| 1. |
- Aahlin, Kristofer, et al.
(författare)
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Preparation of 1-(4-(5-amino-6-(oxazolo[4,5-c]pyridin-2-yl)pyrazin-2-yl)benzoyl)piperazine derivatives as glycogen synthase kinase 3 inhibitors.
- 2011
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Patent (populärvet., debatt m.m.)abstract
- Title compds. I [R1 = H or Me], and their pharmaceutically acceptable salts, are prepd. and disclosed as glycogen synthase kinase 3 (GSK3) inhibitors. Thus, e.g., II was prepd. by cyclization of 3-amino-N-(4-hydroxypyridin-3-yl)pyrazine-2-carboxamide (prepn. given) to get intermediate 3-(oxazolo[4,5-c]pyridin-2-yl)pyrazin-2-amine, which underwent bromination followed by Suzuki reaction with (4-methylpiperazin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone. Compds. of the invention were tested for their selective inhibitory activity of GSK3β, e.g., II exhibited Ki value of 2.3 nM. The invention compds. are useful for the treatment of cognitive disorders, diabetes, cancer, etc. [on SciFinder(R)]
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| 2. |
- Burrows, Jeremy, et al.
(författare)
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Preparation of imidazolyl-pyrimidine derivatives as GSK3 inhibitors.
- 2008
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Patent (populärvet., debatt m.m.)abstract
- Title compds. I [R1 = sulfamoyl, carbamoyl or -R5-R6 and N linked (un)substituted 4- to 7-membered satd. ring which optionally contains an addnl. N, O or S; R5 = O, C(O), C(O)O, C(O)NH, etc., R6 = (un)substituted alkyl, carbocyclyl or heterocyclyl; at least one of X1, X2, X3 and X4 = N, the other three independently = N or C(R9), wherein R9 = H, halo, CN, OH, NH2, alkyl or alkoxy; provided that not more than two of X1, X2, X3 or X4 = N; R2 = halo or CN; R3 = Me, (un)substituted 3-tetrahydropyranyl or 4-tetrahydropyranyl; R4 = H, halo, CN or (un)substituted alkyl], and their pharmaceutically acceptable salts, are prepd. and disclosed as glycogen synthase kinase 3 (GSK3) inhibitors. Thus, e.g., II was prepd. by amidation of 3,5-dichloro-2-pyridinecarboxylic acid with piperidine followed by coupling reaction with 5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine, which was prepd. starting from 5-methyl-4-aminoisoxazole and tetrahydro-2H-pyran-4-one in 5 steps. All the exemplar compds. were evaluated for their GSK3 inhibitory activity in GSK3 inhibition assays with typical Ki values ranging from 0.001 to 10,000 nM. For instance, II exhibited a Ki value of 7 nM. As inhibitors of GSK3, I should prove useful in treatment and prevention of GSK3 assocd. diseases including Alzheimer's disease. [on SciFinder(R)]
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| 3. |
- Huerta, Fernando, et al.
(författare)
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Machine Learning to Reduce Reaction Optimization Lead Time : Proof of Concept with Suzuki, Negishi and Buchwald-Hartwig Cross-Coupling Reactions
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- To date, optimizing reactions let alone predicting the outcome (yield) of known reactions requires expert knowledge and can at best be obtained by computationally complex and expensive modelling. The present investigation tests if machine learning represents a viable approach for predicting a model reaction outcome that could be put into daily production. A prerequisite was replacing advanced scripting techniques with a more approachable data science platform such as Knime®. The Palladium catalyzed Suzuki-Miyaura, Negishi and Buchwald-Hartwig reactions were selected for a classification model of high/low yielding outcome combined with a selection of reaction conditions stemming from a commercial database. Here we present preliminary results of a random forest-based classification model using readily calculated standard medicinal chemistry descriptors from substrates and products yielded high ROC AUC of up to 96%. The descriptors used in the model do not convey anything about the reactivity, only 1D- and 2D- structural information, and performed equal or better than fingerprints, both in terms of prediction and computational requirements. One of the major challenges was the quality of the data and its subsequent curation.
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| 4. |
- Mahajan, Anubha, et al.
(författare)
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:5, s. 560-572
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Tidskriftsartikel (refereegranskat)abstract
- We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background. Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.
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| 5. |
- Proletov, Ian, et al.
(författare)
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Primary and secondary glomerulonephritides 1.
- 2014
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Ingår i: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. - : Oxford University Press (OUP). - 1460-2385. ; 29 Suppl 3:May, s. 186-200
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Tidskriftsartikel (refereegranskat)
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| 6. |
- Sampson, Joshua N., et al.
(författare)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 7. |
- Sanchez Giralt, J. A., et al.
(författare)
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Clinical validation of a capnodynamic method for measuring end-expiratory lung volume in critically ill patients
- 2024
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Ingår i: Critical Care. - : BioMed Central (BMC). - 1364-8535 .- 1466-609X. ; 28:1
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Tidskriftsartikel (refereegranskat)abstract
- RationaleEnd-expiratory lung volume (EELV) is reduced in mechanically ventilated patients, especially in pathologic conditions. The resulting heterogeneous distribution of ventilation increases the risk for ventilation induced lung injury. Clinical measurement of EELV however, remains difficult.ObjectiveValidation of a novel continuous capnodynamic method based on expired carbon dioxide (CO2) kinetics for measuring EELV in mechanically ventilated critically-ill patients.MethodsProspective study of mechanically ventilated patients scheduled for a diagnostic computed tomography exploration. Comparisons were made between absolute and corrected EELVCO2 values, the latter accounting for the amount of CO2 dissolved in lung tissue, with the reference EELV measured by computed tomography (EELVCT). Uncorrected and corrected EELVCO2 was compared with total CT volume (density compartments between − 1000 and 0 Hounsfield units (HU) and functional CT volume, including density compartments of − 1000 to − 200HU eliminating regions of increased shunt. We used comparative statistics including correlations and measurement of accuracy and precision by the Bland Altman method.Measurements and main resultsOf the 46 patients included in the final analysis, 25 had a diagnosis of ARDS (24 of which COVID-19). Both EELVCT and EELVCO2 were significantly reduced (39 and 40% respectively) when compared with theoretical values of functional residual capacity (p < 0.0001). Uncorrected EELVCO2 tended to overestimate EELVCT with a correlation r2 0.58; Bias − 285 and limits of agreement (LoA) (+ 513 to − 1083; 95% CI) ml. Agreement improved for the corrected EELVCO2 to a Bias of − 23 and LoA of (+ 763 to − 716; 95% CI) ml. The best agreement of the method was obtained by comparison of corrected EELVCO2 with functional EELVCT with a r2 of 0.59; Bias − 2.75 (+ 755 to − 761; 95% CI) ml. We did not observe major differences in the performance of the method between ARDS (most of them COVID related) and non-ARDS patients.ConclusionIn this first validation in critically ill patients, the capnodynamic method provided good estimates of both total and functional EELV. Bias improved after correcting EELVCO2 for extra-alveolar CO2 content when compared with CT estimated volume. If confirmed in further validations EELVCO2 may become an attractive monitoring option for continuously monitor EELV in critically ill mechanically ventilated patients.Trial registration: clinicaltrials.gov (NCT04045262).
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| 8. |
- Villa-Islas, Viridiana, et al.
(författare)
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Demographic history and genetic structure in pre-Hispanic Central Mexico
- 2023
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 380:6645
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Tidskriftsartikel (refereegranskat)abstract
- Aridoamerica and Mesoamerica are two distinct cultural areas in northern and central Mexico, respectively, that hosted numerous pre-Hispanic civilizations between 2500 BCE and 1521 CE. The division between these regions shifted southward because of severe droughts ~1100 years ago, which allegedly drove a population replacement in central Mexico by Aridoamerican peoples. In this study, we present shotgun genome-wide data from 12 individuals and 27 mitochondrial genomes from eight pre-Hispanic archaeological sites across Mexico, including two at the shifting border of Aridoamerica and Mesoamerica. We find population continuity that spans the climate change episode and a broad preservation of the genetic structure across present-day Mexico for the past 2300 years. Lastly, we identify a contribution to pre-Hispanic populations of northern and central Mexico from two ancient unsampled “ghost” populations.
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