| 1. |
- de Boer, Eline, et al.
(author)
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Synthetic Oligodeoxynucleotide CpG Motifs Activate Human Complement through Their Backbone Structure and Induce Complement-Dependent Cytokine Release
- 2022
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In: Journal of Immunology. - : American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 209:9, s. 1760-1767
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Journal article (peer-reviewed)abstract
- Bacterial and mitochondrial DNA, sharing an evolutionary origin, act as danger-associated molecular patterns in infectious and sterile inflammation. They both contain immunomodulatory CpG motifs. Interactions between CpG motifs and the complement system are sparsely described, and mechanisms of complement activation by CpG remain unclear. Lepirudin-anticoagulated human whole blood and plasma were incubated with increasing concentrations of three classes of synthetic CpGs: CpG-A, -B, and -C oligodeoxynucleotides and their GpC sequence controls. Complement activation products were analyzed by immunoassays. Cytokine levels were determined via 27-plex beads-based immunoassay, and CpG interactions with individual complement proteins were evaluated using magnetic beads coated with CpG-B. In whole blood and plasma, CpG-B and CpG-C (p < 0.05 for both), but not CpG-A (p > 0.8 for all), led to time- and dose-dependent increase of soluble C5b-9, the alternative complement convertase C3bBbP, and the C3 cleavage product C3bc. GpC-A, -B, and -C changed soluble fluid-phase C5b-9, C3bBbP, and C3bc to the same extent as CpG-A, -B, and -C, indicating a DNA backbone-dependent effect. Dose-dependent CpG-B binding was found to C1q (r = 0.83; p 5 0.006) and factor H (r = 0.93; p < 0.001). The stimulatory complement effect was partly preserved in C2-deficient plasma and completely preserved in MASP-2-deficient serum. CpG-B increased levels of IL-1 beta, IL-2, IL-6, IL-8, MCP-1, and TNF in whole blood, which were completely abolished by inhibition of C5 and C5aR1 (p < 0.05 for all). In conclusion, synthetic analogs of bacterial and mitochondrial DNA activate the complement system via the DNA backbone. We suggest that CpG-B interacts directly with classical and alternative pathway components, resulting in complement-C5aR1-dependent cytokine release.
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| 2. |
- Högman, Marieann, et al.
(author)
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Effects of growth and aging on the reference values of pulmonary nitric oxide dynamics in healthy subjects
- 2017
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In: Journal of Breath Research. - : IOP Publishing. - 1752-7155 .- 1752-7163. ; 11:4
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Journal article (peer-reviewed)abstract
- The lung just like all other organs is affected by age. The lung matures by the age of 20 and age-related changes start around middle age, at 40-50 years. Exhaled nitric oxide (FENO) has been shown to be age, height and gender dependent. We hypothesize that the nitric oxide (NO) parameters alveolar NO (CANO), airway flux (JawNO), airway diffusing capacity (DawNO) and airway wall content (CawNO) will also demonstrate this dependence. Data from healthy subjects were gathered by the current authors from their earlier publications in which healthy individuals were included as control subjects. Healthy subjects (n = 433) ranged in age from 7 to 78 years. Age-stratified reference values of the NO parameters were significantly different. Gender differences were only observed in the 20-49 age group. The results from the multiple regression models in subjects older than 20 years revealed that age, height and gender interaction together explained 6% of variation in FENO at 50 ml s-1 (FENO50), 4% in JawNO, 16% in CawNO, 8% in DawNO and 12% in CANO. In conclusion, in this study we have generated reference values for NO parameters from an extended NO analysis of healthy subjects. This is important in order to be able to use these parameters in clinical practice.
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| 3. |
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| 4. |
- Carvalho, E. de, et al.
(author)
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EU FP7 INFSO-ICT-317669 METIS, D3.1 Positioning of multi-node/multi-antenna technologies
- 2013
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Reports (other academic/artistic)abstract
- This document describes the research activity in multi-node/multi-antenna technologies within METIS and positions it with respect to the state-of-the-art in the academic literature and in the standardization bodies. Based on the state-of-the-art and as well as on the METIS objectives,we set the research objectives and we group the different activities (or technology components) into research clusters with similar research objectives. The technologycomponents and the research objectives have been set to achieve an ambidextrous purpose. On one side we aim at providing the METIS system with those technological components that are a natural but non-trivial evolution of 4G. On the other side, we aim at seeking for disruptivetechnologies that could radically change 5G with respect to 4G. Moreover, we mapped the different technology components to METIS’ other activities and to the overall goals of theproject.
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| 5. |
- Chye, Alexander, et al.
(author)
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Repeated Measures of Modified Rankin Scale Scores to Assess Functional Recovery From Stroke : AFFINITY Study Findings
- 2022
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In: Journal of the American Heart Association. - : Ovid Technologies (Wolters Kluwer Health). - 2047-9980. ; 11:16
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Journal article (peer-reviewed)abstract
- Background: Function after acute stroke using the modified Rankin Scale (mRS) is usually assessed at a point in time. The analytical implications of serial mRS measurements to evaluate functional recovery over time is not completely understood. We compare repeated-measures and single-measure analyses of the mRS from a randomized clinical trialMethods and Results: Serial mRS data from AFFINITY (Assessment of Fluoxetine in Stroke Recovery), a double-blind placebo randomized clinical trial of fluoxetine following stroke (n=1280) were analyzed to identify demographic and clinical associations with functional recovery (reduction in mRS) over 12 months. Associations were identified using single-measure (day 365) and repeated-measures (days 28, 90, 180, and 365) partial proportional odds logistic regression. Ninety-five percent of participants experienced a reduction in mRS after 12 months. Functional recovery was associated with age at stroke <70 years; no prestroke history of diabetes, coronary heart disease, or ischemic stroke; prestroke history of depression, a relationship partner, living with others, independence, or paid employment; no fluoxetine intervention; ischemic stroke (compared with hemorrhagic); stroke treatment in Vietnam (compared with Australia or New Zealand); longer time since current stroke; and lower baseline National Institutes of Health Stroke Scale & Patient Health Questionnaire-9 scores. Direction of associations was largely concordant between single-measure and repeated-measures models. Association strength and variance was generally smaller in the repeated-measures model compared with the single-measure model.Conclusions: Repeated-measures may improve trial precision in identifying trial associations and effects. Further repeated-measures stroke analyses are required to prove methodological value. Registration URL: http://www.anzctr.org.au; Unique identifier: ACTRN12611000774921.
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| 6. |
- Fantini, R, et al.
(author)
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EU FP7 INFSO-ICT-317669 METIS, D3.2 First performance results for multi-node/multi-antenna transmission technologies
- 2014
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Reports (other academic/artistic)abstract
- This deliverable describes the current results of the multi-node/multi-antenna technologies investigated within METIS and analyses the interactions within and outside Work Package 3. Furthermore, it identifies the most promising technologies based on the current state of obtained results. This document provides a brief overview of the results in its first part. The second part, namely the Appendix, further details the results, describes the simulation alignment efforts conducted in the Work Package and the interaction of the Test Cases. The results described here show that the investigations conducted in Work Package 3 are maturing resulting in valuable innovative solutions for future 5G systems.
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| 7. |
- Hankey, Graeme J., et al.
(author)
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Twelve-Month Outcomes of the AFFINITY Trial of Fluoxetine for Functional Recovery After Acute Stroke AFFINITY Trial Steering Committee on Behalf of the AFFINITY Trial Collaboration
- 2021
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In: Stroke. - : Lippincott Williams & Wilkins. - 0039-2499 .- 1524-4628. ; 52:8, s. 2502-2509
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Journal article (peer-reviewed)abstract
- BACKGROUND AND PURPOSE: The AFFINITY trial (Assessment of Fluoxetine in Stroke Recovery) reported that oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and seizures. After trial medication was ceased at 6 months, survivors were followed to 12 months post-randomization. This preplanned secondary analysis aimed to determine any sustained or delayed effects of fluoxetine at 12 months post-randomization. METHODS: AFFINITY was a randomized, parallel-group, double-blind, placebo-controlled trial in adults (n=1280) with a clinical diagnosis of stroke in the previous 2 to 15 days and persisting neurological deficit who were recruited at 43 hospital stroke units in Australia (n=29), New Zealand (4), and Vietnam (10) between 2013 and 2019. Participants were randomized to oral fluoxetine 20 mg once daily (n=642) or matching placebo (n=638) for 6 months and followed until 12 months after randomization. The primary outcome was function, measured by the modified Rankin Scale, at 6 months. Secondary outcomes for these analyses included measures of the modified Rankin Scale, mood, cognition, overall health status, fatigue, health-related quality of life, and safety at 12 months. RESULTS: Adherence to trial medication was for a mean 167 (SD 48) days and similar between randomized groups. At 12 months, the distribution of modified Rankin Scale categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio, 0.93 [95% CI, 0.76-1.14]; P=0.46). Compared with placebo, patients allocated fluoxetine had fewer recurrent ischemic strokes (14 [2.18%] versus 29 [4.55%]; P=0.02), and no longer had significantly more falls (27 [4.21%] versus 15 [2.35%]; P=0.08), bone fractures (23 [3.58%] versus 11 [1.72%]; P=0.05), or seizures (11 [1.71%] versus 8 [1.25%]; P=0.64) at 12 months. CONCLUSIONS: Fluoxetine 20 mg daily for 6 months after acute stroke had no delayed or sustained effect on functional outcome, falls, bone fractures, or seizures at 12 months poststroke. The lower rate of recurrent ischemic stroke in the fluoxetine group is most likely a chance finding.
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| 8. |
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| 9. |
- Nguyen, Huy S., et al.
(author)
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Many-body depletion forces of colloids in a polydisperse polymer dispersant in the long-chain limit
- 2018
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In: Soft Matter. - : Royal Society of Chemistry (RSC). - 1744-683X .- 1744-6848. ; 14:33
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Journal article (peer-reviewed)abstract
- We study a system of spherical non-adsorbing particles immersed in a polydisperse polymer fluid. We derive an analytic expression for the many-body depletion interactions between the colloidal particles in the limit of very long chains. We argue that this expression is essentially exact for long chains and justify this using explicit simulations. In this way we are able to elucidate the profound effect of many-body interactions on the particle thermodynamics. We show that using truncated 2-body depletion interactions leads to strong particle segregation, while the complete many-body description predicts that the total depletion force becomes weak so that the system approximates one which interacts via a so-called Kac potential. This implies that the depletion interactions can be described using mean-field theory. We show that many-body effects cause a significant contraction of the 2-phase region of the particle dispersion. We also investigate the system approaching the (tricritical) θ point, which terminates the line of first-order critical points of the polymer dispersion in a poor solvent and show that many-body effects suppress particle phase transitions.
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| 10. |
- Nguyen, Huy S., et al.
(author)
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Many-body effects in a binary nano-particle mixture dispersed in ideal polymer solutions
- 2019
-
In: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 150:4
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Journal article (peer-reviewed)abstract
- A new mean-field theory is developed to treat a binary mixture of nanoparticles imbedded in a polydisperse polymer solution. The theory is based on a many-body polymer-mediated potential of mean force (PMF) between the particles and remains accurate even in the protein regime, where the particles' diameters cannot necessarily be considered large compared to the polymer radius of gyration. As implemented here, the theory is strictly valid for dilute to semi-dilute polymer solutions near the theta temperature (the so-called theta regime) or when the range of the PMF is strongly affected by the polymer size. For non-adsorbing particles, this is the same regime where the celebrated Asakura-Oosawa (AO) model is often used. Unlike the traditional AO model, however, our approach includes polymer flexibility and is accurate in the protein regime. We use the theory to calculate phase diagrams for a binary mixture of unequal-sized particles, both adsorbing and non-adsorbing. To test the theory, we carry out comparisons with simulations and obtained good quantitative agreement, which gives support to its accuracy. On the other hand, the oft-used approach assuming pairwise-additive potentials of mean force produce quantitatively (and sometime qualitatively) different phase diagrams.
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| 11. |
- Nilsson, Per H., 1980-, et al.
(author)
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A Conformational Change of Complement C5 Is Required for Thrombin-Mediated Cleavage, Revealed by a Novel Ex Vivo Human Whole Blood Model Preserving Full Thrombin Activity
- 2021
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In: Journal of Immunology. - : American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 207:6, s. 1641-1651
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Journal article (peer-reviewed)abstract
- Thrombin activation of C5 connects thrombosis to inflammation. Complement research in whole blood ex vivo necessitates anticoagulation, which potentially interferes with the inflammatory modulation by thrombin. We challenged the concept of thrombin as an activator of native C5 by analyzing complement activation and C5 cleavage in human whole blood anticoagulated with Gly-Pro-Arg-Pro (GPRP), a peptide targeting fibrin polymerization downstream of thrombin, allowing complete endogenous thrombin generation. GPRP dose-dependently inhibited coagulation but allowed for platelet activation in accordance with thrombin generation. Spontaneous and bacterial-induced complement activation by Escherichia coli and Staphylococcus aureus, analyzed at the level of C3 and C5, were similar in blood anticoagulated with GPRP and the thrombin inhibitor lepirudin. In the GPRP model, endogenous thrombin, even at supra-physiologic concentrations, did not cleave native C5, despite efficiently cleaving commercially sourced purified C5 protein, both in buffer and when added to C5-deficient serum. In normal serum, only exogenously added, commercially sourced C5 was cleaved, whereas the native plasma C5 remained intact. Crucially, affinity-purified C5, eluted under mild conditions using an MgCl2 solution, was not cleaved by thrombin. Acidification of plasma to pH # 6.8 by hydrochloric or lactic acid induced a C5 antigenic change, nonreversible by pH neutralization, that permitted cleavage by thrombin. Circular dichroism on purified C5 confirmed the structural change during acidification. Thus, we propose that pH-induced conformational change allows thrombin-mediated cleavage of C5 and that, contrary to previous reports, thrombin does not cleave plasma C5 in its native form, suggesting that thrombin cleavage of C5 may be restricted to certain pathophysiological conditions.
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| 12. |
- Phan-Huy, D.T., et al.
(author)
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5G on Board: How Many Antennas Do We Need on Connected Cars?
- 2016
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In: 2016 IEEE Globecom Workshops (GC Wkshps), 4-8 Dec. 2016. - New York : IEEE. - 2166-0069. - 9781509024827
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Conference paper (peer-reviewed)abstract
- Mobile networks will support increasing numbers of connected vehicles. Successive generations of mobile networks have reduced the cost of data rate, in terms of spectrum usage and power consumption at the base station, by increasingly exploiting the concept of channel state information at the transmitter. Unfortunately, beyond a limiting velocity (which depends on the carrier frequency), networks are no longer cost efficient, since such information is not usable. Recently, channel prediction techniques requiring several antennas on the car roof have been introduced to solve this problem. In this paper, for the first time, we determine the most cost efficient configurations, in terms of numbers of antennas on the car roof and carrier frequency, in various scenarios (highway and dense urban). Our studies show that with a simple prediction technique based on predictor antennas, the network can use twice less spectrum and around 20 dB less power, for cars with 3 antennas on their tops than for cars with the same number of antennas and not using prediction.
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| 13. |
- Phan-Huy, D. -T., et al.
(author)
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Massive Multiple Input Massive Multiple Output for 5G Wireless Backhauling
- 2017
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In: IEEE Globecom Workshops. - 2166-0069. - 9781538639207 ; 2018-January, s. 1-6
-
Conference paper (peer-reviewed)abstract
- In this paper, we propose a new technique for the future fifth generation (5G) cellular network wireless backhauling. We show that hundreds of data streams can be spatially multiplexed through a short range and line of sight "massive multiple input massive multiple output" (MMIMMO) propagation channel thanks to a new low complexity spatial multiplexing scheme, called "block discrete Fourier transform based spatial multiplexing with maximum ratio transmission" (B-DFT-SM-MRT). Its performance in real and existing environments is assessed using ray-tracing tools and advanced antenna models. 1.6 kbits/s/Hz of spectral efficiency is attained, corresponding to 80% of Singular Value Decomposition performance, with a transmitter and a receiver that are 200 and 10,000 times less complex, respectively.
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| 14. |
- Stahl, Andreas, et al.
(author)
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Postnatal weight gain modifies severity and functional outcome of oxygen-induced proliferative retinopathy
- 2010
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In: The American journal of pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 177:6, s. 2715-23
-
Journal article (peer-reviewed)abstract
- In clinical studies, postnatal weight gain is strongly associated with retinopathy of prematurity (ROP). However, animal studies are needed to investigate the pathophysiological mechanisms of how postnatal weight gain affects the severity of ROP. In the present study, we identify nutritional supply as one potent parameter that affects the extent of retinopathy in mice with identical birth weights and the same genetic background. Wild-type pups with poor postnatal nutrition and poor weight gain (PWG) exhibit a remarkably prolonged phase of retinopathy compared to medium weight gain or extensive weight gain pups. A high (r(2) = 0.83) parabolic association between postnatal weight gain and oxygen-induced retinopathy severity is observed, as is a significantly prolonged phase of proliferative retinopathy in PWG pups (20 days) compared with extensive weight gain pups (6 days). The extended retinopathy is concomitant with prolonged overexpression of retinal vascular endothelial growth factor in PWG pups. Importantly, PWG pups show low serum levels of nonfasting glucose, insulin, and insulin-like growth factor-1 as well as high levels of ghrelin in the early postoxygen-induced retinopathy phase, a combination indicative of poor metabolic supply. These differences translate into visual deficits in adult PWG mice, as demonstrated by impaired bipolar and proximal neuronal function. Together, these results provide evidence for a pathophysiological correlation between poor postnatal nutritional supply, slow weight gain, prolonged retinal vascular endothelial growth factor overexpression, protracted retinopathy, and reduced final visual outcome.
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| 15. |
- von Seidlein, Lorenz, et al.
(author)
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The impact of targeted malaria elimination with mass drug administrations on falciparum malaria in Southeast Asia: A cluster randomised trial
- 2019
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In: PLoS Medicine. - : PUBLIC LIBRARY SCIENCE. - 1549-1277 .- 1549-1676. ; 16:2
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Journal article (peer-reviewed)abstract
- Background The emergence and spread of multidrug-resistant Plasmodium falciparum in the Greater Mekong Subregion (GMS) threatens global malaria elimination efforts. Mass drug administration (MDA), the presumptive antimalarial treatment of an entire population to clear the subclinical parasite reservoir, is a strategy to accelerate malaria elimination. We report a cluster randomised trial to assess the effectiveness of dihydroartemisinin-piperaquine (DP) MDA in reducing falciparum malaria incidence and prevalence in 16 remote village populations in Myanmar, Vietnam, Cambodia, and the Lao Peoples Democratic Republic, where artemisinin resistance is prevalent. Methods and findings After establishing vector control and community-based case management and following intensive community engagement, we used restricted randomisation within village pairs to select 8 villages to receive early DP MDA and 8 villages as controls for 12 months, after which the control villages received deferred DP MDA. The MDA comprised 3 monthly rounds of 3 daily doses of DP and, except in Cambodia, a single low dose of primaquine. We conducted exhaustive cross-sectional surveys of the entire population of each village at quarterly intervals using ultrasensitive quantitative PCR to detect Plasmodium infections. The study was conducted between May 2013 and July 2017. The investigators randomised 16 villages that had a total of 8,445 residents at the start of the study. Of these 8,445 residents, 4,135 (49%) residents living in 8 villages, plus an additional 288 newcomers to the villages, were randomised to receive early MDA; 3,790 out of the 4,423 (86%) participated in at least 1 MDA round, and 2,520 out of the 4,423 (57%) participated in all 3 rounds. The primary outcome, P. falciparum prevalence by month 3 (M3), fell by 92% (from 5.1% [171/3,340] to 0.4% [12/2,828]) in early MDA villages and by 29% (from 7.2% [246/3,405] to 5.1% [155/3,057]) in control villages. Over the following 9 months, the P. falciparum prevalence increased to 3.3% (96/2,881) in early MDA villages and to 6.1% (128/2,101) in control villages (adjusted incidence rate ratio 0.41 [95% CI 0.20 to 0.84]; p = 0.015). Individual protection was proportional to the number of completed MDA rounds. Of 221 participants with subclinical P. falciparum infections who participated in MDA and could be followed up, 207 (94%) cleared their infections, including 9 of 10 with artemisinin-and piperaquine- resistant infections. The DP MDAs were well tolerated; 6 severe adverse events were detected during the follow-up period, but none was attributable to the intervention. Conclusions Added to community-based basic malaria control measures, 3 monthly rounds of DP MDA reduced the incidence and prevalence of falciparum malaria over a 1-year period in areas affected by artemisinin resistance. P. falciparum infections returned during the follow-up period as the remaining infections spread and malaria was reintroduced from surrounding areas. Limitations of this study include a relatively small sample of villages, heterogeneity between villages, and mobility of villagers that may have limited the impact of the intervention. These results suggest that, if used as part of a comprehensive, well-organised, and well-resourced elimination programme, DP MDA can be a useful additional tool to accelerate malaria elimination.
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