| 1. |
- Fernandez, J. L. Abelleira, et al.
(author)
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A Large Hadron Electron Collider at CERN
- 2012
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In: Journal of Physics G. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 39:7
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Journal article (peer-reviewed)
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| 2. |
- Retamozo, S., et al.
(author)
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Influence of the age at diagnosis in the disease expression of primary Sjogren's syndrome : Analysis of 12,753 patients from the Sjogren Big Data Consortium
- 2021
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In: Clinical and Experimental Rheumatology. - : CLINICAL & EXPER RHEUMATOLOGY. - 0392-856X .- 1593-098X. ; 39:6, s. S166-S174
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Journal article (peer-reviewed)abstract
- Objective. To analyse how the main components of the disease phenotype (sicca symptoms, diagnostic tests, immunological markers and systemic disease) can be driven by the age at diagnosis of primary Sjogren's syndrome (pSS).Methods. By January 2021, the participant centres had included 12,753 patients from 25 countries that fulfilled the 2002/2016 classification criteria for pSS. The age at diagnosis was defined as the time when the attending physician confirmed fulfilment of the criteria. Patients were clustered according to age at diagnosis. 50 clusters with more than 100 observations (from 27 to 76 years) were used to study the influence of the age at diagnosis in the disease expression.Results. There was a consistent increase in the frequency of oral dryness according to the age at diagnosis, with a frequency of <90% in patients diagnosed at the youngest ages and >95% in those diagnosed at the oldest ages. The smooth curves that best fitted a linear model were the frequency of dry mouth (adjusted R-2 0.87) and the frequency of abnormal oral tests (adjusted R-2 0.72). Therefore, for each 1-year increase in the age at diagnosis, the frequency of dry mouth increased by 0.13%, and the frequency of abnormal oral diagnostic tests by 0.11%. There was a consistent year-by-year decrease in the frequency of all autoantibodies and immunological markers except for cryoglobulins. According to the linear models, for each 1-year increase in the age at diagnosis, the frequency of a positive result decreased by 0.57% (for anti-Ro antibodies), 0.47% (for RF) and 0.42% (for anti-La antibodies). The ESSDAI domains which showed a more consistent decrease were glandular and lymph node involvement (for each 1-year increase in the age at diagnosis, the frequency of activity decreased by 0.18%), and constitutional, cutaneous, and haematological involvements (the frequency decreased by 0.09% for each 1-year increase). In contrast, other domains showed an ascending pattern, especially pulmonary involvement (for each 1-year increase in the age at diagnosis, the frequency of activity increased by 0.22%), and peripheral nerve involvement (the frequency increased by 0.09% for each 1-year increase).Conclusion. The influence of the age at diagnosis on the key phenotypic features of pSS is strong, and should be considered critical not only for designing a personalised diagnostic approach, but also to be carefully considered when analysing the results of diagnostic tests and immunological parameters, and when internal organ involvement is suspected at diagnosis.
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| 5. |
- Bacchus, E., et al.
(author)
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Project 1640 observations of the white dwarf HD 114174 B
- 2017
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In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 469:4, s. 4796-4805
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Journal article (peer-reviewed)abstract
- We present the first near infrared spectrum of the faint white dwarf companion HD 114174 B, obtained with Project 1640. Our spectrum, covering the Y, J and H bands, combined with previous TaRgetting bENchmark-objects with Doppler Spectroscopy (TRENDS) photometry measurements, allows us to place further constraints on this companion. We suggest two possible scenarios; either this object is an old, low-mass, cool H atmosphere white dwarf with T-eff similar to 3800 K or a high-mass white dwarf with T-eff > 6000 K, potentially with an associated cool (T-eff similar to 700 K) brown dwarf or debris disc resulting in an infrared excess in the L' band. We also provide an additional astrometry point for 2014 June 12 and use the modelled companion mass combined with the radial velocity and direct imaging data to place constraints on the orbital parameters for this companion.
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| 6. |
- Flores-Chavez, A., et al.
(author)
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Influence of exposure to climate-related hazards in the phenotypic expression of primary Sjögren's syndrome
- 2023
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In: Clinical and Experimental Rheumatology. - : Clinical and Experimental Rheumatology. - 0392-856X .- 1593-098X. ; 41:12, s. 2437-2447
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Journal article (peer-reviewed)abstract
- Objective To analyse how the key components at the time of diagnosis of the Sjogren's phenotype (epidemiological profile, sicca symptoms, and systemic disease) can be influenced by the potential exposure to climate-related natural hazards. Methods For the present study, the following variables were selected for harmonisation and refinement: age, sex, country, fulfilment of 2002/2016 criteria items, dry eyes, dry mouth, and overall ESSDAI score. Climate-related hazards per country were defined according to the OECD and included seven climate-related hazard types: extreme temperature, extreme precipitation, drought, wildfire, wind threats, river flooding, and coastal flooding. Climatic variables were defined as dichotomous variables according to whether each country is ranked among the ten countries with the most significant exposure. Results After applying data-cleaning techniques and excluding people from countries not included in the OECD climate rankings, the database study analysed 16,042 patients from 23 countries. The disease was diagnosed between 1 and 3 years earlier in people living in countries included among the top 10 worst exposed to extreme precipitation, wildfire, wind threats, river flooding, and coastal flooding. A lower frequency of dry eyes was observed in people living in countries exposed to wind threats, river flooding, and coastal flooding, with a level of statistical association being classified as strong (p<0.0001 for the three variables). The frequency of dry mouth was significantly lower in people living in countries exposed to river flooding (p<0.0001) and coastal flooding (p<0.0001). People living in countries included in the worse climate scenarios for extreme temperature (p<0.0001) and river flooding (p<0.0001) showed a higher mean ESSDAI score in comparison with people living in no-risk countries. In contrast, those living in countries exposed to worse climate scenarios for wind threats (p<0.0001) and coastal flooding (p<0.0001) showed a lower mean ESSDAI score in comparison with people living in no-risk countries. Conclusion Local exposure to extreme climate-related hazards plays a role in modulating the presentation of Sjogren across countries concerning the age at which the disease is diagnosed, the frequency of dryness, and the degree of systemic activity.
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| 7. |
- Brito-Zeron, P., et al.
(author)
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Exposure to air pollution as an environmental determinant of how Sjögren's disease is expressed at diagnosis
- 2023
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In: Clinical and Experimental Rheumatology. - : Clinical and Experimental Rheumatology. - 0392-856X .- 1593-098X. ; 41:12, s. 2448-2457
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Journal article (peer-reviewed)abstract
- ObjectiveTo analyse how the potential exposure to air pollutants can influence the key components at the time of diagnosis of Sjogren's phenotype (epidemiological profile, sicca symptoms, and systemic disease). MethodsFor the present study, the following variables were selected for harmonisation and refinement: age, sex, country, fulfilment of 2002/2016 criteria items, dry eyes, dry mouth, and overall ESSDAI score. Air pollution indexes per country were defined according to the OECD (1990-2021), including emission data of nitrogen and sulphur oxides (NO/SO), particulate matter (PM2.5 and 1.0), carbon monoxide (CO) and volatile organic compounds (VOC) calculated per unit of GDP, Kg per 1000 USD.ResultsThe results of the chi-square tests of independence for each air pollutant with the frequency of dry eyes at diagnosis showed that, except for one, all variables exhibited p-values <0.0001. The most pronounced disparities emerged in the dry eye prevalence among individuals inhabiting countries with the highest NO/SO exposure, a surge of 4.61 percentage points compared to other countries, followed by CO (3.59 points), non-methane (3.32 points), PM2.5 (3.30 points), and PM1.0 (1.60 points) exposures. Concerning dry mouth, individuals residing in countries with worse NO/SO exposures exhibited a heightened frequency of dry mouth by 2.05 percentage points (p<0.0001), followed by non-methane exposure (1.21 percentage points increase, p=0.007). Individuals inhabiting countries with the worst NO/SO, CO, and PM2.5 pollution levels had a higher mean global ESSDAI score than those in lower-risk nations (all p-values <0.0001). When systemic disease was stratified according to DAS into low, moderate, and high systemic activity levels, a heightened proportion of individuals manifesting moderate/severe systemic activity was observed in countries with worse exposures to NO/SO, CO, and PM2.5 pollutant levels. ConclusionFor the first time, we suggest that pollution levels could influence how SjD appears at diagnosis in a large international cohort of patients. The most notable relationships were found between symptoms (dryness and general body symptoms) and NO/SO, CO, and PM2.5 levels.
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| 8. |
- Brito-Zeron, P., et al.
(author)
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How immunological profile drives clinical phenotype of primary Sjögren's syndrome at diagnosis : analysis of 10,500 patients (Sjögren Big Data Project)
- 2018
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In: Clinical and Experimental Rheumatology. - : CLINICAL & EXPER RHEUMATOLOGY. - 0392-856X .- 1593-098X. ; 36:3, s. S102-S112
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Journal article (peer-reviewed)abstract
- Objective: To evaluate the influence of the main immunological markers on the disease phenotype at diagnosis in a large international cohort of patients with primary Sjogren's syndrome (SjS).Methods: The Big Data Sjogren Project Consortium is an international, multicentre registry created in 2014. As a first step, baseline clinical information from leading centres on clinical research in SjS of the 5 continents was collected. The centres shared a harmonised data architecture and conducted cooperative online efforts in order to refine collected data under the coordination of a big data statistical team. Inclusion criteria were the fulfillment of the 2002 classification criteria. Immunological tests were carried out using standard commercial assays.Results: By January 2018, the participant centres had included 10,500 valid patients from 22 countries. The cohort included 9,806 (93%) women and 694 (7%) men, with a mean age at diagnosis of primary SjS of 53 years, mainly White (78%) and included from European countries (71%). The frequency of positive immunological markers at diagnosis was 79.3% for ANA, 73.2% for anti-Ro, 48.6% for RF, 45.1% for anti-La, 13.4% for low C3 levels, 14.5% for low C4 levels and 7.3% for cryoglobulins. Positive autoantibodies (ANA, Ro, La) correlated with a positive result in salivary gland biopsy, while hypocomplementaemia and especially cryoglobulinaemia correlated with systemic activity (mean ESSDAI score of 17.7 for ctyoglobulins, 11.3 for low C3 and 9.2 for low C4, in comparison with 3.8 for negative markers). The immunological markers with a great number of statistically-significant associations (p<0.001) in the organ-by-organ ESSDAI evaluation were cryoglobulins (9 domains), low C3 (8 domains), anti-La (7 domains) and low C4 (6 domains).Conclusion: We confirm the strong influence of immunological markers on the phenotype of primary SjS at diagnosis in the largest multi-ethnic international cohort ever analysed, with a greater influence for cryoglobulinaemic-related markers in comparison with Ro/La autoantibodies and ANA. Immunological patterns play a central role in the phenotypic expression of the disease already at the time of diagnosis, and may guide physicians to design a specific personalised management during the follow-up of patients with primary SjS.
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| 12. |
- Ogishi, M, et al.
(author)
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Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency
- 2022
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In: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 219:10
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Journal article (peer-reviewed)abstract
- Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23–dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.
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| 13. |
- Schneider, K. M., et al.
(author)
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Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment
- 2022
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Journal article (peer-reviewed)abstract
- Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, and therapeutic options for advanced HCC are limited. Here, we observe that intestinal dysbiosis affects antitumor immune surveillance and drives liver disease progression towards cancer. Dysbiotic microbiota, as seen in Nlrp6(-/-) mice, induces a Toll-like receptor 4 dependent expansion of hepatic monocytic myeloid-derived suppressor cells (mMDSC) and suppression of T-cell abundance. This phenotype is transmissible via fecal microbiota transfer and reversible upon antibiotic treatment, pointing to the high plasticity of the tumor microenvironment. While loss of Akkermansia muciniphila correlates with mMDSC abundance, its reintroduction restores intestinal barrier function and strongly reduces liver inflammation and fibrosis. Cirrhosis patients display increased bacterial abundance in hepatic tissue, which induces pronounced transcriptional changes, including activation of fibro-inflammatory pathways as well as circuits mediating cancer immunosuppression. This study demonstrates that gut microbiota closely shapes the hepatic inflammatory microenvironment opening approaches for cancer prevention and therapy. Steatohepatitis is a chronic hepatic inflammation associated with increased risk of hepatocellular carcinoma progression. Here the authors show that intestinal dysbiosis in mice lacking the inflammasome sensor molecule NLRP6 aggravates steatohepatitis and accelerates liver cancer progression, a process that can be delayed by antibiotic treatment.
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| 18. |
- Zhang, Y. S., et al.
(author)
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Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors
- 2017
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In: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 114:12, s. E2293-E2302
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Journal article (peer-reviewed)abstract
- Organ-on-a-chip systems areminiaturizedmicrofluidic 3D human tissue and organ models designed to recapitulate the important biological and physiological parameters of their in vivo counterparts. They have recently emerged as a viable platform for personalized medicine and drug screening. These in vitro models, featuring biomimetic compositions, architectures, and functions, are expected to replace the conventional planar, static cell cultures and bridge the gap between the currently used preclinical animal models and the human body. Multiple organoid models may be further connected together through the microfluidics in a similar manner in which they are arranged in vivo, providing the capability to analyze multiorgan interactions. Although a wide variety of human organ-on-a-chip models have been created, there are limited efforts on the integration of multisensor systems. However, in situ continual measuring is critical in precise assessment of the microenvironment parameters and the dynamic responses of the organs to pharmaceutical compounds over extended periods of time. In addition, automated and noninvasive capability is strongly desired for long-term monitoring. Here, we report a fully integrated modular physical, biochemical, and optical sensing platform through a fluidics-routing breadboard, which operates organ-on-a-chip units in a continual, dynamic, and automated manner.We believe that this platform technology has paved a potential avenue to promote the performance of current organ-on-a-chip models in drug screening by integrating a multitude of real-time sensors to achieve automated in situ monitoring of biophysical and biochemical parameters.
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| 21. |
- Bjornstrom, L, et al.
(author)
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Cross-talk between Stat5b and estrogen receptor-alpha and -beta in mammary epithelial cells
- 2001
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In: Journal of molecular endocrinology. - : Bioscientifica. - 0952-5041 .- 1479-6813. ; 27:1, s. 93-106
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Journal article (peer-reviewed)abstract
- Both 17beta-estradiol and prolactin play important roles in the mammary gland, raising the possibility of functional cross-talk between the two signaling pathways. Here, we demonstrate that estrogen receptor-alpha (ERalpha) and -beta (ERbeta) are both able to potentiate transcription from a Stat5-responsive promoter when activated by prolactin. Potentiation was observed not only in the presence of 17beta-estradiol, but also in the presence of anti-estrogens such as tamoxifen and ICI 182,780. The magnitude of the response was dependent on cell-type: in the HC11 mouse mammary epithelial cell line ERbeta potentiates transcription efficiently whereas ERalpha showed low activity. Conversely, in COS-7 cells, both estrogen receptors were active. We show that activation domains in the N-terminus (AF-1) and the C-terminus (AF-2) of the ERs are dispensable for potentiation. The effects are dependent on the presence of an intact DNA-binding/hinge domain, which we show is capable of interacting with Stat5b in vitro and in HC11 cell extracts. We conclude that ERalpha and ERbeta act as coactivators for Stat5b through a mechanism which is independent of AF-1 and AF-2.
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| 22. |
- Caglar, K, et al.
(author)
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Serum fetuin-a concentration and endothelial dysfunction in chronic kidney disease
- 2008
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In: Nephron. Clinical practice. - : S. Karger AG. - 1660-2110. ; 108:3, s. C233-C240
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Journal article (peer-reviewed)abstract
- <i>Background:</i> Defective endothelial function, an initial step in the development of atherosclerotic plaque, is prevalent in moderate to advanced chronic kidney disease (CKD). In this study, the investigators hypothesized that fetuin-A, a calcification inhibitor, is a novel risk factor for the development of endothelial dysfunction in patients. <i>Methods:</i> 198 nondiabetic patients with a mean age of 44.0 ± 12.4 years and with different stages of CKD were studied. In addition to a detailed metabolic panel, flow-mediated dilatation assessed by high-resolution brachial ultrasonography was performed to determine endothelial dysfunction. Carotid intima-media thickness was also estimated by ultrasonography. Serum fetuin-A concentrations were determined by using a human ELISA method. <i>Results:</i> Endothelial dysfunction was observed in all stages (1–5) of CKD and worsened in parallel to the reduction in estimated glomerular filtration rate. Serum fetuin-A concentrations were also found to be decreased in all but stage 1 CKD. On multiple regression analysis, endothelial dysfunction was independently associated with fetuin-A (β = 0.745, p < 0.001) and intact parathyroid hormone concentrations (β = –0.216, p < 0.001). <i>Conclusion:</i> These data in a selected cohort of CKD patients indicate that fetuin-A may be one of the contributing factors for the development of endothelial dysfunction in CKD patients.
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| 23. |
- Gnad, T., et al.
(author)
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Adenosine activates brown adipose tissue and recruits beige adipocytes via A(2A) receptors
- 2014
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 516:7531
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Journal article (peer-reviewed)abstract
- Brown adipose tissue (BAT) is specialized in energy expenditure, making it a potential target for anti-obesity therapies(1-5). Following exposure to cold, BAT is activated by the sympathetic nervous system with concomitant release of catecholamines and activation of beta-adrenergic receptors(1-5). Because BAT therapies based on cold exposureor beta-adrenergic agonists are clinically not feasible, alternative strategies must be explored. Purinergic co-transmission might be involved in sympathetic control of BAT and previous studies reported inhibitory effects of the purinergic transmitter adenosine in BAT from hamster or rat(6-8). However, the role of adenosine in human BAT is unknown. Here we show that adenosine activates human and murine brown adipocytes at low nanomolar concentrations. Adenosine is released in BAT during stimulation of sympathetic nerves as well as from brown adipocytes. The adenosine A(2A) receptor is the most abundant adenosine receptor in human and murine BAT. Pharmacological blockade or genetic loss of A(2A) receptors in mice causes adecrease in BAT-dependent thermogenesis, whereas treatment with A(2A) agonists significantly increases energy expenditure. Moreover, pharmacological stimulation of A(2A) receptors or injection of lentiviral vectors expressing the A(2A) receptor into white fat induces brown-like cells-so-called beige adipocytes. Importantly, mice fed a high-fat diet and treated with an A(2A) agonist are leaner with improved glucose tolerance. Taken together, our results demonstrate that adenosine-A(2A) signalling plays an unexpected physiological role in sympathetic BAT activation and protects mice from diet-induced obesity. Those findings reveal new possibilities for developing novel obesity therapies.
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