| 561. |
- Fedorowski, Artur, et al.
(författare)
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Antiadrenergic autoimmunity in postural tachycardia syndrome
- 2017
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Ingår i: Europace. - : Oxford University Press (OUP). - 1099-5129. ; 19:7, s. 1211-1219
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Tidskriftsartikel (refereegranskat)abstract
- Aims Postural tachycardia syndrome (POTS), a common and debilitating cardiovascular disorder, is characterized by an exaggerated heart rate increase during orthostasis and a wide spectrum of adrenergic-related symptoms. To determine the aetiology of POTS, we examined a possible pathophysiological role for autoantibodies against α1-adrenergic (α1AR) and β1/2-adrenergic receptors (β1/2AR). Methods and results Immunoglobulin G (IgG) derived from 17 POTS patients, 7 with recurrent vasovagal syncope (VVS), and 11 normal controls was analysed for its ability to modulate activity and ligand responsiveness of α1AR and β1/2AR in transfected cells and to alter contractility of isolated rat cremaster arterioles in vitro. Immunoglobulin G activation of α1AR and β1/2AR was significantly higher in POTS compared with VVS and controls in cell-based assays. Eight, 11, and 12 of the 17 POTS patients possessed autoantibodies that activated α1AR, β1AR and β2AR, respectively. Pharmacological blockade suppressed IgG-induced activation of α1AR and β1/2AR. Eight of 17 POTS IgG decreased the α1AR responsiveness to phenylephrine and 13 of 17 POTS IgG increased the β1AR responsiveness to isoproterenol irrespective of their ability to directly activate their receptors. Postural tachycardia syndrome IgG contracted rat cremaster arterioles, which was reversed by α1AR blockade. The upright heart rate correlated with IgG-mediated β1AR and α1AR activity but not with β2AR activity. Conclusion These data confirm a strong relationship between adrenergic autoantibodies and POTS. They support the concept that allosteric-mediated shifts in the α1AR and β1AR responsiveness are important in the pathophysiology of postural tachycardia.
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| 562. |
- Foley, Nicole M., et al.
(författare)
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A genomic timescale for placental mammal evolution
- 2023
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 380:6643, s. 365-
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Tidskriftsartikel (refereegranskat)abstract
- The precise pattern and timing of speciation events that gave rise to all living placental mammals remain controversial. We provide a comprehensive phylogenetic analysis of genetic variation across an alignment of 241 placental mammal genome assemblies, addressing prior concerns regarding limited genomic sampling across species. We compared neutral genome-wide phylogenomic signals using concatenation and coalescent-based approaches, interrogated phylogenetic variation across chromosomes, and analyzed extensive catalogs of structural variants. Interordinal relationships exhibit relatively low rates of phylogenomic conflict across diverse datasets and analytical methods. Conversely, X-chromosome versus autosome conflicts characterize multiple independent clades that radiated during the Cenozoic. Genomic time trees reveal an accumulation of cladogenic events before and immediately after the Cretaceous-Paleogene (K-Pg) boundary, implying important roles for Cretaceous continental vicariance and the K-Pg extinction in the placental radiation.
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| 563. |
- Fouhy, Fiona, et al.
(författare)
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High-throughput sequencing reveals the incomplete, short-term recovery of infant gut microbiota following parenteral antibiotic treatment with ampicillin and gentamicin
- 2012
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Ingår i: Antimicrobial Agents and Chemotherapy. - Washington, USA : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 56:11, s. 5811-5820
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Tidskriftsartikel (refereegranskat)abstract
- The infant gut microbiota undergoes dramatic changes during the first 2 years of life. The acquisition and development of this population can be influenced by numerous factors, and antibiotic treatment has been suggested as one of the most significant. Despite this, however, there have been relatively few studies which have investigated the short-term recovery of the infant gut microbiota following antibiotic treatment. The aim of this study was to use high-throughput sequencing (employing both 16S rRNA and rpoB-specific primers) and quantitative PCR to compare the gut microbiota of nine infants who underwent parenteral antibiotic treatment with ampicillin and gentamicin (within 48 h of birth), 4 and 8 weeks after the conclusion of treatment, relative to that of nine matched healthy controls. The investigation revealed that the gut microbiota of the antibiotic-treated infants had significantly higher proportions of Proteobacteria (P = 0.0049) and significantly lower proportions of Actinobacteria (P = 0.00001) (and the associated genus Bifidobacterium [P = 0.0132]) as well as the genus Lactobacillus (P = 0.0182) than the untreated controls 4 weeks after the cessation of treatment. By week 8, the Proteobacteria levels remained significantly higher in the treated infants (P = 0.0049), but the Actinobacteria, Bifidobacterium, and Lactobacillus levels had recovered and were similar to those in the control samples. Despite this recovery of total Bifidobacterium numbers, rpoB-targeted pyrosequencing revealed that the number of different Bifidobacterium species present in the antibiotic-treated infants was reduced. It is thus apparent that the combined use of ampicillin and gentamicin in early life can have significant effects on the evolution of the infant gut microbiota, the long-term health implications of which remain unknown.
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| 564. |
- Fretts, Amanda M., et al.
(författare)
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Associations of circulating very-long-chain saturated fatty acids and incident type 2 diabetes : a pooled analysis of prospective cohort studies
- 2019
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Ingår i: American Journal of Clinical Nutrition. - : OXFORD UNIV PRESS. - 0002-9165 .- 1938-3207. ; 109:4, s. 1216-1223
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Tidskriftsartikel (refereegranskat)abstract
- Background: Saturated fatty acids (SFAs) of different chain lengths have unique metabolic and biological effects, and a small number of recent studies suggest that higher circulating concentrations of the very-long-chain SFAs (VLSFAs) arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) are associated with a lower risk of diabetes. Confirmation of these findings in a large and diverse population is needed.Objective: We investigated the associations of circulating VLSFAs 20:0, 22:0, and 24:0 with incident type 2 diabetes in prospective studies.Methods: Twelve studies that are part of the Fatty Acids and Outcomes Research Consortium participated in the analysis. Using Cox or logistic regression within studies and an inverse-variance-weighted meta-analysis across studies, we examined the associations of VLSFAs 20:0, 22:0, and 24:0 with incident diabetes among 51,431 participants.Results: There were 14,276 cases of incident diabetes across participating studies. Higher circulating concentrations of 20:0, 22:0, and 24:0 were each associated with a lower risk of incident diabetes. Pooling across cohorts, the RR (95% CI) for incident diabetes comparing the 90th percentile to the 10th percentile was 0.78 (0.70, 0.87) for 20:0, 0.84 (0.77, 0.91) for 22:0, and 0.75 (0.69, 0.83) for 24:0 after adjustment for demographic, lifestyle, adiposity, and other health factors. Results were fully attenuated in exploratory models that adjusted for circulating 16:0 and triglycerides.Conclusions: Results from this pooled analysis indicate that higher concentrations of circulating VLSFAs 20:0, 22:0, and 24:0 are each associated with a lower risk of diabetes.
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| 565. |
- Friedlein, Rainer, et al.
(författare)
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Electronic structure of conjugated polymers and interfaces in polymer-based electronics
- 2003
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Ingår i: Synthetic Metals (Proceedings of the International Conference on Science and Technology of Synthetic Metals). - 0379-6779. ; 135:1-3, s. 275-277
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Konferensbidrag (refereegranskat)abstract
- The electronic structure of conjugated polymers and interfaces in polymer-based electronics were analyzed. Fine structure were observed in the region of the first resonance with pi-final state symmetry, between 284.1 eV and 285.8 eV. The electronic transitions from the non-dispersed C(1s) level to specific parts of the unoccupied band structure were generated. It was found that for a dispersing valence band, in the presence of a core-hole, a given photon energy corresponded to an excitation into a state with a distinct wave vectors.
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| 566. |
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| 567. |
- Friedlein, Rainer, et al.
(författare)
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Role of electronic localization and charge-vibrational coupling in resonant photoelectron spectra of polymers : Application to poly(para-phenylenevinylene)
- 2004
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Ingår i: Physical Review B. Condensed Matter and Materials Physics. - 1098-0121 .- 1550-235X. ; 69:12
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Tidskriftsartikel (refereegranskat)abstract
- A combination of x-ray absorption and resonant photoemission (RPE) spectroscopy has been used to study the electronic structure of the one-dimensional conjugated polymer poly (para-phenylenevinylene) in nonordered (as prepared) thin films. The dispersion of RPE features for the decay to localized and delocalized bands are qualitatively different. A theory for band dispersion of RPE in polymers is given, showing the important roles of electronic state localization and vibrational (phonon) excitations for the character of the dispersion.
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| 568. |
- Furtado, R. H. M., et al.
(författare)
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Efficacy and Safety of Dapagliflozin in Type 2 Diabetes According to Baseline Blood Pressure: Observations From DECLARE-TIMI 58 Trial
- 2022
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Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 145:21, s. 1581-1591
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Dapagliflozin improved heart failure and kidney outcomes in patients with type 2 diabetes (T2DM) with or at high risk for atherosclerotic cardiovascular disease in the DECLARE-TIMI 58 trial (Dapagliflozin Effect on Cardiovascular Events - Thrombolysis in Myocardial Infarction 58). Here, the aim was to analyze the efficacy and safety of dapagliflozin stratified according to baseline systolic blood pressure (SBP). METHODS: The DECLARE-TIMI 58 trial randomly assigned patients with T2DM and either previous atherosclerotic cardiovascular disease or atherosclerotic cardiovascular disease risk factors to dapagliflozin or placebo. Patients were categorized by baseline SBP levels: <120, 120 to 129, 130 to 139, 140 to 159, and >= 160 mm Hg (normal, elevated, stage 1, stage 2, and severe hypertension, respectively). Efficacy outcomes of interest were hospitalization for heart failure and a renal-specific composite outcome (sustained decrease in estimated glomerular filtration rate by 40%, progression to end-stage renal disease, or renal death). Safety outcomes included symptoms of volume depletion, lower extremity amputations, and acute kidney injury. RESULTS: The trial comprised 17160 patients; mean age, 64.0 +/- 6.8 years; 37.4% women; median duration of T2DM, 11 years; 40.6% with prevalent cardiovascular disease. Overall, dapagliflozin reduced SBP by 2.4 mm Hg (95% CI, 1.9-2.9; F<0.0001) compared with placebo at 48 months. The beneficial effects of dapagliflozin on hospitalization for heart failure and renal outcomes were consistent across all baseline SBP categories, with no evidence of modification of treatment effect (P-interactions = 5 0.28 and 0.52, respectively). Among normotensive patients, the hazard ratios were 0.66 (95% CI, 0.42-1.05) and 0.39 95% CI, 0.19-0.78), respectively, for hospitalization for heart failure and the renal-specific outcome. Events of volume depletion, amputation, and acute kidney injury did not differ with dapagliflozin overall or within any baseline SBP group. CONCLUSIONS: In patients with T2DM with or at high atherosclerotic cardiovascular disease risk, dapagliflozin reduced risk for hospitalization for heart failure and renal outcomes regardless of baseline SBP, with no difference in adverse events of interest at any level of baseline SBP. These results indicate that dapagliflozin provides cardiorenal benefits in patients with T2DM at high atherosclerotic cardiovascular disease risk independent of baseline blood pressure.
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| 569. |
- Gabba, Adele, et al.
(författare)
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MUC1 glycopeptide vaccine modified with a GalNAc glycocluster targets the macrophage galactose c-type lectin on dendritic cells to elicit an improved humoral response
- 2023
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 145:24, s. 13027-13037
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Tidskriftsartikel (refereegranskat)abstract
- Mucin expression and glycosylation patterns on cancer cells differ markedly from healthy cells. Mucin 1 (MUC1) is overexpressed in several solid tumors and presents high levels of aberrant, truncated O-glycans (e.g., Tn antigen). Dendritic cells (DCs) express lectins that bind to these tumor-associated carbohydrate antigens (TACAs) to modulate immune responses. Selectively targeting these receptors with synthetic TACAs is a promising strategy to develop anticancer vaccines and to overcome TACA tolerance. In this work, we prepared, via a solid phase peptide synthesis approach, a modular tripartite vaccine candidate, incorporating a high-affinity glycocluster based on a tetraphenylethylene scaffold, to target the macrophage galactose-type lectin (MGL) on antigen presenting cells. MGL is a C-type lectin receptor that binds Tn antigens and can route them to human leukocyte antigen class II or I, making it an attractive target for anticancer vaccines. Conjugation of the glycocluster to a library of MUC1 glycopeptides bearing the Tn antigen is shown to promote uptake and recognition of the TACA by DCs via MGL. In vivo testing revealed that immunization with the newly designed vaccine construct bearing the GalNAc glycocluster induced a higher titer of anti-Tn-MUC1 antibodies compared to the TACAs alone. Additionally, the antibodies obtained bind a library of tumor-associated saccharide structures on MUC1 and MUC1-positive breast cancer cells. Conjugation of a high-affinity ligand for MGL to tumor-associated MUC1 glycopeptide antigens has a synergistic impact on antibody production.
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| 570. |
- Ghaziani, Emma, et al.
(författare)
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Easily Conducted Tests During the First Week Post-stroke Can Aid the Prediction of Arm Functioning at 6 Months.
- 2020
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Ingår i: Frontiers in neurology. - : Frontiers Media SA. - 1664-2295. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Prognostic models can estimate the recovery of arm functioning after stroke, guide the selection of individual training strategies, and inform patient selection in clinical trials. Several models for early prediction of arm recovery have been proposed, but their implementation has been hindered by insufficient external validation, limited evidence of their impact on patient outcomes, and reliance on predictors that are not feasible in regular clinical practice. Objectives: To determine the predictive value of new and previously reported tests that can be easily conducted in regular clinical settings for early prognosis of two levels of favorable arm recovery at 6 months post-stroke. Methods: We performed a secondary analysis of merged data (n = 223) from two Scandinavian prospective longitudinal cohorts. The candidate predictors were seven individual tests of motor function and the sensory function measured by the Fugl-Meyer Assessment of Upper Extremity within 7 days post-stroke, and the whole motor section of this assessment. For each candidate predictor, we calculated the adjusted odds ratio (OR) of two levels of residual motor impairment in the affected arm at 6 months post-stroke: moderate-to-mild (≥32 points on the motor section of the Fugl-Meyer Assessment of Upper Extremity, FMA-UE) and mild (FMA-UE ≥ 58 points). Results: Patients with partial shoulder abduction (OR 14.6), elbow extension (OR 15.9), and finger extension (OR 9.5) were more likely to reach FMA-UE ≥ 32. Patients with full function on all individual motor tests (OR 5.5-35.3) or partial elbow extension, pronation/supination, wrist dorsiflexion and grasping ability (OR 2.1-18.3) were more likely to achieve FMA-UE ≥ 58 compared with those with absent function. Intact sensory function (OR 2.0-2.2) and moderate motor impairment on the FMA-UE (OR 7.5) were also associated with favorable outcome. Conclusions: Easily conducted motor tests can be useful for early prediction of arm recovery. The added value of this study is the prediction of two levels of a favorable functional outcome from simple motor tests. This knowledge can be used in the development of prognostic models feasible in regular clinical settings, inform patient selection and stratification in future trials, and guide clinicians in the selection of individualized training strategies for improving arm functioning after stroke. Clinical Trial Registration: ClinicalTrials.gov: NCT02250365, NCT01115348.
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