Uppsala University

About: Uppsala University is a education organization based out in Uppsala, Sweden. It is known for research contribution in the topics: Population & Gene. The organization has 36485 authors who have published 107509 publications receiving 4220668 citations. The organization is also known as: Uppsala universitet & uu.se.

Polar Molecular Surface Properties Predict the Intestinal Absorption of Drugs in Humans

Abstract: Purpose A theoretical method has been devised for prediction of drug absorption after oral administration to humans Methods Twenty structurally diverse model drugs, ranging from 03 to 100% absorbed, were investigated The compounds also displayed diversity in physicochemical properties such as lipophilicity, hydrogen bonding potential and molecular size The dynamic molecular surface properties of the compounds were calculated, taking into account their three-dimensional shape and flexibility Results An excellent sigmoidal relationship was established between the absorbed fraction after oral administration to humans (FA) and the dynamic polar molecular surface area (PSAd) (r2 = 094) The relationship was stronger than those obtained for more established predictors of drug absorption Drugs that are completely absorbed (FA > 90%) had a PSAd ≤ 60 A2 while drugs that are 140 A2 Conclusions The results indicate that PS Ad can be used to differentiate poorly absorbed drugs at an early stage of the drug discovery process

Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs

Abstract: Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not been developed. We report that Cre under control of the promoter of Pdgfrb (Pdgfrb-Cre) inactivates loxP-flanked genes in mouse HSCs with high efficiency. We used this system to delete the gene encoding α(v) integrin subunit because various α(v)-containing integrins have been suggested as central mediators of fibrosis in multiple organs. Such depletion protected mice from carbon tetrachloride-induced hepatic fibrosis, whereas global loss of β₃, β₅ or β₆ integrins or conditional loss of β₈ integrins in HSCs did not. We also found that Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of the α(v) integrin subunit using this system was protective in other models of organ fibrosis, including pulmonary and renal fibrosis. Pharmacological blockade of α(v)-containing integrins by a small molecule (CWHM 12) attenuated both liver and lung fibrosis, including in a therapeutic manner. These data identify a core pathway that regulates fibrosis and suggest that pharmacological targeting of all α(v) integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.

Constructing Organizations: The Example of Public Sector Reform

Abstract: Organizations are socially constructed phenomena. A crucial task for organizational research is to analyze how and why people construct organizations rather than other social forms. In this paper, it is argued that recent public-sector reforms can be interpreted as attempts at constructing organizations. Public-sector entities that could formerly be described as agents or arenas have been transformed into `more complete' organizations by installing or reinforcing local identity, hierarchy and rationality. This interpretation helps to explain important aspects of the reform process.