Visiblelightmediated copper photocatalysis for organic syntheses

Drug dosing in encephalopathic neonates treated with therapeutic hypothermia is challenging; exposure is dependent on body size and maturation but can also be influenced by factors related to disease and treatment. A better understanding of underlying pharmacokinetic principles is essential to guide drug dosing in this population. The prospective multicenter cohort study PharmaCool was designed to investigate the pharmacokinetics of commonly used drugs in neonatal encephalopathy. In the present study, all data obtained in the PharmaCool study were combined to study the structural system specific effects of body size, maturation, recovery of organ function, and temperature on drug clearance using nonlinear mixed effects modeling. Data collected during the first 5 days of life from 192 neonates treated with therapeutic hypothermia were included. An integrated population pharmacokinetic model of seven drugs (morphine, midazolam, lidocaine, phenobarbital, amoxicillin, gentamicin, and benzylpenicillin) and five metabolites (morphine-3-glucuronide, morphine-6-glucuronide, 1-hydroxymidazolam, hydroxymidazolam glucuronide, and monoethylglycylxylidide) was successfully developed based on previously developed models for the individual drugs. For all compounds, body size was related to clearance using allometric relationships and maturation was described with gestational age in a fixed sigmoidal Hill equation. Organ recovery after birth was incorporated using postnatal age. Clearance increased by 1.23%/hours of life (95% confidence interval (CI) 1.03-1.43) and by 0.54%/hours of life (95% CI 0.371-0.750) for high and intermediate clearance compounds, respectively. Therapeutic hypothermia reduced clearance of intermediate clearance compounds only, by 6.83%/°C (95% CI 5.16%/°C-8.34%/°C). This integrated model can be used to facilitate drug dosing and future pharmacokinetic studies in this population.Deregulation of GSK-3β is strongly implicated in a variety of serious brain conditions, such as Alzheimer disease, bipolar disorder and schizophrenia. To understand how GSK-3β becomes dysregulated in these conditions, it is important to understand its physiological functions in the central nervous system. In this context, GSK-3β plays a role in the induction of NMDA receptor-dependent long-term depression (LTD) and several substrates for GSK-3β have been identified in this form of synaptic plasticity, including KLC-2, PSD-95 and tau. Stabilization of NMDA receptors at synapses has also been shown to involve GSK-3β, but the substrates involved are currently unknown. Recent work has identified phosphatidylinositol 4 kinase type IIα (PI4KIIα) as a neuronal GSK-3β substrate that can potentially regulate the surface expression of AMPA receptors. In the present study, we investigated the synaptic role of PI4KIIα in organotypic rat hippocampal slices. We found that knockdown of PI4KIIα has no effect on synaptic AMPA receptor-mediated synaptic transmission but substantially reduces NMDA receptor-mediated synaptic transmission. Furthermore, the ability of the selective GSK-3 inhibitor, CT99021, to reduce the amplitude of NMDA receptor-mediated currents was occluded in shRNA-PI4KIIα transfected neurons. The effects of knocking down PI4KIIα were fully rescued by a shRNA-resistant wild-type construct, but not by a mutant construct that cannot be phosphorylated by GSK-3β. These data suggest that GSK-3β phosphorylates PI4KIIα to stabilize NMDA receptors at the synapse.Rising temperatures are leading to permafrost thaw over vast areas of the northern hemisphere. In the Canadian Arctic, permafrost degradation is causing significant changes in surface water quality due to the release of solutes that can alter conductivity, water clarity, and nutrient levels. For this study, we examined how changes in water quality associated with permafrost thaw might impact zooplankton, a group of organisms that play an important role in the food web of Arctic lakes. We conducted a biological and water quality survey of 37 lakes in the Mackenzie Delta region of Canada's Northwest Territories. We then used this dataset to develop models linking variation in the abundance, diversity, and evenness of zooplankton communities to physicochemical, biological, and spatial variables. see more Subsequently, we used these models to predict how zooplankton communities might respond as water quality is altered by permafrost thaw. Our models explained 47%, 68%, and 69% of the variation in zooplankton abundance, diversity, and evenness, respectively. Importantly, the most parsimonious models always included variables affected by permafrost thaw, such as calcium and conductivity. Predictions based on our models suggest significant increases in zooplankton abundance (1.6-3.6-fold) and decreases in diversity (1.2-1.7-fold) and evenness (1.1-1.4-fold) in response to water quality changes associated with permafrost thaw. These changes are in line with those described for significant perturbations such as eutrophication, acidification, and the introduction of exotic species such as the spiny water flea (Bythotrephes). Given their important role in aquatic food webs, we expect these changes in zooplankton communities will have ramifications for organisms at higher (fish) and lower (phytoplankton) trophic positions in Arctic lakes.In a high-yield one-pot synthesis, the reactions of [Cp*M(η 5 -P 5 )] (M = Fe ( 1 ), Ru ( 2 )) with I 2 resulted in the selective formation of [Cp*MP 6 I 6 ] + salts ( 3 , 4 ). The products comprise unprecedented all-cis tripodal triphosphino-cyclotriphosphine ligands. The iodination of [Cp*Fe(η 5 -As 5 )] ( 6 ) gave, in addition to [Fe(CH 3 CN) 6 ] 2+ salts of the rare [As 6 I 8 ] 2- (in 7 ) and [As 4 I 14 ] 2-- (in 8 ) anions, the first di-cationic Fe-As triple decker complex [(Cp*Fe) 2 (μ,η 5 5 -As 5 )][As 6 I 8 ] ( 9 ). Instead, the iodination of [Cp*Ru(η 5 -As 5 )] ( 10 ) did not result in the full cleavage of the M-As bonds, but, instead, a number of dinuclear complexes were obtained [(Cp*Ru) 2 (μ,η 5 5 -As 5 )][As 6 I 8 ] 0.5 ( 11 ) represents the first Ru-As 5 triple decker complex, thus completing the series of monocationic complexes [(Cp R M) 2 (μ,η 5 5 -E 5 )] + (M = Fe, Ru; E = P, As). [(Cp*Ru) 2 As 8 I 6 ] ( 12 ) crystallizing as a racemic mixture of both enantiomers, while [(Cp*Ru) 2 As 4 I 4 ] ( 13 ) crystallizes as a symmetric and an asymmetric isomer and features a unique tetramer of AsI arsinidene units as a middle deck.