-0.07)(+1.42) at z approximate to 3.44 to -2.86(-infinity)(+0.76) Z approximate to 76 at z approximate to 5.48, however no strong evolution is seen between the 68% confidence regions in L*-alpha parameter space. Using the Ly alpha line flux as a proxy for star formation activity, and integrating the observed luminosity functions, we find that LAEs' contribution to the cosmic star formation rate density rises with redshift until it is comparable to that from continuum-selected samples by z approximate to 6. This implies that LAEs may contribute more to the star-formation activity of the early Universe than previously thought, as any additional intergalactic medium (IGM) correction would act to further boost the Ly alpha luminosities. Linally, assuming fiducial values for the escape of Ly alpha and LyC radiation, and the dumpiness of the IGM, we integrated the maximum likelihood luminosity function at 5.00 < z < 6.64 and find we require only a small extrapolation beyond the data (<1 dex in luminosity) for LAEs alone to maintain an ionised IGM at z approximate to 6.
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| 23. |
- Elbagir, S, et al.
(author)
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ANTI-PHOSPHATIDYLSERINE/PROTHROMBIN ANTIBODIES AND VASCULAR EVENTS ASSOCIATE POSITIVELY WITH HLA-DRB1*13 AND NEGATIVELY WITH HLA-DRB1*03 IN SLE
- 2022
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In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 658-659
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Conference paper (other academic/artistic)abstract
- Anti-phosphatidylserine/prothrombin antibodies (anti-PS/PT) associate with thrombotic events (1). HLA-DRB1 alleles contribute to the occurrence of conventional antiphospholipid antibodies (aPL), including anti-beta2glycoprotein-I (beta2GPI) and anti-cardiolipin (CL) (2).ObjectivesWe investigated associations between anti-PS/PT and HLA-DRB1 alleles and thrombosis in patients with SLE. Conventional aPL were included for comparison.MethodsWe included 341 consecutive Swedish SLE patients, with information on general cardiovascular risk factors, including blood lipids, lupus anticoagulant (LAC) and thrombotic events. Anti-PS/PT, anti-beta2GPI and anti-CL of IgA/G/M isotypes were quantified in parallel using particle-based multi-analyte technology. The 99th percentiles among 162 age- and sex-matched populations controls were used as cutoffs. HLA-DRB1 typing was performed using sequence-specific primer PCR.ResultsAnti-PS/PT antibodies associated positively with HLA-DRB1*13 (odds ratio [OR] 2.7, P=0.002), whereas anti-beta2GPI and anti-CL antibodies associated primarily with HLA-DRB1*04 (OR 2.5, P=0.0005; Table 1). These associations remained after adjustment for other significant HLA-DRB1 alleles identified in Table 1 (Figure 1a and b) also for LAC (Figure 1c), and also after adjustment for age and gender (not shown). HLA-DRB1*13, but not DRB1*04, remained as an independent risk factor for thrombosis after adjustment for significant HLA alleles (Figure 1d), and also after adjustment for cardiovascular risk factors in stepwise regression (not shown). Mediation analysis showed that 31.3% of the HLA-DRB1*13-related risk for thrombosis was mediated by anti-PS/PT positivity. HLA-DRB1*03, on the other hand, associated negatively with thrombotic events (Figure 1d) as well as with all aPL (Figure 1a-c). HLA-DRB1*03 had thrombo-protective effect in aPL positive patients (Figure 1d). Additionally, HLA-DRB1*03 positivity was associated with a favourable lipid profile regarding high-density lipoprotein (median 1.4 vs. 1.2 mmol/L, p=0.02) and triglycerides (median 0.9 vs 1.1 mmol/L, p=0.04); whereas no other HLA-DRB1 alleles showed any associations to lipid levels.Table 1.Frequency of individual HLA DRB1 and associations with antibody phenotypes. Odds ratios (OR) and confidence intervals (CI) for being antibody positive given a specific HLA allele and corresponding p values were calculated using Chi2 tests, with significant associations underlined.HLA DRB1HLA-DRB1 n (%) total patientsAnti-PS/PT positive (any isotype) n=48OR (95%CI); PAnti-β2GPI or anti-CL positive (any isotype) n=96OR (95%CI); P*0141 (12.9%)4 (8.3%)0.6 (0.2-1.7); 0.311 (11.4%)0.8 (0.4-1.7); 0.6*03147 (46.5%)13 (27.1%)0.4 (0.2-0.7); 0.00433 (34.4%)0.5 (0.3-0.8); 0.006*0494 (29.7%)18 (37.5%)1.6 (0.8-2.9); 0.241 (42.7%)2.5 (1.5-4.1); 0.0005*0728 (8.9%)6 (12.5%)1.5 (0.6-4); 0.49 (9.4%)1 (0.4-2.4); 0.9*0828 (8.9%)6 (12.5%)1.6 (0.6-4.3); 0.39 (9.4%)1.2 (0.5-2.7); 0.7*099 (2.8%)1 (2.1%)0.7 (0.1-5.5); 0.72 (2.1%)0.6 (0.1-3.0); 0.5*107 (2.2%)0 (0)NA2 (2.1%)0.9 (0.2-4.6); 0.9*1127 (8.5%)6 (12.5%)1.6 (0.6-4.3); 0.38 (8.3%)0.9 (0.4-2.2); 0.8*127 (2.2%)0 (0)NA1 (1%)0.4 (0.05-3.7); 0.4*1379 (25%)21 (43.7%)2.7 (1.4-5.2); 0.00233 (34.3%)2 (1.2-3.4%); 0.01*146 (1.9%)2 (4.2%)3.7 (0.6-23); 0.12 (2.1%)1.4 (0.2-8.9); 0.8*15118 (37.3%)12 (48%)0.5 (0.2-0.9); 0.04527 (28.1%)0.5 (0.3-0.9); 0.01*168 (2.5%)1 (2.1%)0.8 (0.09-6.4); 0.84 (4.2%)2.2 (0.5-9.2); 0.2ConclusionHLA-DRB1*13 confers risk for both anti-PS/PT and thrombotic events in SLE. The association between HLA-DRB1*13 and thrombosis is largely, but not entirely, mediated through anti-PS/PT. Due to the negative association of HLA-DRB1*03 with aPL and the positive association with favourable lipid levels, HLA-DRB1*03 seems to identify a subgroup of SLE patients with reduced vascular risk.References[1]Elbagir S et al. Lupus 2021;30(8):1289.[2]Lundström E et al. Ann Rheum Dis 2013;72:1018.Disclosure of InterestsSahwa Elbagir: None declared, Lina M. Diaz-Gallo: None declared, Giorgia Grosso: None declared, Agneta Zickert: None declared, Iva Gunnarsson: None declared, Michael Mahler Employee of: Dr Mahler is employee of Werfen., Elisabet Svenungsson Speakers bureau: Dr Svennungson has obtained speaker’s fees from Janssen., Grant/research support from: Dr Svennungson has obtained research grant from Merck., Johan Rönnelid Speakers bureau: Dr Rönnelid has given paid lectures for Thermo Fisher Scientific., Consultant of: Dr Rönnelid has been a member of the Scientific Advisory Board for Thermo Fisher Scientific.
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| 24. |
- Fudamoto, Yoshinobu, et al.
(author)
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The Extended [C II] under Construction? : Observation of the Brightest High-z Lensed Star-forming Galaxy at z=6.2
- 2024
-
In: Astrophysical Journal. - : Institute of Physics Publishing (IOPP). - 0004-637X .- 1538-4357. ; 961:1
-
Journal article (peer-reviewed)abstract
- We present results of [C ii] 158 μm emission line observations, and report the spectroscopic redshift confirmation of a strongly lensed (μ ∼ 20) star-forming galaxy, MACS0308-zD1 at z = 6.2078 ± 0.0002. The [C ii] emission line is detected with a signal-to-noise ratio >6 within the rest-frame UV-bright clump of the lensed galaxy (zD1.1) and exhibits multiple velocity components; the narrow [C ii] has a velocity full width half maximum (FWHM) of 110 ± 20 km s−1, while broader [C ii] is seen with an FWHM of 230 ± 50 km s−1. The broader [C ii] component is blueshifted (−80 ± 20 km s−1) with respect to the narrow [C ii] component, and has a morphology that extends beyond the UV-bright clump. We find that, while the narrow [C ii] emission is most likely associated with zD1.1, the broader component is possibly associated with a physically distinct gas component from zD1.1 (e.g., outflowing or inflowing gas). Based on the nondetection of λ158μm dust continuum, we find that MACS0308-zD1's star formation activity occurs in a dust-free environment indicated by a strong upper limit of infrared luminosity ≲9 × 108L⊙. Targeting this strongly lensed faint galaxy for follow-up Atacama Large Millimeter/submillimeter Array and JWST observations will be crucial to characterize the details of typical galaxy growth in the early Universe.
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| 25. |
- Hsiao, Tiger Yu-Yang, et al.
(author)
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JWST Reveals a Possible z similar to 11 Galaxy Merger in Triply Lensed MACS0647-JD
- 2023
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In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8205 .- 2041-8213. ; 949:2
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Journal article (peer-reviewed)abstract
- MACS0647-JD is a triply lensed z similar to 11 galaxy originally discovered with the Hubble Space Telescope. The three lensed images are magnified by factors of similar to 8, 5, and 2 to AB mag 25.1, 25.6, and 26.6 at 3.5 mu m. The brightest is over a magnitude brighter than other galaxies recently discovered at similar redshifts z > 10 with JWST. Here, we report new JWST imaging that clearly resolves MACS0647-JD as having two components that are either merging galaxies or stellar complexes within a single galaxy. The brighter larger component "A" is intrinsically very blue (ss similar to-2.6 +/- 0.1), likely due to very recent star formation and no dust, and is spatially extended with an effective radius similar to 70 +/- 24 pc. The smaller component "B" (r similar to 20-+ 58 pc) appears redder (ss similar to-2 +/- 0.2), likely because it is older (100-200 Myr) with mild dust extinction (AV similar to 0.1 mag). With an estimated stellar mass ratio of roughly 2:1 and physical projected separation similar to 400 pc, we may be witnessing a galaxy merger 430 million years after the Big Bang. We identify galaxies with similar colors in a high-redshift simulation, finding their star formation histories to be dissimilar, which is also suggested by the spectral energy distribution fitting, suggesting they formed further apart. We also identify a candidate companion galaxy "C" similar to 3 kpc away, likely destined to merge with A and B. Upcoming JWST Near Infrared Spectrograph observations planned for 2023 January will deliver spectroscopic redshifts and more physical properties for these tiny magnified distant galaxies observed in the early universe.
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| 26. |
- Johansen, Jeanne D., et al.
(author)
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European Society of Contact Dermatitis guideline for diagnostic patch testing : recommendations on best practice
- 2015
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In: Contact Dermatitis. - : Wiley. - 0105-1873 .- 1600-0536. ; 73:4, s. 195-221
-
Research review (peer-reviewed)abstract
- The present guideline summarizes all aspects of patch testing for the diagnosis of contact allergy in patients suspected of suffering, or having been suffering, from allergic contact dermatitis or other delayed-type hypersensitivity skin and mucosal conditions. Sections with brief descriptions and discussions of different pertinent topics are followed by a highlighted short practical recommendation. Topics comprise, after an introduction with important definitions, materials, technique, modifications of epicutaneous testing, individual factors influencing the patch test outcome or necessitating special considerations, children, patients with occupational contact dermatitis and drug eruptions as special groups, patch testing of materials brought in by the patient, adverse effects of patch testing, and the final evaluation and patient counselling based on this judgement. Finally, short reference is made to aspects of (continuing) medical education and to electronic collection of data for epidemiological surveillance.
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| 27. |
- Kim, Keunho J., et al.
(author)
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Small Region, Big Impact : Highly Anisotropic Lyman-continuum Escape from a Compact Starburst Region with Extreme Physical Properties
- 2023
-
In: Astrophysical Journal Letters. - 2041-8205 .- 2041-8213. ; 955:1
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Journal article (peer-reviewed)abstract
- Extreme, young stellar populations are considered to be the primary contributor to cosmic reionization. How the Lyman continuum (LyC) escapes these galaxies remains highly elusive, and it is challenging to observe this process in actual LyC emitters without resolving the relevant physical scales. We investigate the Sunburst Arc, a strongly lensed LyC emitter at z = 2.37 that reveals an exceptionally small-scale (tens of parsecs) region of high LyC escape. The small (<100 pc) LyC-leaking region has extreme properties: a very blue UV slope (β = −2.9 ± 0.1), a high ionization state ([O iii] λ5007/[O ii] λ3727 = 11 ± 3 and [O iii] λ5007/Hβ = 6.8 ± 0.4), strong oxygen emission (EW([O iii]) = 1095 ± 40 Å), and a high Lyα escape fraction (0.3 ± 0.03), none of which are found in nonleaking regions of the galaxy. The leaking region's UV slope is consistent with approximately "pure" stellar light that is minimally contaminated by the surrounding nebular continuum emission or extinguished by dust. These results suggest a highly anisotropic LyC escape process such that LyC is produced and escapes from a small, extreme starburst region where the stellar feedback from an ionizing star cluster creates one or more "pencil-beam" channels in the surrounding gas through which LyC can directly escape. Such anisotropic escape processes imply that random sight-line effects drive the significant scatters between measurements of galaxy properties and LyC escape fraction, and that strong lensing is a critical tool for resolving the processes that regulate the ionizing budget of galaxies for reionization.
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| 28. |
- Klingstedt, Therése, et al.
(author)
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Distinct Spacing Between Anionic Groups: An Essential Chemical Determinant for Achieving Thiophene-Based Ligands to Distinguish Beta-Amyloid or Tau Polymorphic Aggregates
- 2015
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In: Chemistry - A European Journal. - : Wiley-VCH Verlag. - 0947-6539 .- 1521-3765. ; 21:25, s. 9072-9082
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Journal article (peer-reviewed)abstract
- The accumulation of protein aggregates is associated with many devastating neurodegenerative diseases and the existence of distinct aggregated morphotypes has been suggested to explain the heterogeneous phenotype reported for these diseases. Thus, the development of molecular probes able to distinguish such morphotypes is essential. We report an anionic tetrameric oligothiophene compound that can be utilized for spectral assignment of different morphotypes of -amyloid or tau aggregates present in transgenic mice at distinct ages. The ability of the ligand to spectrally distinguish between the aggregated morphotypes was reduced when the spacing between the anionic substituents along the conjugated thiophene backbone was altered, which verified that specific molecular interactions between the ligand and the protein aggregate are necessary to detect aggregate polymorphism. Our findings provide the structural and functional basis for the development of new fluorescent ligands that can distinguish between different morphotypes of protein aggregates.
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| 29. |
- Laskey, M., et al.
(author)
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Multi-armed bandit models for 2D grasp planning with uncertainty
- 2015
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In: IEEE International Conference on Automation Science and Engineering. - : IEEE conference proceedings. - 9781467381833 ; , s. 572-579
-
Conference paper (peer-reviewed)abstract
- For applications such as warehouse order fulfillment, robot grasps must be robust to uncertainty arising from sensing, mechanics, and control. One way to achieve robustness is to evaluate the performance of candidate grasps by sampling perturbations in shape, pose, and gripper approach and to compute the probability of force closure for each candidate to identify a grasp with the highest expected quality. Since evaluating the quality of each grasp is computationally demanding, prior work has turned to cloud computing. To improve computational efficiency and to extend this work, we consider how Multi-Armed Bandit (MAB) models for optimizing decisions can be applied in this context. We formulate robust grasp planning as a MAB problem and evaluate convergence times towards an optimal grasp candidate using 100 object shapes from the Brown Vision 2D Lab Dataset with 1000 grasp candidates per object. We consider the case where shape uncertainty is represented as a Gaussian process implicit surface (GPIS) with Gaussian uncertainty in pose, gripper approach angle, and coefficient of friction. We find that Thompson Sampling and the Gittins index MAB methods converged to within 3% of the optimal grasp up to 10x faster than uniform allocation and 5x faster than iterative pruning.
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| 30. |
- Meena, Ashish Kumar, et al.
(author)
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Two Lensed Star Candidates at z similar or equal to 4.8 behind the Galaxy Cluster MACS J0647.7+7015
- 2023
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In: Astrophysical Journal Letters. - : Institute of Physics (IOP). - 2041-8205 .- 2041-8213. ; 944:1
-
Journal article (peer-reviewed)abstract
- We report the discovery of two extremely magnified lensed star candidates behind the galaxy cluster MACS J0647.7+015 using recent multiband James Webb Space Telescope (JWST) NIRCam observations. The star candidates are seen in a previously known, z (phot) similar or equal to 4.8 dropout giant arc that straddles the critical curve. The candidates lie near the expected critical curve position, but lack clear counter-images on the other side of it, suggesting these are possibly stars undergoing caustic crossings. We present revised lensing models for the cluster, including multiply imaged galaxies newly identified in the JWST data, and use them to estimate background macro-magnifications of at least greater than or similar to 90 and greater than or similar to 50 at the positions of the two candidates, respectively. With these values, we expect effective, caustic-crossing magnifications of similar to[10(3)-10(5)] for the two star candidates. The spectral energy distributions of the two candidates match well the spectra of B-type stars with best-fit surface temperatures of similar to 10,000 K, and similar to 12,000 K, respectively, and we show that such stars with masses greater than or similar to 20 M (circle dot) and greater than or similar to 50 M (circle dot), respectively, can become sufficiently magnified to be observable. We briefly discuss other alternative explanations and conclude that these objects are likely lensed stars, but also acknowledge that the less-magnified candidate may alternatively reside in a star cluster. These star candidates constitute the second highest-redshift examples to date after Earendel at z (phot) similar or equal to 6.2, establishing further the potential of studying extremely magnified stars at high redshifts with JWST. Planned future observations, including with NIRSpec, will enable a more detailed view of these candidates in the near future.
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| 31. |
- Meena, Ashish Kumar, et al.
(author)
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Two Lensed Star Candidates at z ≃ 4.8 behind the Galaxy Cluster MACS J0647.7+7015
- 2023
-
In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8205 .- 2041-8213. ; 944:1
-
Journal article (peer-reviewed)abstract
- We report the discovery of two extremely magnified lensed star candidates behind the galaxy cluster MACS J0647.7+015 using recent multiband James Webb Space Telescope (JWST) NIRCam observations. The star candidates are seen in a previously known, zphot ≃ 4.8 dropout giant arc that straddles the critical curve. The candidates lie near the expected critical curve position, but lack clear counter-images on the other side of it, suggesting these are possibly stars undergoing caustic crossings. We present revised lensing models for the cluster, including multiply imaged galaxies newly identified in the JWST data, and use them to estimate background macro-magnifications of at least ≳90 and ≳50 at the positions of the two candidates, respectively. With these values, we expect effective, caustic-crossing magnifications of ∼[103–105] for the two star candidates. The spectral energy distributions of the two candidates match well the spectra of B-type stars with best-fit surface temperatures of ∼10,000 K, and ∼12,000 K, respectively, and we show that such stars with masses ≳20 M⊙ and ≳50 M⊙, respectively, can become sufficiently magnified to be observable. We briefly discuss other alternative explanations and conclude that these objects are likely lensed stars, but also acknowledge that the less-magnified candidate may alternatively reside in a star cluster. These star candidates constitute the second highest-redshift examples to date after Earendel at zphot ≃ 6.2, establishing further the potential of studying extremely magnified stars at high redshifts with JWST. Planned future observations, including with NIRSpec, will enable a more detailed view of these candidates in the near future.
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| 32. |
- Novotny, Renata, et al.
(author)
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Conversion of Synthetic A beta to In Vivo Active Seeds and Amyloid Plaque Formation in a Hippocampal Slice Culture Model
- 2016
-
In: Journal of Neuroscience. - : SOC NEUROSCIENCE. - 0270-6474 .- 1529-2401. ; 36:18, s. 5084-5093
-
Journal article (peer-reviewed)abstract
- The aggregation of amyloid-beta peptide (A beta) inbrain is an early event and hallmark of Alzheimers disease (AD). We combined the advantages of in vitro and in vivo approaches to study cerebral beta-amyloidosis by establishing a long-term hippocampal slice culture(HSC) model. While no A beta deposition was noted in untreated HSCs of postnatal A beta precursor protein transgenic (APP tg) mice, A beta deposition emerged in HSCs when cultures were treated once with brain extract from aged APP tg mice and the culture medium was continuously supplemented with synthetic A beta. Seeded A beta deposition was also observed under the same conditions in HSCs derived from wild-type or App-null mice but in no comparable way when HSCs were fixed before cultivation. Both the nature of the brain extract and the synthetic A beta species determined the conformational characteristics of HSCA beta deposition. HSCA beta deposits induced a microglia response, spine loss, and neuritic dystrophy but no obvious neuron loss. Remarkably, in contrast to in vitro aggregated synthetic A beta, homogenates of A beta deposits containing HSCs induced cerebral beta-amyloidosis upon intracerebral inoculation into young APP tg mice. Our results demonstrate that a living cellular environment promotes the seeded conversion of synthetic A beta into a potent in vivo seeding-active form.
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| 33. |
- Rasmussen, Jay, et al.
(author)
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Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimers disease
- 2017
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In: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 114:49, s. 13018-13023
-
Journal article (peer-reviewed)abstract
- The molecular architecture of amyloids formed in vivo can be interrogated using luminescent conjugated oligothiophenes (LCOs), a unique class of amyloid dyes. When bound to amyloid, LCOs yield fluorescence emission spectra that reflect the 3D structure of the protein aggregates. Given that synthetic amyloid-beta peptide (A beta) has been shown to adopt distinct structural conformations with different biological activities, we asked whether A beta can assume structurally and functionally distinct conformations within the brain. To this end, we analyzed the LCO-stained cores of beta-amyloid plaques in postmortem tissue sections from frontal, temporal, and occipital neocortices in 40 cases of familial Alzheimers disease (AD) or sporadic (idiopathic) AD (sAD). The spectral attributes of LCO-bound plaques varied markedly in the brain, but the mean spectral properties of the amyloid cores were generally similar in all three cortical regions of individual patients. Remarkably, the LCO amyloid spectra differed significantly among some of the familial and sAD subtypes, and between typical patients with sAD and those with posterior cortical atrophy AD. Neither the amount of A beta nor its protease resistance correlated with LCO spectral properties. LCO spectral amyloid phenotypes could be partially conveyed to A beta plaques induced by experimental transmission in a mouse model. These findings indicate that polymorphic A beta-amyloid deposits within the brain cluster as clouds of conformational variants in different AD cases. Heterogeneity in the molecular architecture of pathogenic A beta among individuals and in etiologically distinct subtypes of AD justifies further studies to assess putative links between A beta conformation and clinical phenotype.
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| 34. |
- Seita, D., et al.
(author)
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Large-scale supervised learning of the grasp robustness of surface patch pairs
- 2017
-
In: 2016 IEEE International Conference on Simulation, Modeling, and Programming for Autonomous Robots, SIMPAR 2016. - : Institute of Electrical and Electronics Engineers Inc.. - 9781509046164 ; , s. 216-223
-
Conference paper (peer-reviewed)abstract
- The robustness of a parallel-jaw grasp can be estimated by Monte Carlo sampling of perturbations in pose and friction but this is not computationally efficient. As an alternative, we consider fast methods using large-scale supervised learning, where the input is a description of a local surface patch at each of two contact points. We train and test with disjoint subsets of a corpus of 1.66 million grasps where robustness is estimated by Monte Carlo sampling using Dex-Net 1.0. We use the BIDMach machine learning toolkit to compare the performance of two supervised learning methods: Random Forests and Deep Learning. We find that both of these methods learn to estimate grasp robustness fairly reliably in terms of Mean Absolute Error (MAE) and ROC Area Under Curve (AUC) on a held-out test set. Speedups over Monte Carlo sampling are approximately 7500x for Random Forests and 1500x for Deep Learning.
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| 35. |
- Tanrioever, Gaye, et al.
(author)
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Prominent microglial inclusions in transgenic mouse models of alpha-synucleinopathy that are distinct from neuronal lesions
- 2020
-
In: Acta neuropathologica communications. - : BMC. - 2051-5960. ; 8:1
-
Journal article (peer-reviewed)abstract
- Alpha-synucleinopathies are a group of progressive neurodegenerative disorders, characterized by intracellular deposits of aggregated alpha-synuclein (alpha S). The clinical heterogeneity of these diseases is thought to be attributed to conformers (or strains) of alpha S but the contribution of inclusions in various cell types is unclear. The aim of the present work was to study alpha S conformers among different transgenic (TG) mouse models of alpha-synucleinopathies. To this end, four different TG mouse models were studied (Prnp-h[A53T]alpha S; Thy1-h[A53T]alpha S; Thy1-h[A30P]alpha S; Thy1-m alpha S) that overexpress human or murine alpha S and differed in their age-of-symptom onset and subsequent disease progression. Postmortem analysis of end-stage brains revealed robust neuronal alpha S pathology as evidenced by accumulation of alpha S serine 129 (p-alpha S) phosphorylation in the brainstem of all four TG mouse lines. Overall appearance of the pathology was similar and only modest differences were observed among additionally affected brain regions. To study alpha S conformers in these mice, we used pentameric formyl thiophene acetic acid (pFTAA), a fluorescent dye with amyloid conformation-dependent spectral properties. Unexpectedly, besides the neuronal alpha S pathology, we also found abundant pFTAA-positive inclusions in microglia of all four TG mouse lines. These microglial inclusions were also positive for Thioflavin S and showed immunoreactivity with antibodies recognizing the N-terminus of alpha S, but were largely p-alpha S-negative. In all four lines, spectral pFTAA analysis revealed conformational differences between microglia and neuronal inclusions but not among the different mouse models. Concomitant with neuronal lesions, microglial inclusions were already present at presymptomatic stages and could also be induced by seeded alpha S aggregation. Although nature and significance of microglial inclusions for human alpha-synucleinopathies remain to be clarified, the previously overlooked abundance of microglial inclusions in TG mouse models of alpha-synucleinopathy bears importance for mechanistic and preclinical-translational studies.
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| 36. |
- Vanzella, Eros, et al.
(author)
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JWST/NIRCam Probes Young Star Clusters in the Reionization Era Sunrise Arc
- 2023
-
In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 945:1
-
Journal article (peer-reviewed)abstract
- Star cluster formation in the early universe and its contribution to reionization remains largely unconstrained to date. Here we present JWST/NIRCam imaging of the most highly magnified galaxy known at z ∼ 6, the Sunrise arc. We identify six young massive star clusters (YMCs) with measured radii spanning from ∼20 down to ∼1 pc (corrected for lensing magnification), estimated stellar masses of ∼106–7 M⊙, and ages of 1–30 Myr based on SED fitting to photometry measured in eight filters extending to rest frame 7000 Å. The resulting stellar mass surface densities are higher than 1000 M⊙ pc−2 (up to a few 105 M⊙ pc−2), and their inferred dynamical ages qualify the majority of these systems as gravitationally bound stellar clusters. The star cluster ages map the progression of star formation along the arc, with two evolved systems (≳10 Myr old) followed by very young clusters. The youngest stellar clusters (<5 Myr) show evidence of prominent Hβ+[O ııı] emission based on photometry with equivalent widths larger than >1000 Å rest frame and are hosted in a 200 pc sized star-forming complex. Such a region dominates the ionizing photon production with a high efficiency log(ξion [Hz erg-1]~25.7 . A significant fraction of the recently formed stellar mass of the galaxy (10%–30%) occurred in these YMCs. We speculate that such sources of ionizing radiation boost the ionizing photon production efficiency, which eventually carves ionized channels that might favor the escape of Lyman continuum radiation. The survival of some of the clusters would make them the progenitors of massive and relatively metal-poor globular clusters in the local universe.
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| 37. |
- Wegenast-Braun, Bettina M., et al.
(author)
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Spectral Discrimination of Cerebral Amyloid Lesions after Peripheral Application of Luminescent Conjugated Oligothiophenes
- 2012
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In: American Journal of Pathology. - : Elsevier. - 0002-9440 .- 1525-2191. ; 181:6, s. 1953-1960
-
Journal article (peer-reviewed)abstract
- In vivo imaging of pathological protein aggregates provides essential knowledge of the kinetics and implications of these lesions in the progression of proteopathies, such as Alzheimer disease. Luminescent conjugated oligothiophenes are amyloid-specific ligands that bind and spectrally distinguish different types of amyloid aggregates. Herein, we report that heptamer formyl thiophene acetic acid (hFTAA) passes the blood-brain barrier after systemic administration and specifically binds to extracellular beta-amyloid deposits in the brain parenchyma (A beta plaques) and in the vasculature (cerebral beta-amyloid angiopathy) of beta-amyloid precursor protein transgenic APP23 mice. Moreover, peripheral application of hFIAA also stained intracellular lesions of hyperphosphorylated Tau protein in P301S Tau transgenic mice. Spectral profiling of all three amyloid types was acquired ex vivo using two-photon excitation. hFTAA revealed a distinct shift in its emission spectra when bound to A beta plaques versus Tau lesions. Furthermore, a spectral shift was observed for A beta plaques versus cerebral beta-amyloid angiopathy, indicating that different amyloid types and structural variances of a specific amyloid type can be distinguished. In conclusion, by adding spectral signatures to amyloid lesions, our results pave the way for a new area of in vivo amyloid imaging, allowing in vivo differentiation of amyloid (sub)types and monitoring changes of their structure/composition over time. (Am J Pathol 2012, 181: 1953-1960 http://dx.doi.org/10.1016/j.ajpath.2012.08.031)
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| 38. |
- Welch, Brian, et al.
(author)
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A highly magnified star at redshift 6.2
- 2022
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In: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 603:7903, s. 815-818
-
Journal article (peer-reviewed)abstract
- Galaxy clusters magnify background objects through strong gravitational lensing. Typical magnifications for lensed galaxies are factors of a few but can also be as high as tens or hundreds, stretching galaxies into giant arcs(1,2). Individual stars can attain even higher magnifications given fortuitous alignment with the lensing cluster. Recently, several individual stars at redshifts between approximately 1 and 1.5 have been discovered, magnified by factors of thousands, temporarily boosted by microlensing(3-6). Here we report observations of a more distant and persistent magnified star at a redshift of 6.2 +/- 0.1, 900 million years after the Big Bang. This star is magnified by a factor of thousands by the foreground galaxy cluster lens WHL0137-08 (redshift 0.566), as estimated by four independent lens models. Unlike previous lensed stars, the magnification and observed brightness (AB magnitude, 27.2) have remained roughly constant over 3.5 years of imaging and follow-up. The delensed absolute UV magnitude, -10 +/- 2, is consistent with a star of mass greater than 50 times the mass of the Sun. Confirmation and spectral classification are forthcoming from approved observations with the James Webb Space Telescope.
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| 39. |
- Welch, Brian, et al.
(author)
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JWST Imaging of Earendel, the Extremely Magnified Star at Redshift z=6.2
- 2022
-
In: Astrophysical Journal Letters. - : Institute of Physics (IOP). - 2041-8205 .- 2041-8213. ; 940
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Journal article (peer-reviewed)abstract
- The gravitationally lensed star WHL 0137-LS, nicknamed Earendel, was identified with a photometric redshift z (phot) = 6.2 +/- 0.1 based on images taken with the Hubble Space Telescope. Here we present James Webb Space Telescope (JWST) Near Infrared Camera images of Earendel in eight filters spanning 0.8-5.0 mu m. In these higher-resolution images, Earendel remains a single unresolved point source on the lensing critical curve, increasing the lower limit on the lensing magnification to mu > 4000 and restricting the source plane radius further to r < 0.02 pc, or similar to 4000 au. These new observations strengthen the conclusion that Earendel is best explained by an individual star or multiple star system and support the previous photometric redshift estimate. Fitting grids of stellar spectra to our photometry yields a stellar temperature of T (eff) similar to 13,000-16,000 K, assuming the light is dominated by a single star. The delensed bolometric luminosity in this case ranges from log(L)=5.8 L-theta, which is in the range where one expects luminous blue variable stars. Follow-up observations, including JWST NIRSpec scheduled for late 2022, are needed to further unravel the nature of this object, which presents a unique opportunity to study massive stars in the first billion years of the universe.
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- Wilkinson, S. Mark, et al.
(author)
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The European baseline series and recommended additions : 2023
- 2023
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In: Contact Dermatitis. - : Wiley. - 0105-1873 .- 1600-0536. ; 88:2, s. 87-92
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Research review (peer-reviewed)abstract
- The European baseline series was last updated in 2019. This article discusses the reasoning behind a further iteration of the series for 2023.
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