| 1. |
- Burstedt, Marie, et al.
(författare)
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Retinal dystrophy associated with RLBP1 retinitis pigmentosa : a five-year prospective natural history study
- 2023
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Ingår i: Investigative Ophthalmology and Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 0146-0404 .- 1552-5783. ; 64:13
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To assess the progression in functional and structural measures over a five-year period in patients with retinal dystrophy caused by RLBP1 gene mutation.Methods: This prospective, noninterventional study included patients with biallelic RLBP1 mutations from two clinical sites in Sweden and Canada. Key assessments included ocular examinations, visual functional measures (best-corrected visual acuity [BCVA], contrast sensitivity [CS], dark-adaptation [DA] kinetics up to six hours for two wavelengths [450 and 632 nm], Humphrey visual fields [HVF], full-field flicker electroretinograms), and structural ocular assessments.Results: Of the 45 patients enrolled, 38 completed the full five years of follow-up. At baseline, patients had BCVA ranging from -0.2 to 1.3 logMAR, poor CS, HVF defects, and prominent thinning in central foveal thickness. All patients had extremely prolonged DA rod recovery of approximately six hours at both wavelengths. The test-retest repeatability was high across all anatomic and functional endpoints. Cross-sectionally, poorer VA was associated with older age (right eye, correlation coefficient [CC]: 0.606; left eye, CC: -0.578; P < 0.001) and HVF MD values decreased with age (right eye, CC: -0.672, left eye, CC: -0.654; P < 0.001). However, no major changes in functional or structural measures were noted longitudinally over the five-year period.Conclusions: This natural history study, which is the first study to monitor patients with RLBP1 RD for five years, showed that severely delayed DA sensitivity recovery, a characteristic feature of this disease, was observed in all patients across all age groups (17-69 years), making it a potentially suitable efficacy assessment for gene therapy treatment in this patient population.
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| 2. |
- Laudani, Claudio, et al.
(författare)
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Short Duration of DAPT Versus De-Escalation After Percutaneous Coronary Intervention for Acute Coronary Syndromes
- 2022
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Ingår i: JACC. - : Elsevier BV. - 1936-8798 .- 1876-7605. ; 15:3, s. 268-277
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The aim of this study was to compare short dual antiplatelet therapy (DAPT) and de-escalation in a network meta-analysis using standard DAPT as common comparator.BACKGROUND: In patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), shortening DAPT and de-escalating to a lower potency regimen mitigate bleeding risk. These strategies have never been randomly compared.METHODS: Randomized trials of DAPT modulation strategies in patients with ACS undergoing PCI were identified. All cause death was the primary outcome. Secondary outcomes included net adverse cardiovascular events (NACE), major adverse cardiovascular events, and their components. Frequentist and Bayesian network meta-analyses were conducted. Treatments were ranked on the basis of posterior probability. Sensitivity analyses were performed to explore sources of heterogeneity.RESULTS: Twenty-nine studies encompassing 50,602 patients were included. The transitivity assumption was fulfilled. In the frequentist indirect comparison, the risk ratio (RR) for all-cause death was 0.98 (95% CI: 0.68-1.43). De-escalation reduced the risk for NACE (RR: 0.87; 95% CI: 0.70-0.94) and increased major bleeding (RR: 1.54; 95% CI: 1.07-2.21). These results were consistent in the Bayesian meta-analysis. De-escalation displayed a >95% probability to rank first for NACE, myocardial infarction, stroke, stent thrombosis, and minor bleeding, while short DAPT ranked first for major bleeding. These findings were consistent in node-split and multiple sensitivity analyses.CONCLUSIONS: In patients with ACS undergoing PCI, there was no difference in all-cause death between short DAPT and de-escalation. De-escalation reduced the risk for NACE, while short DAPT decreased major bleeding. These data characterize 2 contemporary strategies to personalize DAPT on the basis of treatment objectives and risk profile.
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| 3. |
- Macchi, Chiara, et al.
(författare)
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Leptin, Resistin, and Proprotein Convertase Subtilisin/Kexin Type 9 - The Role of STAT3
- 2020
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Ingår i: The American journal of pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 190:11, s. 2226-2236
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Tidskriftsartikel (refereegranskat)abstract
- In a condition of dysfunctional visceral fat depots, as in the case of obesity, alterations in adipokines levels may be detrimental for the cardiovascular system. The proinflammatory leptin and resistin adipokines have been described as possible links between obesity and atherosclerosis. The present study was aimed at evaluating whether proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein metabolism, is induced by leptin and resistin through the involvement of the inflammatory pathway of signal transducer and activator of transcript 3 (STAT3). In HepG2 cells, leptin and resistin upregulated PCSK9 gene and protein expression as well as the phosphorylation of STAT3. Upon STAT3 silencing, leptin and resistin lost their ability to activate PCSK9. The knock-down of STAT3 did not affect the expression of leptin and resistin receptors as well as that of PCSK9. The analysis of human PCSK9 promoter region showed that the two adipokines raise PCSK9 promoter activity via the involvement of sterol regulatory element motif. In healthy male, a positive association between circulating leptin and PCSK9 levels was found only when BMI was < 25 kg/m2. In conclusion, our study identified STAT3 as one of the molecular regulators of leptin- and resistin-mediated transcriptional induction of PCSK9.
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| 4. |
- Niu, Mengyao, et al.
(författare)
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Fungal oxylipins direct programmed developmental switches in filamentous fungi
- 2020
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Ingår i: Nature Communications. - : NATURE RESEARCH. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Filamentous fungi differentiate along complex developmental programs directed by abiotic and biotic signals. Currently, intrinsic signals that govern fungal development remain largely unknown. Here we show that an endogenously produced and secreted fungal oxylipin, 5,8-diHODE, induces fungal cellular differentiation, including lateral branching in pathogenic Aspergillus fumigatus and Aspergillus flavus, and appressorium formation in the rice blast pathogen Magnaporthe grisea. The Aspergillus branching response is specific to a subset of oxylipins and is signaled through G-protein coupled receptors. RNA-Seq profiling shows differential expression of many transcription factors in response to 5,8-diHODE. Screening of null mutants of 33 of those transcription factors identifies three transcriptional regulators that appear to mediate the Aspergillus branching response; one of the mutants is locked in a hypo-branching phenotype, while the other two mutants display a hyper-branching phenotype. Our work reveals an endogenous signal that triggers crucial developmental processes in filamentous fungi, and opens new avenues for research on the morphogenesis of filamentous fungi.
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| 5. |
- Ritacca, Alessandra G., et al.
(författare)
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Unraveling the Reaction Mechanism of Mo/Cu CO Dehydrogenase Using QM/MM Calculations
- 2022
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Ingår i: ACS Catalysis. - : American Chemical Society (ACS). - 2155-5435. ; 12:12, s. 7336-7343
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Tidskriftsartikel (refereegranskat)abstract
- Some microorganisms, like the aerobic soil bacteria, Oligotropha carboxidovorans, have the capability to oxidize the highly toxic atmospheric gas carbon monoxide (CO) into CO2 through CO dehydrogenase enzymes, whose active site contains a bimetallic MoCu center. Over the last decades, a number of experimental and theoretical investigations were devoted to understanding the mechanism of CO oxidation and, in particular, the role of a very stable thiocarbonate intermediate that may be formed during the catalytic cycle. The occurrence of such an intermediate was reported to make the CO2 release step kinetically difficult. In this work, by using an accurate QM/MM approach and energy refinement by means of the BigQM method, we were able to determine the role of such an intermediate and propose a novel mechanism for the oxidation of CO into CO2 by Mo/Cu CO dehydrogenase. Surprisingly, we found that the detachment of CO2 occurs directly from the product of the Mo=O nucleophilic attack reaction on the carbon of CO aided by the transient coordination of the active site glutamate to the Mo ion. The estimated activation barrier is in good agreement with the experimental one, while the thiocarbonate turned out to not interfere with the CO-oxidation catalytic cycle. The results highlight the importance of the environmental effects in the assembly of the molecular model and in the choice of the computational protocol. Our accurate modeling of the enzyme also allowed us to exclude the involvement of a frustrated Lewis pair in the CO-oxidation mechanism, which has recently been suggested based on an analysis of structural and electronic features of synthetic mimics of the Mo/Cu CO dehydrogenase active site.
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| 6. |
- Rovaletti, Anna, et al.
(författare)
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Can Water Act as a Nucleophile in CO Oxidation Catalysed by Mo/Cu CO-Dehydrogenase? Answers from Theory
- 2022
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Ingår i: ChemPhysChem. - : Wiley. - 1439-4235 .- 1439-7641. ; 23:8
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Tidskriftsartikel (refereegranskat)abstract
- The aerobic CO dehydrogenase from Oligotropha carboxidovorans is an environmentally crucial bacterial enzyme for maintenance of subtoxic concentration of CO in the lower atmosphere, as it allows for the oxidation of CO to CO2 which takes place at its Mo−Cu heterobimetallic active site. Despite extensive experimental and theoretical efforts, significant uncertainties still concern the reaction mechanism for the CO oxidation. In this work, we used the hybrid quantum mechanical/molecular mechanical approach to evaluate whether a water molecule present in the active site might act as a nucleophile upon formation of the new C−O bond, a hypothesis recently suggested in the literature. Our study shows that activation of H2O can be favoured by the presence of the Mo=Oeq group. However, overall our results suggest that mechanisms other than the nucleophilic attack by Mo=Oeq to the activated carbon of the CO substrate are not likely to constitute reactive channels for the oxidation of CO by the enzyme.
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| 7. |
- Rovaletti, Anna, et al.
(författare)
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How general is the effect of the bulkiness of organic ligands on the basicity of metal-organic catalysts? H2-evolving Mo oxides/sulphides as case studies
- 2022
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Ingår i: Physical chemistry chemical physics : PCCP. - : Royal Society of Chemistry (RSC). - 1463-9084 .- 1463-9076. ; 24:48, s. 29471-29479
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Tidskriftsartikel (refereegranskat)abstract
- Tailoring the activity of an organometallic catalyst usually requires a targeted ligand design. Tuning the ligand bulkiness and tuning the electronic properties are popular approaches, which are somehow interdependent because substituents of different sizes within ligands can determine inter alia the occurrence of different degrees of inductive effects. Ligand basicity, in particular, turned out to be a key property for the modulation of protonation reactions occurring in vacuo at the metals in complexes bearing organophosphorus ligands; however, when the same reactions take place in a polar organic solvent, their energetics becomes dependent on the trade-off between ligand basicity and bulkiness, with the polarity of the solvent playing a key role in this regard [Bancroft et al., Inorg. Chem., 1986, 25, 3675; Rovaletti et al., J. Phys. Org. Chem., 2018, 31, e3748]. In the present contribution, we carried out molecular dynamics and density functional theory calculations on water-soluble Mo-based catalysts for proton reduction, in order to study the energetics of protonation reactions in complexes where the incipient proton binds a catalytically active ligand (i.e., an oxide or a disulphide). We considered complexes either soaked in water or in a vacuum, and featuring N-based ancillary ligands of different bulkiness (i.e. cages constituted either by pyridine or isoquinoline moieties). Our results show that the energetics of protonation events can be affected by ancillary ligand bulkiness even when the metal center does not play the role of the H+ acceptor. In vacuo, protonation at the O or S atom in the α position relative to the metal in complexes featuring the bulky isoquinoline-based ligand is more favored by around 10 kcal mol−1 when compared to the case of the pyridine-based counterparts, a difference that is almost zero when the same reactions occur in water. Such an outcome is rationalized in light of the different electrostatic properties of complexes bearing ancillary ligands of different sizes. The overall picture from theory indicates that such effects of ligand bulkiness can be relevant for the design of green chemistry catalysts that undergo protonation steps in water solutions.
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| 8. |
- Rovaletti, Anna, et al.
(författare)
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QM/MM study of the binding of H2 to MoCu CO dehydrogenase : development and applications of improved H2 van der Waals parameters
- 2021
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Ingår i: Journal of Molecular Modeling. - : Springer Science and Business Media LLC. - 1610-2940 .- 0948-5023. ; 27:3
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Tidskriftsartikel (refereegranskat)abstract
- The MoCu CO dehydrogenase enzyme not only transforms CO into CO2 but it can also oxidise H2. Even if its hydrogenase activity has been known for decades, a debate is ongoing on the most plausible mode for the binding of H2 to the enzyme active site and the hydrogen oxidation mechanism. In the present work, we provide a new perspective on the MoCu-CODH hydrogenase activity by improving the in silico description of the enzyme. Energy refinement—by means of the BigQM approach—was performed on the intermediates involved in the dihydrogen oxidation catalysis reported in our previously published work (Rovaletti, et al. “Theoretical Insights into the Aerobic Hydrogenase Activity of Molybdenum–Copper CO Dehydrogenase.” Inorganics 7 (2019) 135). A suboptimal description of the H2–HN(backbone) interaction was observed when the van der Waals parameters described in previous literature for H2 were employed. Therefore, a new set of van der Waals parameters is developed here in order to better describe the hydrogen–backbone interaction. They give rise to improved binding modes of H2 in the active site of MoCu CO dehydrogenase. Implications of the resulting outcomes for a better understanding of hydrogen oxidation catalysis mechanisms are proposed and discussed.
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