Alcohol use disorder (AUD) is one of the most common, but still poorly treated, psychiatric conditions.  https://www.selleckchem.com/products/nms-p937-nms1286937.html  Developing new treatments requires a better understanding of the aetiology of symptoms and evaluation of novel therapeutic targets in preclinical studies. Recent developments in our understanding of the reinforcement-based cognitive biases (RBCBs) that contribute to the development of AUD and its treatment offer new opportunities for both clinical and preclinical research. In this review, we first briefly describe psychological and cognitive theories that involve various aspects of reinforcement sensitivity in the development, maintenance, and recurrence of alcohol addiction. Furthermore, in separate sections, we describe studies investigating RBCBs and their neural, neurochemical, and pharmacological correlates, and we discuss possible interactions between RBCBs and trajectories of AUD. Finally, we describe how recent translational studies using state-of-the-art animal models can facilitate our understanding of the role of reinforcement sensitivity and RBCBs in various aspects of AUD.The heteropolysaccharide xylan is a valuable source of sustainable chemicals and materials from renewable biomass sources. A complete hydrolysis of this major hemicellulose component requires a diverse set of enzymes including endo-β-1,4-xylanases, β-xylosidases, acetylxylan esterases, α-l-arabinofuranosidases, and α-glucuronidases. Notably, the most studied xylanases from glycoside hydrolase family 11 (GH11) have exclusively been endo-β-1,4- and β-1,3-xylanases. However, a recent analysis of a metatranscriptome library from a microbial lignocellulose community revealed GH11 enzymes capable of releasing solely xylobiose from xylan. Although initial biochemical studies clearly indicated their xylobiohydrolase mode of action, the structural features that drive this new activity still remained unclear. It was also not clear whether the enzymes acted on the reducing or nonreducing end of the substrate. Here, we solved the crystal structure of MetXyn11 in the apo and xylobiose-bound forms. The structure of MetXyn11 revealed the molecular features that explain the observed pattern on xylooligosaccharides released by this nonreducing end xylobiohydrolase.Mechanism-based kinetic models are rigorous tools to analyze enzymatic reactions, but their extension to actual conditions of the biocatalytic synthesis can be difficult. Here, we demonstrate (mechanistic-empirical) hybrid modeling for systematic optimization of the sucrose phosphorylase-catalyzed glycosylation of glycerol from sucrose, to synthesize the cosmetic ingredient α-glucosyl glycerol (GG). The empirical model part was developed to capture nonspecific effects of high sucrose concentrations (up to 1.5 M) on microscopic steps of the enzymatic trans-glycosylation mechanism. Based on verified predictions of the enzyme performance under initial rate conditions (Level 1), the hybrid model was expanded by microscopic terms of the reverse reaction to account for the full-time course of GG synthesis (Level 2). Lastly (Level 3), the application of the hybrid model for comprehensive window-of-operation analysis and constrained optimization of the GG production (~250 g/L) was demonstrated. Using two candidate sucrose phosphorylases (from Leuconostoc mesenteroides and Bifidobacterium adolescentis), we reveal the hybrid model as a powerful tool of "process decision making" to guide rational selection of the best-suited enzyme catalyst. Our study exemplifies a closing of the gap between enzyme kinetic models considered for mechanistic research and applicable in technologically relevant reaction conditions; and it highlights the important benefit thus realizable for biocatalytic process development.
  P-glycoprotein (P-gp) exhibits a broad specificity for substrates and affects their pharmacokinetics, especially intestinal absorption. However, it is challenging to predict in vivo P-gp mediated drug-drug interaction (DDI) and nonlinear absorption in the pre-clinical stage. The purpose of this study is to evaluate the use of hMDR1-MAC mice carrying human P-gp and lacking their own murine P-gp to quantitatively predict human P-gp mediated DDI and nonlinear absorption.
 
  The P-gp substrates (aliskiren, betrixaban, celiprolol, digoxin, fexofenadine, and talinolol) were administered orally to wild-type, Mdr1a/b-KO, and hMDR1-MAC mice and their plasma concentrations were measured. We calculated the ratio of AUC (AUCR) in mice (AUC
  /AUC
  or AUC
  /AUC
  ) estimated as attributable to complete P-gp inhibition and the human AUCR with and without P-gp inhibitor administration. The correlations of AUCR
  with AUCR
  and AUCR
  were investigated. For aliskiren, betrixaban, and celiprolol, the K
  and V
  values for P-gp in hMDR1-MAC mice and humans were optimized from different dosing studies using GastroPlus. The correlations of K
  and V
  for P-gp between human and hMDR1-MAC mice were investigated.
 
  A better correlation between AUCR
  and AUCR
  (R
  = 0.88) was observed. Moreover, good relationships of K
  (R
  = 1.00) and V
  (R
  = 0.98) for P-gp between humans and hMDR1-MAC mice were observed.
 
  These results suggest that P-gp mediated DDI and nonlinear absorption can be predicted using hMDR1-MAC mice. These mice are a useful in vivo tool for quantitatively predicting P-gp mediated disposition in drug discovery and development.
 These results suggest that P-gp mediated DDI and nonlinear absorption can be predicted using hMDR1-MAC mice. These mice are a useful in vivo tool for quantitatively predicting P-gp mediated disposition in drug discovery and development.
  Here we report long-term results after stereotactic radiosurgery (SRS) with Gamma Knife (GKRS) for Cushing disease. We further evaluated the potential role of the biological effective dose (BED) in the cure of this disease.
 
  A retrospective review of a prospectively collected database (n = 26) was undertaken at Lille University Hospital, France. The mean follow-up period was 66 months (median 80, range 19–108). The mean marginal prescribed dose was 28.5 Gy (median 27.5, range 24–35) and the mean BED was 208.5 Gy2.47 (median 228.1, range 160–248). We divided patients with endocrine remission into a high BED group (160–228 Gy2.47, n = 6) and a low BED group (228–248 Gy2.47, n = 12).
 
  Eighteen (69.2%) patients had endocrine remission in the absence of any pharmacological therapy after a mean of 36 months (median 24, range 6–98). The actuarial probability of endocrine remission was 59% at 3 years and 77.6% at 7 years, which remained stable up to 10 years.