The etiology of depression is still poorly understood, but two major causative hypotheses have been put forth: the monoamine deficiency and the stress hypotheses of depression. We evaluate these ...hypotheses using animal models of endogenous depression and chronic stress. The endogenously depressed rat and its control strain were developed by bidirectional selective breeding from the Wistar-Kyoto (WKY) rat, an accepted model of major depressive disorder (MDD). The WKY More Immobile (WMI) substrain shows high immobility/despair-like behavior in the forced swim test (FST), while the control substrain, WKY Less Immobile (WLI), shows no depressive behavior in the FST. Chronic stress responses were investigated by using Brown Norway, Fischer 344, Lewis and WKY, genetically and behaviorally distinct strains of rats. Animals were either not stressed (NS) or exposed to chronic restraint stress (CRS). Genome-wide microarray analyses identified differentially expressed genes in hippocampi and amygdalae of the endogenous depression and the chronic stress models. No significant difference was observed in the expression of monoaminergic transmission-related genes in either model. Furthermore, very few genes showed overlapping changes in the WMI vs WLI and CRS vs NS comparisons, strongly suggesting divergence between endogenous depressive behavior- and chronic stress-related molecular mechanisms. Taken together, these results posit that although chronic stress may induce depressive behavior, its molecular underpinnings differ from those of endogenous depression in animals and possibly in humans, suggesting the need for different treatments. The identification of novel endogenous depression-related and chronic stress response genes suggests that unexplored molecular mechanisms could be targeted for the development of novel therapeutic agents.
N,N-Bis-(2,6-diisopropylphenyl)dihydroimidazolium chloride with palladium(II) acetate (2 mol %) was used as catalyst, without added base, to efficiently cross couple aryl, vinyl, and alkyl boronates ...and boronic acids with aryldiazonium tetrafluoroborate substrates. The reactions were performed at 0 °C or rt, giving product in 2 to 4 h with 80 to 90% yields for isolated materials. Diazonium ions, formed in situ, also cross couple under these conditions.
An objective, laboratory-based diagnostic tool could increase the diagnostic accuracy of major depressive disorders (MDDs), identify factors that characterize patients and promote individualized ...therapy. The goal of this study was to assess a blood-based biomarker panel, which showed promise in adolescents with MDD, in adult primary care patients with MDD and age-, gender- and race-matched nondepressed (ND) controls. Patients with MDD received cognitive behavioral therapy (CBT) and clinical assessment using self-reported depression with the Patient Health Questionnaire-9 (PHQ-9). The measures, including blood RNA collection, were obtained before and after 18 weeks of CBT. Blood transcript levels of nine markers of ADCY3, DGKA, FAM46A, IGSF4A/CADM1, KIAA1539, MARCKS, PSME1, RAPH1 and TLR7, differed significantly between participants with MDD (N=32) and ND controls (N=32) at baseline (q< 0.05). Abundance of the DGKA, KIAA1539 and RAPH1 transcripts remained significantly different between subjects with MDD and ND controls even after post-CBT remission (defined as PHQ-9 <5). The ROC area under the curve for these transcripts demonstrated high discriminative ability between MDD and ND participants, regardless of their current clinical status. Before CBT, significant co-expression network of specific transcripts existed in MDD subjects who subsequently remitted in response to CBT, but not in those who remained depressed. Thus, blood levels of different transcript panels may identify the depressed from the nondepressed among primary care patients, during a depressive episode or in remission, or follow and predict response to CBT in depressed individuals.
Early-onset major depressive disorder (MDD) is a serious and prevalent psychiatric illness in adolescents and young adults. Current treatments are not optimally effective. Biological markers of ...early-onset MDD could increase diagnostic specificity, but no such biomarker exists. Our innovative approach to biomarker discovery for early-onset MDD combined results from genome-wide transcriptomic profiles in the blood of two animal models of depression, representing the genetic and the environmental, stress-related, etiology of MDD. We carried out unbiased analyses of this combined set of 26 candidate blood transcriptomic markers in a sample of 15-19-year-old subjects with MDD (N=14) and subjects with no disorder (ND, N=14). A panel of 11 blood markers differentiated participants with early-onset MDD from the ND group. Additionally, a separate but partially overlapping panel of 18 transcripts distinguished subjects with MDD with or without comorbid anxiety. Four transcripts, discovered from the chronic stress animal model, correlated with maltreatment scores in youths. These pilot data suggest that our approach can lead to clinically valid diagnostic panels of blood transcripts for early-onset MDD, which could reduce diagnostic heterogeneity in this population and has the potential to advance individualized treatment strategies.
Chiral N‐heterocyclic carbene ligands based on 2.2paracyclophanes form complexes with rhodium. These catalysts can be used in the high‐yielding and enantioselective asymmetric conjugate addition of ...arylboron compounds to cyclic and acyclic enones (see scheme).
Catalytic asymmetric allylic oxidation of cyclic olefins ocurrs for the first time in very high (94−99% ee) enantioselectivity using copper(I) complexes of malonyl derived bisoxazolines and ...tert-butyl p-nitroperbenzoate giving allyl benzoates in moderate yield. The copper complex, 15 mol %, was used in acetonitrile at −20 °C over an extended period, 5−12 d, with excess olefin together with one equivalent of perester. The S-esters were generated in accord with the model proposed previously for the (S,S)-bisoxazoline ligand. An η2 intermediate was ruled out using low-temperature 13C NMR with the complex in the presence of olefin.
Catalyst formed from N,N-bis(2,6-diisopropylphenyl)dihydroimidazolium chloride and palladium(II) acetate (2 mol %) was used, without added base, to efficiently produce Heck coupled products with ...olefins and aryl diazonium tetrafluoroborate substrates. The reactions were performed at room temperature, giving product in 2−4 h with 80−90% yields for isolated materials. Diazonium ions, formed in situ directly from anilines, also couple under these conditions.
The boron enolate of pyrone 2 undergoes asymmetric aldol reactions with aldehydes to give protected anti 1,2-diols 3. The pyrone is readily available from trans stilbene using asymmetric ...dihydroxylation. Yields for the aldol reaction range from 62 to 92% and the selectivities from 6:1 to >20:1 for the anti isomers. Protection and hydrogenolysis of the products can be used to remove the pyrone, giving differentially protected diol intermediates 12 that are amenable to multistep synthesis.
Bulky phenanthracenyl imidazolium-derived carbene ligands were investigated for copper-free Sonogashira coupling with terminal acetylenes. Aryl bromides and iodides gave coupled products in excellent ...yields from the Pd(PPh3)2Cl2 complex with potassium t-butoxide and 18-crown-6 in THF. A remarkable dependence on the size of the ligand was found. The highest yields were obtained with the bulky 2,9-dicyclohexyl-10-phenanthryl ligand 5.
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