| 1. |
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
- Swat, M. J., et al.
(författare)
-
Pharmacometrics Markup Language (PharmML) : Opening New Perspectives for Model Exchange in Drug Development
- 2015
-
Ingår i: CPT. - : American Society for Clinical Pharmacology & Therapeutics. - 2163-8306. ; 4:6, s. 316-319
-
Tidskriftsartikel (refereegranskat)abstract
- The lack of a common exchange format for mathematical models in pharmacometrics has been a long-standing problem. Such a format has the potential to increase productivity and analysis quality, simplify the handling of complex workflows, ensure reproducibility of research, and facilitate the reuse of existing model resources. Pharmacometrics Markup Language (PharmML), currently under development by the Drug Disease Model Resources (DDMoRe) consortium, is intended to become an exchange standard in pharmacometrics by providing means to encode models, trial designs, and modeling steps.
|
|
| 6. |
- Acosta, R. P., et al.
(författare)
-
A Model-Data Comparison of the Hydrological Response to Miocene Warmth : Leveraging the MioMIP1 Opportunistic Multi-Model Ensemble
- 2024
-
Ingår i: Paleoceanography and Paleoclimatology. - 2572-4517 .- 2572-4525. ; 39:1
-
Tidskriftsartikel (refereegranskat)abstract
- The Miocene (23.03-5.33 Ma) is recognized as a period with close to modern-day paleogeography, yet a much warmer climate. With large uncertainties in future hydroclimate projections, Miocene conditions illustrate a potential future analog for the Earth system. A recent opportunistic Miocene Model Intercomparison Project 1 (MioMIP1) focused on synthesizing published Miocene climate simulations and comparing them with available temperature reconstructions. Here, we build on this effort by analyzing the hydrological cycle response to Miocene forcings across early-to-middle (E2MMIO; 20.03-11.6 Ma) and middle-to-late Miocene (M2LMIO; 11.5-5.33 Ma) simulations with CO2 concentrations ranging from 200 to 850 ppm and providing a model-data comparison against available precipitation reconstructions. We find global precipitation increases by similar to 2.1 and 2.3% per degree of warming for E2MMIO and M2LMIO simulations, respectively. Models generally agree on a wetter than modern-day tropics; mid and high-latitude, however, do not agree on the sign of subtropical precipitation changes with warming. Global monsoon analysis suggests most monsoon regions, except the North American Monsoon, experience higher precipitation rates under warmer conditions. Model-data comparison shows that mean annual precipitation is underestimated by the models regardless of CO2 concentration, particularly in the mid- to high-latitudes. This suggests that the models may not be (a) resolving key processes driving the hydrological cycle response to Miocene boundary conditions and/or (b) other boundary conditions or processes not considered here are critical to reproducing Miocene hydroclimate. This study highlights the challenges in modeling and reconstructing the Miocene hydrological cycle and serves as a baseline for future coordinated MioMIP efforts. This study looks at Earth's hydrological cycle during the Miocene (23-5 million years ago). During this period, the Earth's climate was 3-7 degrees C warmer than today, with carbon dioxide (CO2) estimates ranging between 400 and 850 ppm. Understanding how the hydrological cycle responded during warmer climate conditions can give us insight into what might happen as the Earth gets warmer. We analyzed a suite of Miocene paleoclimate simulations with different CO2 concentrations in the atmosphere and compared them against fossil plant data, which gives an estimate of the average annual rainfall during the period. We found that during the Miocene global rainfall increased by about 2.1%-2.3% for each degree of warming. The models agree that the tropics, mid- and high-latitude, became wetter than they are today but have lower agreement on whether subtropical areas got wetter or drier as they warmed. Compared to proxies, models consistently underestimated how much rain fell in a year, especially in the mid- to high-latitude. This illustrates the challenges in reconstructing the Miocene's hydrological cycle and suggests that the models might not fully capture the range of uncertainties associated with changes in the hydrological cycle due to warming or other factors that differentiated the Miocene. A multi-model comparison of the hydrological cycle in early-to-middle and middle-to-late Miocene simulations is conductedModels generally agree on wetter than modern tropics, middle and high latitudes, but not on the sign of subtropical precipitation changesModel-data comparison shows mean annual precipitation is underestimated by the models, particularly in the mid- to high-latitudes
|
|
| 7. |
- Burls, N. J., et al.
(författare)
-
Simulating Miocene Warmth : Insights From an Opportunistic Multi-Model Ensemble (MioMIP1)
- 2021
-
Ingår i: Paleoceanography and Paleoclimatology. - 2572-4517 .- 2572-4525. ; 36:5
-
Tidskriftsartikel (refereegranskat)abstract
- The Miocene epoch, spanning 23.03-5.33 Ma, was a dynamic climate of sustained, polar amplified warmth. Miocene atmospheric CO2 concentrations are typically reconstructed between 300 and 600 ppm and were potentially higher during the Miocene Climatic Optimum (16.75-14.5 Ma). With surface temperature reconstructions pointing to substantial midlatitude and polar warmth, it is unclear what processes maintained the much weaker-than-modern equator-to-pole temperature difference. Here, we synthesize several Miocene climate modeling efforts together with available terrestrial and ocean surface temperature reconstructions. We evaluate the range of model-data agreement, highlight robust mechanisms operating across Miocene modeling efforts and regions where differences across experiments result in a large spread in warming responses. Prescribed CO2 is the primary factor controlling global warming across the ensemble. On average, elements other than CO2, such as Miocene paleogeography and ice sheets, raise global mean temperature by similar to 2 degrees C, with the spread in warming under a given CO2 concentration (due to a combination of the spread in imposed boundary conditions and climate feedback strengths) equivalent to similar to 1.2 times a CO2 doubling. This study uses an ensemble of opportunity: models, boundary conditions, and reference data sets represent the state-of-art for the Miocene, but are inhomogeneous and not ideal for a formal intermodel comparison effort. Acknowledging this caveat, this study is nevertheless the first Miocene multi-model, multi-proxy comparison attempted so far. This study serves to take stock of the current progress toward simulating Miocene warmth while isolating remaining challenges that may be well served by community-led efforts to coordinate modeling and data activities within a common analytical framework.
|
|
| 8. |
|
|
| 9. |
- Al-Khan, A., et al.
(författare)
-
IFPA Meeting 2010 Workshops Report II: Placental pathology; Trophoblast invasion; Fetal sex; Parasites and the placenta; Decidua and embryonic or fetal loss; Trophoblast differentiation and syncytialisation
- 2011
-
Ingår i: Placenta. - : Elsevier BV. - 1532-3102 .- 0143-4004. ; 32:Suppl. 2, s. 90-99
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Workshops are an important part of the IFPA annual meeting. At IFPA Meeting 2010 diverse topics were discussed in twelve themed workshops, six of which are summarized in this report. 1. The placental pathology workshop focused on clinical correlates of placenta accreta/percreta. 2. Mechanisms of regulation of trophoblast invasion and spiral artery remodeling were discussed in the trophoblast invasion workshop. 3. The fetal sex and intrauterine stress workshop explored recent work on placental sex differences and discussed them in the context of whether boys live dangerously in the womb.4. The workshop on parasites addressed inflammatory responses as a sign of interaction between placental tissue and parasites. 5. The decidua and embryonic/fetal loss workshop focused on key regulatory mediators in the decidua, embryo and fetus and how alterations in expression may contribute to different diseases and adverse conditions of pregnancy. 6. The trophoblast differentiation and syncytialisation workshop addressed the regulation of villous cytotrophoblast differentiation and how variations may lead to placental dysfunction and pregnancy complications. (C) 2011 Published by IFPA and Elsevier Ltd.
|
|
| 10. |
- Martin, David, et al.
(författare)
-
Defining Major Surgery: A Delphi Consensus Among European Surgical Association (ESA) Members
- 2020
-
Ingår i: World Journal of Surgery. - : Springer Science and Business Media LLC. - 0364-2313 .- 1432-2323. ; 44:7, s. 2211-2219
-
Tidskriftsartikel (refereegranskat)abstract
- © 2020, Société Internationale de Chirurgie. Background: Major surgery is a term frequently used but poorly defined. The aim of the present study was to reach a consensus in the definition of major surgery within a panel of expert surgeons from the European Surgical Association (ESA). Methods: A 3-round Delphi process was performed. All ESA members were invited to participate in the expert panel. In round 1, experts were inquired by open- and closed-ended questions on potential criteria to define major surgery. Results were analyzed and presented back anonymously to the panel within next rounds. Closed-ended questions in round 2 and 3 were either binary or statements to be rated on a Likert scale ranging from 1 (strong disagreement) to 5 (strong agreement). Participants were sent 3 reminders at 2-week intervals for each round. 70% of agreement was considered to indicate consensus. Results: Out of 305 ESA members, 67 (22%) answered all the 3 rounds. Significant comorbidities were the only preoperative factor retained to define major surgery (78%). Vascular clampage or organ ischemia (92%), high intraoperative blood loss (90%), high noradrenalin requirements (77%), long operative time (73%) and perioperative blood transfusion (70%) were procedure-related factors that reached consensus. Regarding postoperative factors, systemic inflammatory response (76%) and the need for intensive or intermediate care (88%) reached consensus. Consequences of major surgery were high morbidity (>30% overall) and mortality (>2%). Conclusion: ESA experts defined major surgery according to extent and complexity of the procedure, its pathophysiological consequences and consecutive clinical outcomes.
|
|
| 11. |
|
|
| 12. |
- Abelein, A, et al.
(författare)
-
High-yield Production of Amyloid-β Peptide Enabled by a Customized Spider Silk Domain
- 2020
-
Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 235-
-
Tidskriftsartikel (refereegranskat)abstract
- During storage in the silk gland, the N-terminal domain (NT) of spider silk proteins (spidroins) keeps the aggregation-prone repetitive region in solution at extreme concentrations. We observe that NTs from different spidroins have co-evolved with their respective repeat region, and now use an NT that is distantly related to previously used NTs, for efficient recombinant production of the amyloid-β peptide (Aβ) implicated in Alzheimer’s disease. A designed variant of NT from Nephila clavipes flagelliform spidroin, which in nature allows production and storage of β-hairpin repeat segments, gives exceptionally high yields of different human Aβ variants as a solubility tag. This tool enables efficient production of target peptides also in minimal medium and gives up to 10 times more isotope-labeled monomeric Aβ peptides per liter bacterial culture than previously reported.
|
|
| 13. |
- Costeira-Paulo, Joana, et al.
(författare)
-
Lipids Shape the Electron Acceptor-Binding Site of the Peripheral Membrane Protein Dihydroorotate Dehydrogenase
- 2018
-
Ingår i: Cell Chemical Biology. - : Elsevier BV. - 2451-9456 .- 2451-9448. ; 25:3, s. 309-317
-
Tidskriftsartikel (refereegranskat)abstract
- The interactions between proteins and biological membranes are important for drug development, but remain notoriously refractory to structural investigation. We combine non-denaturing mass spectrometry (MS) with molecular dynamics (MD) simulations to unravel the connections among co-factor, lipid, and inhibitor binding in the peripheral membrane protein dihydroorotate dehydrogenase (DHODH), a key anticancer target. Interrogation of intact DHODH complexes by MS reveals that phospholipids bind via their charged head groups at a limited number of sites, while binding of the inhibitor brequinar involves simultaneous association with detergent molecules. MD simulations show that lipids support flexible segments in the membrane-binding domain and position the inhibitor and electron acceptor-binding site away from the membrane surface, similar to the electron acceptor-binding site in respiratory chain complex I. By complementing MS with MD simulations, we demonstrate how a peripheral membrane protein uses lipids to modulate its structure in a similar manner as integral membrane proteins.
|
|
| 14. |
- Harding-Esch, Emma M., et al.
(författare)
-
Impact of a single round of mass drug administration with azithromycin on active trachoma and ocular Chlamydia trachomatis prevalence and circulating strains in The Gambia and Senegal
- 2019
-
Ingår i: Parasites & Vectors. - : BMC. - 1756-3305. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Mass drug administration (MDA) with azithromycin is a cornerstone of the trachoma elimination strategy. Although the global prevalence of active trachoma has declined considerably, prevalence persists or even increases in some communities and districts. To increase understanding of MDA impact, we investigated the prevalence of active trachoma and ocular C. trachomatis prevalence, organism load, and circulating strains at baseline and one-year post-MDA in The Gambia and Senegal.Methods: Pre- and one-year post-MDA, children aged 0-9 years were examined for clinical signs of trachoma in six Gambian and 12 Senegalese villages. Ocular swabs from each child's right conjunctiva were tested for evidence of ocular C. trachomatis infection and organism load (ompA copy number), and ompA and multi-locus sequence typing (MLST) was performed.Results: A total of 1171 children were examined at baseline and follow-up in The Gambia. Active trachoma prevalence decreased from 23.9% to 17.7%, whereas ocular C. trachomatis prevalence increased from 3.0% to 3.8%. In Senegal, 1613 and 1771 children were examined at baseline and follow-up, respectively. Active trachoma prevalence decreased from 14.9% to 8.0%, whereas ocular C. trachomatis prevalence increased from 1.8% to 3.6%. Higher organism load was associated with having active trachoma and severe inflammation. Sequence typing demonstrated that all Senegalese samples were genovar A, whereas Gambian samples were a mix of genovars A and B. MLST provided evidence of clustering at village and household levels and demonstrated differences of strain variant frequencies in Senegal, indicative of an "outbreak". MLST, including partial ompA typing, provided greater discriminatory power than complete ompA typing.Conclusions: We found that one round of MDA led to an overall decline in active trachoma prevalence but no impact on ocular C. trachomatis infection, with heterogeneity observed between villages studied. This could not be explained by MDA coverage or number of different circulating strains pre- and post-MDA. The poor correlation between active trachoma and infection prevalence supports the need for further work on alternative indicators to clinical signs for diagnosing ocular C. trachomatis infection. MLST typing has potential molecular epidemiology utility, including better understanding of transmission dynamics, although relationship to whole-genome sequence variability requires further exploration.
|
|
| 15. |
|
|
| 16. |
- Biverstal, H, et al.
(författare)
-
Functionalization of amyloid fibrils via the Bri2 BRICHOS domain
- 2020
-
Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 21765-
-
Tidskriftsartikel (refereegranskat)abstract
- Amyloid fibrils are mechanically robust and partly resistant to proteolytic degradation, making them potential candidates for scaffold materials in cell culture, tissue engineering, drug delivery and other applications. Such applications of amyloids would benefit from the possibility to functionalize the fibrils, for example by adding growth factors or cell attachment sites. The BRICHOS domain is found in a family of human proteins that harbor particularly amyloid-prone regions and can reduce aggregation as well as toxicity of several different amyloidogenic peptides. Recombinant human (rh) BRICHOS domains have been shown to bind to the surface of amyloid-β (Aβ) fibrils by immune electron microscopy. Here we produce fusion proteins between mCherry and rh Bri2 BRICHOS and show that they can bind to different amyloid fibrils with retained fluorescence of mCherry in vitro as well as in cultured cells. This suggests a “generic” ability of the BRICHOS domain to bind fibrillar surfaces that can be used to synthesize amyloid decorated with different protein functionalities.
|
|
| 17. |
|
|
| 18. |
- Ribba, B, et al.
(författare)
-
A review of mixed-effects models of tumor growth and effects of anticancer drug treatment used in population analysis
- 2014
-
Ingår i: CPT. - : Wiley. - 2163-8306. ; 3:5, s. 1-10
-
Tidskriftsartikel (refereegranskat)abstract
- Population modeling of tumor size dynamics has recently emerged as an important tool in pharmacometric research. A series of new mixed-effects models have been reported recently, and we present herein a synthetic view of models with published mathematical equations aimed at describing the dynamics of tumor size in cancer patients following anticancer drug treatment. This selection of models will constitute the basis for the Drug Disease Model Resources (DDMoRe) repository for models on oncology.
|
|
