A ruthenium-catalyzed, redox neutral C−O bond cleavage of 2-aryloxy-1-arylethanols was developed that yields cleavage products in 62−98% isolated yield. This reaction is applicable to breaking the ...key ethereal bond found in lignin-related polymers. The bond transformation proceeds by a tandem dehydrogenation/reductive ether cleavage. Initial mechanistic investigations indicate that the ether cleavage is most likely an organometallic C−O activation. A catalytic depolymerization of a lignin-related polymer quantitatively yields the corresponding monomer with no added reagent.
Elevations in peripheral inflammatory markers have been reported in patients with psychosis. Whether this represents an inflammatory process defined by individual or subgroups of markers is unclear. ...Further, relationships between peripheral inflammatory marker elevations and brain structure, cognition, and clinical features of psychosis remain unclear. We hypothesized that a pattern of plasma inflammatory markers, and an inflammatory subtype established from this pattern, would be elevated across the psychosis spectrum and associated with cognition and brain structural alterations. Clinically stable psychosis probands (Schizophrenia spectrum, n = 79; Psychotic Bipolar disorder, n = 61) and matched healthy controls (HC, n = 60) were assessed for 15 peripheral inflammatory markers, cortical thickness, subcortical volume, cognition, and symptoms. A combination of unsupervised exploratory factor analysis and hierarchical clustering was used to identify inflammation subtypes. Levels of IL6, TNFα, VEGF, and CRP were significantly higher in psychosis probands compared to HCs, and there were marker-specific differences when comparing diagnostic groups. Individual and/or inflammatory marker patterns were associated with neuroimaging, cognition, and symptom measures. A higher inflammation subgroup was defined by elevations in a group of 7 markers in 36% of Probands and 20% of HCs. Probands in the elevated inflammatory marker group performed significantly worse on cognitive measures of visuo-spatial working memory and response inhibition, displayed elevated hippocampal, amygdala, putamen and thalamus volumes, and evidence of gray matter thickening compared to the proband group with low inflammatory marker levels. These findings specify the nature of peripheral inflammatory marker alterations in psychotic disorders and establish clinical, neurocognitive and neuroanatomic associations with increased inflammatory activation in psychosis. The identification of a specific subgroup of patients with inflammatory alteration provides a potential means for targeting treatment with anti-inflammatory medications.
Risperidone is a second-generation antipsychotic drug metabolized to an active metabolite, 9-hydroxyrisperidone, primarily by cytochrome P450 (CYP) 2D6 and to a lesser extent by CYP3A4. The extent to ...which drug metabolism genetics impacts risperidone and 9-hydroxyrisperidone exposure has not been clarified.
A systematic review and meta-analysis evaluated the impact of genetically defined CYP2D6 function on risperidone pharmacokinetics applying a standardized genotype-phenotype translation system.
A comprehensive electronic database search identified studies reporting relationships between genetically determined CYP2D6 metabolism and risperidone pharmacokinetic properties. The exposure of risperidone or active moiety (risperidone + 9-hydroxyrisperidone) was measured by dose-adjusted steady-state serum or plasma concentration or area under the concentration-time curve as primary outcomes. Subjects were assigned to CYP2D6 poor metabolizer, intermediate metabolizer, normal metabolizer, or ultrarapid metabolizer groups using a standardized genotype-phenotype translation method. Effect sizes between groups were pooled and stratified by single or multiple dosing regimens.
A total of 15 studies involving 2125 adult subjects were included in the meta-analysis. Following multiple-dose oral administration, compared with CYP2D6 normal metabolizers, the risperidone dose-adjusted steady-state serum/plasma concentration was 2.35-fold higher in intermediate metabolizers (95% confidence interval CI 1.77-3.13, p<0.0001) and 6.20-fold higher in poor metabolizers (95% CI 5.05-7.62, p<0.0001); the active moiety dose-adjusted steady-state concentration was 1.18-fold higher in intermediate metabolizers (95% CI 1.11-1.25, p<0.0001) and 1.44-fold higher in poor metabolizers (95% CI 1.23-1.69, p<0.0001). Higher area under the concentration-time curve of risperidone and active moiety was also found in single-dose studies.
Genetically defined impaired CYP2D6 activity is associated with increased exposure of both risperidone and risperidone + 9-hydroxyrisperidone in adults receiving oral formulations. Additional studies are needed to quantify the clinical impact of these relationships.
Identifying genetic contributors to cognitive impairments in psychosis-spectrum disorders can advance understanding of disease pathophysiology. Although CNS medications are known to affect cognitive ...performance, they are often not accounted for in genetic association studies. In this study, we performed a genome-wide association study (GWAS) of global cognitive performance, measured as composite z-scores from the Brief Assessment of Cognition in Schizophrenia (BACS), in persons with psychotic disorders and controls (N = 817; 682 cases and 135 controls) from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Analyses accounting for anticholinergic exposures from both psychiatric and non-psychiatric medications revealed five significantly associated variants located at the chromosome 3p21.1 locus, with the top SNP rs1076425 in the inter-alpha-trypsin inhibitor heavy chain 1 (ITIH1) gene (P = 3.25×E-9). The inclusion of anticholinergic burden improved association models (P < 0.001) and the number of significant SNPs identified. The effect sizes and direction of effect of the top variants remained consistent when investigating findings within individuals receiving specific antipsychotic drugs and after accounting for antipsychotic dose. These associations were replicated in a separate study sample of untreated first-episode psychosis. The chromosome 3p21.1 locus was previously reported to have association with the risk for psychotic disorders and cognitive performance in healthy individuals. Our findings suggest that this region may be a psychosis risk locus that is associated with cognitive mechanisms. Our data highlight the general point that the inclusion of medication exposure information may improve the detection of gene-cognition associations in psychiatric genetic research.
In noisy environments, listeners tend to hear a speaker's voice yet struggle to understand what is said. The most effective way to improve intelligibility in such conditions is to watch the speaker's ...mouth movements. Here we identify the neural networks that distinguish understanding from merely hearing speech, and determine how the brain applies visual information to improve intelligibility. Using functional magnetic resonance imaging, we show that understanding speech-in-noise is supported by a network of brain areas including the left superior parietal lobule, the motor/premotor cortex, and the left anterior superior temporal sulcus (STS), a likely apex of the acoustic processing hierarchy. Multisensory integration likely improves comprehension through improved communication between the left temporal–occipital boundary, the left medial-temporal lobe, and the left STS. This demonstrates how the brain uses information from multiple modalities to improve speech comprehension in naturalistic, acoustically adverse conditions.
Optimizing antipsychotic pharmacotherapy is often challenging due to significant variability in effectiveness and tolerability. Genetic factors influencing pharmacokinetics and pharmacodynamics may ...contribute to some of this variability. Research studies have characterized these pharmacogenetic relationships, and some genetic markers are now available as clinical tests. These advances in pharmacogenetics research and test availability have great potential to improve clinical outcomes and quality of life in psychiatric patients. For clinicians considering using pharmacogenetics, it is important to understand the clinical implications and also the limitations of markers included in currently available tests. This review focuses on pharmacokinetic and pharmacodynamic gene variants that are currently available in commercial genetic testing panels. Associations of these variants with clinical efficacy and adverse effects, as well as other clinical implications, in antipsychotic pharmacotherapy are discussed.
While ZnO has excellent electrical properties, it has not been widely used for dye-sensitized solar cells, in part because ZnO is chemically less stable than widely used TiO2. The functional groups ...typically used for surface passivation and for attaching dye molecules either bind weakly or etch the ZnO surface. We have compared the formation of molecular layers from alkane molecules with terminal carboxylic acid, alcohol, amine, phosphonic acid, or thiol functional groups on single-crystal zinc oxide (101̅0) surfaces. Atomic force microscopy (AFM) images show that alkyl carboxylic acids etch the surface whereas alkyl amine and alkyl alcohols bind only weakly on the ZnO(101̅0) surface. Phosphonic acid-terminated molecules were found to bind to the surface in a heterogeneous manner, forming clusters of molecules. Alkanethiols were found to bind to the surface, forming highly uniform monolayers with some etching detected after long immersion times in an alkanethiol solution. Monolayers of hexadecylphosphonic acid and octadecanethiol were further analyzed by Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), and electrochemical measurements. AFM scratching shows that thiols were bound strongly to the ZnO surface, suggesting the formation of strong Zn–S covalent bonds. Surprisingly, the tridentate phosphonic acids adhered much more weakly than the monodentate thiol. The influence of organic grafting on the charge transfer to ZnO was studied by time-resolved surface photovoltage measurements and electrochemical impedance measurements. Our results show that the grafting of thiols to ZnO leads to robust surfaces and reduces the surface band bending due to midgap surface states.
To reduce stimulus transduction artifacts in EEG while using insert earphones.
Reference Equivalent Threshold SPLs were assessed for Etymotic ER-4B earphones in 15 volunteers. Auditory brainstem ...responses (ABRs) and middle latency responses (MLRs)-as well as long-duration complex ABRs-to click and /dα/ speech stimuli were recorded in a single-case design.
Transduction artifacts occurred in raw EEG responses, but they were eliminated by shielding, counter-phasing (averaging across stimuli 180° out of phase), or rereferencing.
Clinical grade ABRs, MLRs, and cABRs can be recorded with a standard digital EEG system and high-fidelity insert earphones, provided one or more techniques are used to remove the stimulus transduction artifact.
The brain uses context and prior knowledge to repair degraded sensory inputs and improve perception. For example, listeners hear speech continuing uninterrupted through brief noises, even if the ...speech signal is artificially removed from the noisy epochs. In a functional MRI study, we show that this temporal filling-in process is based on two dissociable neural mechanisms: the subjective experience of illusory continuity, and the sensory repair mechanisms that support it. Areas mediating illusory continuity include the left posterior angular gyrus (AG) and superior temporal sulcus (STS) and the right STS. Unconscious sensory repair occurs in Broca's area, bilateral anterior insula, and pre-supplementary motor area. The left AG/STS and all the repair regions show evidence for word-level template matching and communicate more when fewer acoustic cues are available. These results support a two-path process where the brain creates coherent perceptual objects by applying prior knowledge and filling-in corrupted sensory information.
Mindfulness Based Stress Reduction (MBSR) is an effective non-pharmacologic treatment for veterans with PTSD. Extensive work has identified epigenetic factors related to PTSD disease risk and ...pathophysiology, but how these factors influence treatment response is unclear. Serotonin signaling and hypothalamic-pituitary-adrenal (HPA) axis functioning may be perturbed in PTSD and are molecular pathways targeted by PTSD treatments. To identify potential biomarkers for treatment response, we utilized genomic DNA isolated from peripheral blood samples from veterans with PTSD who were responders (
= 11) or non-responders (
= 11) to MBSR as part of a clinical trial. We assessed methylation levels at CpG sites in regions of the serotonin transporter (
) previously associated with expression and depression outcomes, as well as the Intron 7 region of the FK506 binding protein 5 (
) containing known glucocorticoid response elements suggested to regulate this gene. Selected subjects were matched across MBSR responder status by baseline symptoms, age, sex, current smoking status, and current antidepressant use. Percent methylation was compared between responders and non-responders at baseline (pre-MBSR treatment). Additionally, percent change in methylation from baseline to post-treatment was compared between responders and non-responders. There was a significant time x responder group interaction for methylation in
intron 7 bin 2
= 7.492,
= 0.013 whereby responders had a decrease in methylation and non-responders had an increase in methylation from before to after treatment in this region. Analyses of the three CpG sites within bin 2 revealed a significant time x responder group interaction for CpG_35558513
= 5.551,
= 0.029 which resides in a known glucocorticoid response element (GRE). Decreases in
methylation after treatment in responders as compared to increases in non-responders suggest that effective meditation intervention may be associated with stress-related pathways at the molecular level. These preliminary findings suggest that DNA methylation signatures within
are potential indicators of response to meditation treatment in PTSD and require validation in larger cohorts.
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