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- Ruilope, LM, et al.
(författare)
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Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
- 2019
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Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. <b><i>Patients and</i></b> <b><i>Methods:</i></b> The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m<sup>2</sup> and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. <b><i>Conclusions:</i></b> FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
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- Wang, HD, et al.
(författare)
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Global, regional, national, and selected subnational levels of stillbirths, neonatal, infant, and under-5 mortality, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015
- 2016
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Ingår i: Lancet (London, England). - : Elsevier. - 1474-547X .- 0140-6736. ; 388:10053, s. 1725-1774
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Tidskriftsartikel (refereegranskat)
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- Zhu, RJ, et al.
(författare)
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Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms
- 2021
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Ingår i: Cell research. - : Springer Science and Business Media LLC. - 1748-7838 .- 1001-0602. ; 31:12, s. 1244-1262
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Tidskriftsartikel (refereegranskat)abstract
- The infusion of coronavirus disease 2019 (COVID-19) patients with mesenchymal stem cells (MSCs) potentially improves clinical symptoms, but the underlying mechanism remains unclear. We conducted a randomized, single-blind, placebo-controlled (29 patients/group) phase II clinical trial to validate previous findings and explore the potential mechanisms. Patients treated with umbilical cord-derived MSCs exhibited a shorter hospital stay (P = 0.0198) and less time required for symptoms remission (P = 0.0194) than those who received placebo. Based on chest images, both severe and critical patients treated with MSCs showed improvement by day 7 (P = 0.0099) and day 21 (P = 0.0084). MSC-treated patients had fewer adverse events. MSC infusion reduced the levels of C-reactive protein, proinflammatory cytokines, and neutrophil extracellular traps (NETs) and promoted the maintenance of SARS-CoV-2-specific antibodies. To explore how MSCs modulate the immune system, we employed single-cell RNA sequencing analysis on peripheral blood. Our analysis identified a novel subpopulation of VNN2+ hematopoietic stem/progenitor-like (HSPC-like) cells expressing CSF3R and PTPRE that were mobilized following MSC infusion. Genes encoding chemotaxis factors — CX3CR1 and L-selectin — were upregulated in various immune cells. MSC treatment also regulated B cell subsets and increased the expression of costimulatory CD28 in T cells in vivo and in vitro. In addition, an in vivo mouse study confirmed that MSCs suppressed NET release and reduced venous thrombosis by upregulating kindlin-3 signaling. Together, our results underscore the role of MSCs in improving COVID-19 patient outcomes via maintenance of immune homeostasis.
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| 23. |
- Abt, I, et al.
(författare)
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Inclusive V-0 production cross sections from 920 GeV fixed target proton-nucleus collisions
- 2003
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Ingår i: European Physical Journal C. Particles and Fields. - : Springer Science and Business Media LLC. - 1434-6044. ; 29:2, s. 181-190
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Tidskriftsartikel (refereegranskat)abstract
- Inclusive differential cross sections dsigma(pA)/dx(F) and dsigma(pA)/dp(t)(2) for the production of K-S(0), Lambda, and (&ULambda;) over bar particles are measured at HERA in proton-induced reactions on C, Al, Ti, and W targets. The incident beam energy is 920 GeV, corresponding to roots = 41.6 GeV in the proton-nucleon system. The ratios of differential cross sections dsigma(pA)(K-S(0))/dsigma(pA)(Lambda) and dsigma(pA)((&ULambda;) over bar)/dsigma(pA) (Lambda) are measured to be 6.2 +/- 0.5 and 0.66 +/- 0.07, respectively, for x(F) approximate to -0.06. No significant dependence upon the target material is observed. Within errors, the slopes of the transverse momentum distributions da,Ald t also show no significant dependence upon the target material. The dependence of the extrapolated total cross sections sigma(pA) on the atomic mass A of the target material is discussed, and the deduced cross sections per nucleon sigma(pN) are compared with results obtained at other energies.
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| 24. |
- Abt, I, et al.
(författare)
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Measurement of the b(b)over-bar production cross section in 920 GeV fixed-target proton-nucleus collisions
- 2003
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Ingår i: European Physical Journal C. Particles and Fields. - : Springer Science and Business Media LLC. - 1434-6044. ; 26:3, s. 345-355
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Tidskriftsartikel (refereegranskat)abstract
- Using the HERA-B detector, the b (b) over bar production cross section has been measured in 920 GeV proton collisions on carbon and titanium targets. The b (b) over bar production was tagged via inclusive bottom quark decays into J/psi by exploiting the longitudinal separation of J/psi --> l(+)l(-) decay vertices from the primary proton-nucleus interaction. Both e(+)e(-) and mu(+)mu(-) channels have been reconstructed and the combined analysis yields the cross section sigma(b (b) over bar) = 32(-12)(+14)(stat) (+6)(-7)(sys) nb/nucleon.
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- Dai, KF, et al.
(författare)
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HIV-1 Vaccine-elicited Antibodies Reverted to Their Inferred Naive Germline Reveal Associations between Binding Affinity and in vivo Activation
- 2016
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6, s. 20987-
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Tidskriftsartikel (refereegranskat)abstract
- The elicitation of HIV-1 broadly neutralizing antibodies following envelope glycoprotein (Env) vaccination is exceedingly difficult. Suboptimal engagement of naïve B cells is suggested to limit these low frequency events, especially at the conserved CD4bs. Here, we analyzed CD4bs-directed monoclonal antibodies (mAbs) elicited by YU2 gp140-foldon trimers in a non-human primate by selective sorting using CD4bs “knock out” trimers. Following two inoculations, the CD4bs-directed mAbs efficiently recognized the eliciting immunogen in their affinity-maturing state but did not recognize CD4bs-defective probes. We reverted these mAbs to their most likely inferred germline (igL) state, leaving the HCDR3 unaltered, to establish correlates of in vitro affinity to in vivo activation. Most igL-reverted mAbs bound the eliciting gp140 immunogen, indicating that CD4bs-directed B cells possessing reasonable affinity existed in the naïve repertoire. We detected relatively high affinities for the majority of the igL mAbs to gp120 and of Fabs to gp140, which, as expected, increased when the antibodies ‘matured’ following vaccination. Affinity increases were associated with slower off-rates as well as with acquisition of neutralizing capacity. These data reveal in vitro binding properties associated with in vivo activation that result in functional archiving of antigen-specific B cells elicited by a complex glycoprotein antigen following immunization.
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| 36. |
- Huang, QW, et al.
(författare)
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Effects of inhaled nitric oxide and high-frequency ventilation in rabbits with meconium aspiration
- 1999
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Ingår i: Biology of the neonate. - : S. Karger AG. - 0006-3126. ; 76:6, s. 374-382
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To evaluate effects of inhaled nitric oxide (iNO) in experimental meconium aspiration treated with high-frequency (HFV) or conventional mechanical ventilation (CMV). Ventilated adult rabbits had meconium instilled intratracheally resulting in respiratory failure as evidenced by more than 50% reduction of dynamic lung compliance (Cdyn) and increase in mean oxygenation index (OI) from 1 to 16. The animals were then allocated to 2 groups treated without (control) or with iNO at 20 ppm (NO). In each group the animals were initially ventilated with CMV or HFV mode for 3 h and then in a crossover fashion with HFV or CMV for another 3 h (CMV→HFV, HFV→CMV), respectively. In the first 3 h of treatment, the animals subjected to HFV-CMV in the control, and those with both HFV-CMV and CMV-HFV in the NO group had significantly reduced OI. In the subsequent 3 h, the animals in the control group with CMV-HFV did not improve in OI and those with HFV-CMV had deteriorated. In the NO group with both CMV-HFV and HFV-CMV moderate improvement of OI was observed. Platelet aggregation capability and counts were significantly decreased and bleeding time prolonged in animals receiving iNO treatment. These results suggest that both HFV alone and a combined treatment of iNO with either CMV or HFV are more effective in improving blood oxygenation than that of CMV in this animal model. The influence of iNO on platelet aggregation should be considered.
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| 38. |
- Jolma, A, et al.
(författare)
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Binding specificities of human RNA-binding proteins toward structured and linear RNA sequences
- 2020
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Ingår i: Genome research. - : Cold Spring Harbor Laboratory. - 1549-5469 .- 1088-9051. ; 30:7, s. 962-973
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Tidskriftsartikel (refereegranskat)abstract
- RNA-binding proteins (RBPs) regulate RNA metabolism at multiple levels by affecting splicing of nascent transcripts, RNA folding, base modification, transport, localization, translation, and stability. Despite their central role in RNA function, the RNA-binding specificities of most RBPs remain unknown or incompletely defined. To address this, we have assembled a genome-scale collection of RBPs and their RNA-binding domains (RBDs) and assessed their specificities using high-throughput RNA-SELEX (HTR-SELEX). Approximately 70% of RBPs for which we obtained a motif bound to short linear sequences, whereas ∼30% preferred structured motifs folding into stem–loops. We also found that many RBPs can bind to multiple distinctly different motifs. Analysis of the matches of the motifs in human genomic sequences suggested novel roles for many RBPs. We found that three cytoplasmic proteins—ZC3H12A, ZC3H12B, and ZC3H12C—bound to motifs resembling the splice donor sequence, suggesting that these proteins are involved in degradation of cytoplasmic viral and/or unspliced transcripts. Structural analysis revealed that the RNA motif was not bound by the conventional C3H1 RNA-binding domain of ZC3H12B. Instead, the RNA motif was bound by the ZC3H12B's PilT N terminus (PIN) RNase domain, revealing a potential mechanism by which unconventional RBDs containing active sites or molecule-binding pockets could interact with short, structured RNA molecules. Our collection containing 145 high-resolution binding specificity models for 86 RBPs is the largest systematic resource for the analysis of human RBPs and will greatly facilitate future analysis of the various biological roles of this important class of proteins.
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| 40. |
- Kilpelainen, TO, et al.
(författare)
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Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity
- 2019
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Ingår i: Nature communications. - London : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 376-
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Tidskriftsartikel (refereegranskat)abstract
- Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.
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| 43. |
- Liu, Y, et al.
(författare)
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Serum IGFBP7 levels associate with insulin resistance and the risk of metabolic syndrome in a Chinese population
- 2015
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5, s. 10227-
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Tidskriftsartikel (refereegranskat)abstract
- Metabolic syndrome (MetS), one of the major public health concerns, is regarded as the “common soil” of incidence of common chronic diseases and may increase the risk of type 2 diabetes. The predominant underlying mechanism of MetS is insulin resistance (IR). Additionally, previous studies have indicated that IGFBP7 has high affinity of binding with insulin and might induce IR. The objective of this study was to firstly evaluate the associations of serum IGFBP7 levels with IR and MetS with a relatively large sample and population based design. In a population based MetS case-control study, HOMA-IR was used to evaluate the insulin sensitivity and serum IGFBP7 levels were determined with chemiluminescence–linked immunoassay. As a result, the subjects of MetS and IR had higher serum levels of IGFBP7 than control healthy subjects. High serum IGFBP7 levels increased the risk of MetS and IR. Serum IGFBP7 levels were also found to be significantly correlated with metabolic-associated parameters of Waist-to-hip ratio (WHR), HDL and LDL. These findings suggest that serum IGFBP7 levels are associated with IR and MetS, providing new insight into the mechanism of IR and Mets. IGFBP7 may be a potential interventional target for IR and Mets.
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