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  • 1
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2020-02-21)
    Abstract: Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences ( XIAP, CYBA, SH2D1A, PCSK1 ). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB . The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P   〈  4 × 10 −10 ), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P   〈  5 × 10 −10 ). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2553671-0
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  • 2
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2022-06-22)
    Type of Medium: Online Resource
    ISSN: 2041-1723
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2553671-0
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  • 3
    Online Resource
    Online Resource
    Copernicus GmbH ; 2022
    In:  Weather and Climate Dynamics Vol. 3, No. 3 ( 2022-09-26), p. 1113-1138
    In: Weather and Climate Dynamics, Copernicus GmbH, Vol. 3, No. 3 ( 2022-09-26), p. 1113-1138
    Abstract: Abstract. It has long been recognized that a rich variety of Alpine south-foehn flavours exist that are related to varying flow conditions above crest level, the presence and intensity of orographic precipitation on the Alpine south side, and the Po Valley stratification. This study presents a systematic 5-year climatology of different foehn types. The classification relies on 2329 foehn hours, which are diagnosed using a station-based foehn index for Altdorf in the Swiss Reuss Valley. Operational analyses at 1 km horizontal resolution are employed to classify foehn hours with a decision tree that is based on foehn forecasting experience. Mean wind direction and speed in a circle with 100 km radius centred around Altdorf are considered to differentiate between three main foehn types (deep foehn, shallow foehn, gegenstrom foehn). In addition, upstream precipitation and its extent beyond the Alpine crest are used to distinguish three deep-foehn subtypes (dry foehn, moist foehn, dimmer foehn). The main foehn types differ distinctively in the synoptic conditions over the Alps. During deep foehn, pronounced southwesterlies ahead of an upper-level trough induce upstream orographic precipitation. Shallow foehn, in turn, is associated with cross-Alpine temperature differences that provoke a gap flow. The gegenstrom-foehn type is also restricted to major gaps, but a strong westerly flow prevails above crest level. The deep-foehn subtypes primarily differ in terms of the upper-level trough. While a weaker trough and the influence of an upper-level ridge over the Mediterranean inhibit precipitation (dry foehn), a deeper trough which is closer to the Alps induces stronger crest-level winds and intense precipitation on the Alpine south side (dimmer foehn). The different foehn types are found to strongly affect the local characteristics at Altdorf, which are investigated using station measurements. Backward trajectories from Altdorf are calculated for each of the foehn hours and used to define three clusters of air parcels depending upon their upstream thermodynamic evolution. Trajectories in cluster 1 are diabatically heated and transported within a low-level easterly barrier jet in the Po Valley prior to their ascent to crest level. They constitute the main precipitating airstream and, hence, are of key importance for moist foehn and dimmer foehn. Cluster-2 and cluster-3 trajectories are subject to weak diabatic heating or even diabatic cooling. They originate from southerly to southwesterly regions and from either slightly below or above crest level. Accordingly, these air parcels are associated with little to no precipitation, and as such, they take a key role for dry foehn, shallow foehn and gegenstrom foehn. Furthermore, these three foehn types feature a pronounced stable layer over the Po Valley, which, to some extent, inhibits air parcels to ascend from lower levels. In summary, the study introduces a systematic classification of south foehn using state-of-the-art data sets. It concludes by setting the new classification into a historic context and revisiting the rich body of literature with respect to different Alpine south-foehn types. In particular, analogies to and discrepancies with the existing conceptual models of “Swiss foehn” and “Austrian foehn” are discussed.
    Type of Medium: Online Resource
    ISSN: 2698-4016
    Language: English
    Publisher: Copernicus GmbH
    Publication Date: 2022
    detail.hit.zdb_id: 2982467-9
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  • 4
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 319, No. 5 ( 2020-11-01), p. H995-H1007
    Abstract: Postconditioning attenuates inflammation and fibrosis in myocardial infarction (MI). The aim of this study was to investigate whether postconditioning with the cytosine-phosphate-guanine (CpG)-containing Toll-like receptor-9 (TLR9) ligand 1668-thioate (CpG) can modulate inflammation and remodeling in reperfused murine MI. Thirty minutes of left descending coronary artery (LAD) occlusion was conducted in 12-wk-old C57BL/6 mice. Mice were treated with CpG intraperitoneally 5 min before reperfusion. The control group received PBS; the sham group did not undergo ischemia. M-mode echocardiography (3, 7, and 28 days) and Millar left ventricular (LV) catheterization were performed (7 and 28 days) before the hearts were excised and harvested for immunohistochemical (6 h, 24 h, 3 days, 7 days, and 28 days), gene expression (6 h, 24 h, and 3 days; Taqman RT-qPCR), protein, and FACS analysis (24 h and 3 days). Mice treated with CpG showed significantly better LV function after 7 and 28 days of reperfusion. Protein and mRNA expressions of proinflammatory and anti-inflammatory cytokines were significantly induced after CpG treatment. Histology revealed fewer macrophages in CpG mice after 24 h, confirmed by FACS analysis with a decrease in both classically M1- and alternative M2a-monocytes. CpG treatment reduced apoptosis and cardiomyocyte loss and was associated with induction of adaptive mechanisms, e.g., of heme-oxigenase-1 and β-/α-myosin heavy chain (MHC) ratio. Profibrotic markers collagen type Iα (Col-Ια) and Col-III induction was abrogated in CpG mice, accompanied by fewer myofibroblasts. This led to the formation of a smaller scar. Differential matrix metalloproteinase (MMP)/tissue inhibitor of metalloproteinase (TIMP) expression contributed to attenuated remodeling in CpG, resulting in preserved cardiac function in a Toll-like receptor 1- and TLR9-dependent manner. Our study suggests a cardioprotective mechanism of CpG postconditioning, involving Toll-like receptor-driven modulation of inflammation. This is followed by attenuated remodeling and preserved LV function. NEW & NOTEWORTHY Cytosine-phosphate-guanine (CpG) postconditioning seems to mediate inflammation via Toll-like receptor-1 and Toll-like receptor-9 signaling. Enhanced cytokine and chemokine expressions are partly attenuated by IL-10 and matrix metalloproteinase-8 (MMP8) induction, being associated with lower macrophage infiltration and M1-monocyte differentiation. Furthermore, switch from α- to β-MHC and balanced MMP/TIMP expression led to lesser cardiomyocyte apoptosis, smaller scar size, and preserved cardiac function. Data of pharmacological postconditioning have been widely disappointing to date. Our study suggests a new pathway promoting myocardial postconditioning via Toll-like receptor activation.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    RVK:
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2020
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Institute for Operations Research and the Management Sciences (INFORMS) ; 2020
    In:  Operations Research Vol. 68, No. 1 ( 2020-01), p. 214-232
    In: Operations Research, Institute for Operations Research and the Management Sciences (INFORMS), Vol. 68, No. 1 ( 2020-01), p. 214-232
    Abstract: In the multilevel aggregation problem (MLAP), requests arrive at the nodes of an edge-weighted tree [Formula: see text] and have to be served eventually. A service is defined as a subtree [Formula: see text] of [Formula: see text] that contains the root of [Formula: see text] . This subtree [Formula: see text] serves all requests that are pending in the nodes of [Formula: see text] , and the cost of this service is equal to the total weight of [Formula: see text]. Each request also incurs waiting cost between its arrival and service times. The objective is to minimize the total waiting cost of all requests plus the total cost of all service subtrees. MLAP is a generalization of some well-studied optimization problems; for example, for trees of depth 1, MLAP is equivalent to the Transmission Control Protocol acknowledgment problem, whereas for trees of depth 2, it is equivalent to the joint replenishment problem. Aggregation problems for trees of arbitrary depth arise in multicasting, sensor networks, communication in organization hierarchies, and supply chain management. The instances of MLAP associated with these applications are naturally online, in the sense that aggregation decisions need to be made without information about future requests. Constant-competitive online algorithms are known for MLAP with one or two levels. However, it has been open whether there exist constant-competitive online algorithms for trees of depth more than 2. Addressing this open problem, we give the first constant-competitive online algorithm for trees of arbitrary (fixed) depth. The competitive ratio is [Formula: see text] , where [Formula: see text] is the depth of [Formula: see text] . The algorithm works for arbitrary waiting cost functions, including the variant with deadlines.
    Type of Medium: Online Resource
    ISSN: 0030-364X , 1526-5463
    RVK:
    Language: English
    Publisher: Institute for Operations Research and the Management Sciences (INFORMS)
    Publication Date: 2020
    detail.hit.zdb_id: 2019440-7
    detail.hit.zdb_id: 123389-0
    SSG: 3,2
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  • 6
    In: Earth System Science Data, Copernicus GmbH, Vol. 15, No. 7 ( 2023-07-20), p. 3075-3094
    Abstract: Abstract. Saharan dust outbreaks have profound effects on ecosystems, climate, human health, and the cryosphere in Europe. However, the spatial deposition pattern of Saharan dust is poorly known due to a sparse network of ground measurements. Following the extreme dust deposition event of February 2021 across Europe, a citizen science campaign was launched to sample dust on snow over the Pyrenees and the European Alps. This somewhat improvised campaign triggered wide interest since 152 samples were collected from the snow in the Pyrenees, the French Alps, and the Swiss Alps in less than 4 weeks. Among the 152 samples, 113 in total could be analysed, corresponding to 70 different locations. The analysis of the samples showed a large variability in the dust properties and amount. We found a decrease in the deposited mass and particle sizes with distance from the source along the transport path. This spatial trend was also evident in the elemental composition of the dust as the iron mass fraction decreased from 11 % in the Pyrenees to 2 % in the Swiss Alps. At the local scale, we found a higher dust mass on south-facing slopes, in agreement with estimates from high-resolution remote sensing data. This unique dataset, which resulted from the collaboration of several research laboratories and citizens, is provided as an open dataset to benefit a large community and to enable further scientific investigations. Data presented in this study are available at https://doi.org/10.5281/zenodo.7969515 (Dumont et al., 2022a).
    Type of Medium: Online Resource
    ISSN: 1866-3516
    Language: English
    Publisher: Copernicus GmbH
    Publication Date: 2023
    detail.hit.zdb_id: 2475469-9
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  • 7
    In: Research and Reports in Urology, Informa UK Limited, Vol. Volume 13 ( 2021-07), p. 495-499
    Type of Medium: Online Resource
    ISSN: 2253-2447
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2021
    detail.hit.zdb_id: 2649530-2
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  • 8
    In: Journal of Clinical Medicine, MDPI AG, Vol. 9, No. 9 ( 2020-09-02), p. 2841-
    Abstract: The collection of lymphatic fluids (lymphoceles) is a frequent adverse event following renal transplantation. A variety of surgical and medical factors has been linked to this entity, but reliable data on risk factors and long-term outcomes are lacking. This retrospective single-center study included 867 adult transplant recipients who received a kidney transplantation from 2006 to 2015. We evaluated for patient and graft survival, rejection episodes, or detectable donor-specific antibodies (dnDSA) in patients with identified lymphoceles in comparison to controls. We identified 305/867 (35.2%) patients with lymphocele formation, of whom 72/867 (8.3%) needed intervention. Multivariate analysis identified rejection episode as an independent risk factor (OR 1.61, CI 95% 1.17–2.21, p = 0.003) for lymphocele formation, while delayed graft function was independently associated with symptomatic lymphoceles (OR 1.9, CI 95% 1.16–3.12, p = 0.011). Interestingly, there was no difference in detectable dnDSA between groups with a similar graft and patient survival in all groups after 10 years. Lymphoceles frequently occur after transplantation and were found to be independently associated with rejection episodes, while symptomatic lymphoceles were associated with delayed graft function in our cohort. As both are inflammatory processes, they might play a causative role in the formation of lymphoceles. However, development or intervention of lymphoceles did not lead to impaired graft survival in the long-term.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2662592-1
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  • 9
    In: Physical Review D, American Physical Society (APS), Vol. 95, No. 5 ( 2017-3-31)
    Type of Medium: Online Resource
    ISSN: 2470-0010 , 2470-0029
    Language: English
    Publisher: American Physical Society (APS)
    Publication Date: 2017
    detail.hit.zdb_id: 2844732-3
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  • 10
    In: The Journal of cell biology, Rockefeller University Press, Vol. 125, No. 3 ( 1994-05-01), p. 625-638
    Abstract: The retinoblastoma gene product (pRB) participates in the regulation of the cell division cycle through complex formation with numerous cellular regulatory proteins including the potentially oncogenic cyclin D1. Extending the current view of the emerging functional interplay between pRB and D-type cyclins, we now report that cyclin D1 expression is positively regulated by pRB. Cyclin D1 mRNA and protein is specifically downregulated in cells expressing SV40 large T antigen, adenovirus E1A, and papillomavirus E7/E6 oncogene products and this effect requires intact RB-binding, CR2 domain of E1A. Exceptionally low expression of cyclin D1 is also seen in genetically RB-deficient cell lines, in which ectopically expressed wild-type pRB results in specific induction of this G1 cyclin. At the functional level, antibody-mediated cyclin D1 knockout experiments demonstrate that the cyclin D1 protein, normally required for G1 progression, is dispensable for passage through the cell cycle in cell lines whose pRB is inactivated through complex formation with T antigen, E1A, or E7 oncoproteins as well as in cells which have suffered loss-of-function mutations of the RB gene. The requirement for cyclin D1 function is not regained upon experimental elevation of cyclin D1 expression in cells with mutant RB, while reintroduction of wild-type RB into RB-deficient cells leads to restoration of the cyclin D1 checkpoint. These results strongly suggest that pRB serves as a major target of cyclin D1 whose cell cycle regulatory function becomes dispensable in cells lacking functional RB. Based on available data including this study, we propose a model for an autoregulatory feedback loop mechanism that regulates both the expression of the cyclin D1 gene and the activity of pRB, thereby contributing to a G1 phase checkpoint control in cycling mammalian cells.
    Type of Medium: Online Resource
    ISSN: 0021-9525 , 1540-8140
    RVK:
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 1994
    detail.hit.zdb_id: 1421310-2
    SSG: 12
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