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| 2. |
- Bentham, James, et al.
(författare)
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A century of trends in adult human height
- 2016
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Ingår i: eLIFE. - 2050-084X. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.522.7) and 16.5 cm (13.319.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
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| 3. |
- Bentham, James, et al.
(författare)
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A century of trends in adult human height
- 2016
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Ingår i: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 5
-
Tidskriftsartikel (refereegranskat)abstract
- Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3– 19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8– 144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
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| 4. |
- Beal, Jacob, et al.
(författare)
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Robust estimation of bacterial cell count from optical density
- 2020
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data.
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| 6. |
- Bodare, Sofia, 1984-, et al.
(författare)
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Origin and demographic history of the endemic Taiwan spruce (Picea morrisonicola)
- 2013
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Ingår i: Ecology and Evolution. - : Wiley. - 2045-7758. ; 3:10, s. 3320-3333
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Tidskriftsartikel (refereegranskat)abstract
- Taiwan spruce (Picea morrisonicola) is a vulnerable conifer species endemic to the island of Taiwan. A warming climate and competition from subtropical tree species has limited the range of Taiwan spruce to the higher altitudes of the island. Using seeds sampled from an area in the central mountain range of Taiwan, 15 nuclear loci were sequenced in order to measure genetic variation and to assess the long-term genetic stability of the species. Genetic diversity is low and comparable to other spruce species with limited ranges such as Picea breweriana, Picea chihuahuana, and Picea schrenkiana. Importantly, analysis using approximate Bayesian computation (ABC) provides evidence for a drastic decline in the effective population size approximately 0.3–0.5 million years ago (mya). We used simulations to show that this is unlikely to be a false-positive result due to the limited sample used here. To investigate the phylogenetic origin of Taiwan spruce, additional sequencing was performed in the Chinese spruce Picea wilsonii and combined with previously published data for three other mainland China species, Picea purpurea, Picea likiangensis, and P. schrenkiana. Analysis of population structure revealed that P. morrisonicola clusters most closely with P. wilsonii, and coalescent analyses using the program MIMAR dated the split to 4–8 mya, coincidental to the formation of Taiwan. Considering the population decrease that occurred after the split, however, led to a much more recent origin.
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| 7. |
- Sou, Tomás, et al.
(författare)
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Model-Informed Drug Discovery and Development in Pulmonary Delivery : Biopharmaceutical Pharmacometric Modeling for Formulation Evaluation of Pulmonary Suspensions
- 2020
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Ingår i: ACS Omega. - : AMER CHEMICAL SOC. - 2470-1343. ; 5:40, s. 25733-25746
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Tidskriftsartikel (refereegranskat)abstract
- For respiratory conditions, targeted drug delivery to the lungs could produce higher local concentrations with reduced risk of adverse events compared to systemic administration. Despite the increasing interest in pulmonary delivery, the pharmacokinetics (PK) of drugs following pulmonary administration remains to be elucidated. In this context, the application of modeling and simulation methodologies to characterize PK properties of compounds following pulmonary administration remains a scarcity. Pseudomonas aeruginosa (PA) lung infections are resistant to many of the current antibiotic therapies. Targeted treatments for pulmonary delivery could be particularly beneficial for these local conditions. In this study, we report the application of biopharmaceutical pharmacometrics (BPMX) for the analysis of PK data from three investigational antimicrobial agents following pulmonary administration of a suspension formulation. The observed drug concentration-time profiles in lungs and plasma of the compound series were combined for simultaneous analysis and modeling. The developed model describes the PK data, taking into account formulation properties, and provides a mechanism to predict dissolved drug concentrations in the lungs available for activity. The model was then used to evaluate formulation effects and the impact of variability on total and dissolved drug concentrations in lungs and plasma. The predictions suggest that these therapies for lung delivery should ideally be delivered in a sustained release formulation with high solubility for maximum local exposure in lungs for efficacy, with rapid systemic clearance in plasma for reduced risk of unwanted systemic adverse effects. This work shows the potential benefits of BPMX and the role it can play to support drug discovery and development in pulmonary delivery.
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| 8. |
- Soukarieh, Fadi, et al.
(författare)
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Design and Evaluation of New Quinazolin-4(3H)-one Derived PqsR Antagonists as Quorum Sensing Quenchers in Pseudomonas aeruginosa
- 2021
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Ingår i: ACS - Infectious Diseases. - : American Chemical Society (ACS). - 2373-8227. ; 7:9, s. 2666-2685
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Tidskriftsartikel (refereegranskat)abstract
- P. aeruginosa (PA) continues to pose a threat to global public health due to its high levels of antimicrobial resistance (AMR). The ongoing AMR crisis has led to an alarming shortage of effective treatments for resistant microbes, and hence there is a pressing demand for the development of novel antimicrobial interventions. The potential use of antivirulence therapeutics to tackle bacterial infections has attracted considerable attention over the past decades as they hamper the pathogenicity of target microbes with reduced selective pressure, minimizing the emergence of resistance. One such approach is to interfere with the PA pqs quorum sensing system which upon the interaction of PqsR, a Lys-R type transcriptional regulator, with its cognate signal molecules 4-hydroxy-2-heptylquinoline (HHQ) and 2-heptyl-3-hydroxy-4-quinolone (PQS), governs multiple virulence traits and host-microbe interactions. In this study, we report the hit identification and optimization of PqsR antagonists using virtual screening coupled with whole cell assay validation. The optimized hit compound 61 ((R)-2-(4-(3-(6-chloro-4-oxoquinazolin-3(4H)-yl)-2-hydroxypropoxy)phenyl)acetonitrile) was found to inhibit the expression of the PA P-pqsA promoter controlled by PqsR with an IC50 of 1 mu M. Using isothermal titration calorimetry, a K-d of 10 nM for the P-qsR ligand binding domain (PqsR(LBD)) was determined for 61. Furthermore, the crystal structure of 61 with PqsR(LBD) was attained with a resolution of 2.65 angstrom. Compound 61 significantly reduced levels of pyocyanin, PQS, and HHQ in PAO1-L, PA14 lab strains and PAK6085 clinical isolate. Furthermore, this compound potentiated the effect of ciprofloxacin in early stages of biofilm treatment and in Galleria mellonella infected with PA. Altogether, this data shows 61 as a potent PqsR inhibitor with potential for hit to lead optimization toward the identification of a PA QS inhibitor which can be advanced into preclinical development.
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| 9. |
- Soukarieh, Fadi, et al.
(författare)
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Design, Synthesis, and Evaluation of New 1H-Benzo[d]imidazole Based PqsR Inhibitors as Adjuvant Therapy for Pseudomonas aeruginosa Infections
- 2024
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 67:2, s. 1008-1023
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Tidskriftsartikel (refereegranskat)abstract
- Pseudomonas aeruginosa is one of the top priority pathogens that requires immediate attention according to the World Health Organisation (WHO). Due to the alarming shortage of novel antimicrobials, targeting quorum sensing (QS), a bacterial cell to cell signaling system controlling virulence, has emerged as a promising approach as an antibiotic adjuvant therapy. Interference with the pqs system, one of three QS systems in P. aeruginosa, results in reduction of bacterial virulence gene expression and biofilm maturation. Herein, we report a hit to lead process to fine-tune the potency of our previously reported inhibitor 1 (IC50 3.2 mu M in P. aeruginosa PAO1-L), which led to the discovery of 2-(4-(3-((6-chloro-1-isopropyl-1H-benzo[d]imidazol-2-yl)amino)-2-hydroxypropoxy)phenyl)acetonitrile (6f) as a potent PqsR antagonist. Compound 6f inhibited the PqsR-controlled P-pqsA-lux transcriptional reporter fusion in P. aeruginosa at low submicromolar concentrations. Moreover, 6f showed improved efficacy against P. aeruginosa CF isolates with significant inhibition of pyocyanin, 2-alkyl-4(1H)-quinolones production.
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| 10. |
- Soukarieh, Fadi, et al.
(författare)
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Hit Identification of New Potent PqsR Antagonists as Inhibitors of Quorum Sensing in Planktonic and Biofilm Grown Pseudomonas aeruginosa
- 2020
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Ingår i: Frontiers in Chemistry. - : FRONTIERS MEDIA SA. - 2296-2646. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Current treatments for Pseudomonas aeruginosa infections are becoming less effective because of the increasing rates of multi-antibiotic resistance. Pharmacological targeting of virulence through inhibition of quorum sensing (QS) dependent virulence gene regulation has considerable therapeutic potential. In P. aeruginosa, the pqs QS system regulates the production of multiple virulence factors as well as biofilm maturation and is a promising approach for developing antimicrobial adjuvants for combatting drug resistance. In this work, we report the hit optimisation for a series of potent novel inhibitors of PqsR, a key regulator of the pqs system, bearing a 2-((5-methyl-5H-[1,2,4]triazino[5,6-b]indol-3-yl)thio) acetamide scaffold. The initial hit compound 7 (PAO1-L IC50 0.98 +/- 0.02 mu M, PA14 inactive at 10 mu M) was obtained through a virtual screening campaign performed on the PqsR ligand binding domain using the University of Nottingham Managed Chemical Compound Collection. Hit optimisation gave compounds with enhanced potency against strains PAO1-L and PA14, evaluated using P. aeruginosa pqs-based QS bioreporter assays. Compound 40 (PAO1-L IC50 0.25 +/- 0.12 mu M, PA14 IC50 0.34 +/- 0.03 mu M) is one of the most potent PqsR antagonists reported showing significant inhibition of P. aeruginosa pyocyanin production and pqs system signaling in both planktonic cultures and biofilms. The co-crystal structure of 40 with the PqsR ligand binding domain revealed the specific binding interactions occurring between inhibitor and this key regulatory protein.
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