| 1. |
|
|
| 2. |
- Langefeld, Carl D., et al.
(författare)
-
Transancestral mapping and genetic load in systemic lupus erythematosus
- 2017
-
Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
- Croker, D. M., et al.
(författare)
-
Demonstrating the Influence of Solvent Choice and Crystallization Conditions on Phenacetin Crystal Habit and Particle Size Distribution
- 2015
-
Ingår i: Organic Process Research & Development. - Washinhton, USA : American Chemical Society (ACS). - 1083-6160 .- 1520-586X. ; 19:12, s. 1826-1836
-
Tidskriftsartikel (refereegranskat)abstract
- Phenacetin was used as a model pharmaceutical compound to investigate the impact of solvent choice and crystallization conditions on the crystal habit and size distribution of the final crystallized product. The crystal habit of phenacetin was explored using crash-cooling crystallization (kinetically controlled) and slow evaporative crystallization (thermodynamically controlled) in a wide range of organic solvents. In general, a variety of needle-type shapes (needles, rods, or blades) were recovered from fast-cooling crystallizations, in contrast to hexagonal blocks obtained from slow evaporative crystallizations. The solubility of phenacetin was measured in five solvents from 10-70 degrees C to allow for the design of larger-scale crystallization experiments. Supersaturation and the nucleation temperature were independently controlled in isothermal desupersaturation experiments to investigate the impact of each on crystal habit and size. The crystal size (needle cross-sectional area) decreased with increasing supersaturation because of higher nucleation rates at higher supersaturation, and elongated needles were recovered: Increasing the nucleation temperature resulted in the production of larger crystals with decreased needle aspect ratios. Antisolvent phenacetin crystallizations were developed for three solvent/antisolvent systems using four different antisolvent addition rates to simultaneously probe the crystal habit and size of the final product. In general, increasing the antisolvent addition rate, associated with increased rate of generation of supersaturation, resulted in the production of shorter needle crystals.
|
|
| 7. |
|
|
| 8. |
- O'Mahony, M. A., et al.
(författare)
-
Investigation into the mechanism of solution-mediated transformation from FI to FIII carbamazepine : The role of dissolution and the interaction between polymorph surfaces
- 2013
-
Ingår i: Crystal Growth and Design. - : American Chemical Society (ACS). - 1528-7505 .- 1528-7483. ; 13:5, s. 1861-1871
-
Tidskriftsartikel (refereegranskat)abstract
- The solution mediated polymorphic transformation (SMPT) of the pharmaceutical compound carbamazepine was investigated in ethanol. Bulk transformation experiments were performed by monitoring the solution concentration and polymorphic composition over time during the transformation from the metastable FI polymorph to the stable FIII polymorph for a variety of initial conditions. Microscopic techniques, single-crystal X-ray diffraction, and computational methods were used to analyze the transformation. The nucleating behavior of the stable FIII polymorph was a significant factor affecting the transformation time across the range of experiments. The surfaces of the metastable FI particles were responsible for the nucleation of FIII during the transformation. However, no specific lattice matching or epitaxy was conclusively identified. A modest amount of dissolution of the FI particles was found to favor the nucleation of FIII but where extensive dissolution or no significant dissolution occurred this had a negative effect on the nucleation of FIII.
|
|
| 9. |
- O'Mahony, M. A., et al.
(författare)
-
Measuring the solubility of a quickly transforming metastable polymorph of carbamazepine
- 2013
-
Ingår i: Organic Process Research and Development. - : American Chemical Society (ACS). - 1083-6160 .- 1520-586X. ; 17:3, s. 512-518
-
Tidskriftsartikel (refereegranskat)abstract
- The solubility of the stable FIII polymorph of the pharmaceutical compound carbamazepine was measured by determining its solubility gravimetrically in ethanol and methanol. Where the metastable FI polymorph was suspended in a solution of ethanol, the stable FIII polymorph nucleated immediately, initiating a solution-mediated transformation from FI to FIII. This meant that the FI polymorph was not in thermodynamic equilibrium with the solution as FI was continually dissolving while FIII was growing. We show that the solubility of FI can be accurately measured by in situ microscopy using an adaption of the bracketing method, and the results show that the solubility is close to but higher than the maximum solution concentration reached during the solution mediated transformation from FI to FIII carbamazepine in both solvents. The technique demonstrates a relatively simple and robust method for determining the solubility of a metastable crystalline phase which transforms quickly in solution.
|
|
| 10. |
- O'Mahony, M., et al.
(författare)
-
Investigating the dissolution of the metastable triclinic polymorph of carbamazepine using in situ microscopy
- 2014
-
Ingår i: CrystEngComm. - Royal Society of Chemistry (RSC)) : Royal Society of Chemistry (RSC). - 1466-8033. ; 16:20, s. 4133-4141
-
Tidskriftsartikel (refereegranskat)abstract
- Despite a tendency to undergo solution-mediated polymorphic transformation, the dissolution behaviour of the metastable FI (triclinic) polymorph of the pharmaceutical compound carbamazepine (CBZ) was investigated using in situ optical microscopy. Experiments were performed at an undersaturation where single crystals of the metastable FI polymorph dissolved. Dissolution in different solvents was investigated at a constant undersaturation. Separately the sublimation of FI was examined and additionally the dissolution was observed at undersaturations where the more stable FIII polymorph crystallized. The results show that both the dissolution and sublimation of FI occur primarily in the direction of the a-axis of the FI crystal structure where the CBZ molecules are found to stack in this direction. The order for the dissolution rate of FI was acetonitrile ≥ methanol > ethanol. The order of the dissolution rates in each of the solvents is inversely correlated to the viscosity and the binding energy of the solvents with the (100) surface of FI in each of the solvents. This suggests that the rate determining step for the dissolution may be either the diffusion or the detachment of CBZ molecules from the surface of FI. A notable difference in dissolution behaviour is also observed at undersaturations where the more stable FIII polymorph nucleates and grows.
|
|
