Inter-subject stability and regional concentration estimates of 3D-FID-MRSI in the human brain at 7 T.

PURPOSE: Recently, a 3D-concentric ring trajectory (CRT)-based free induction decay (FID)-MRSI sequence was introduced for fast high-resolution metabolic imaging at 7 T. This technique provides metabolic ratio maps of almost the entire brain within clinically feasible scan times, but its robustness has not yet been thoroughly investigated. Therefore, we have assessed quantitative concentration estimates and their variability in healthy volunteers using this approach. METHODS: We acquired whole-brain 3D-CRT-FID-MRSI at 7 T in 15 min with 3.4 mm nominal isometric resolution in 24 volunteers (12 male, 12 female, mean age 27 ± 6 years). Concentration estimate maps were calculated for 15 metabolites using internal water referencing and evaluated in 55 different regions of interest (ROIs) in the brain. Data quality, mean metabolite concentrations, and their inter-subject coefficients of variation (CVs) were compared for all ROIs. RESULTS: Of 24 datasets, one was excluded due to motion artifacts. The concentrations of total choline, total creatine, glutamate, myo-inositol, and N-acetylaspartate in 44 regions were estimated within quality thresholds. Inter-subject CVs (mean over 44 ROIs/minimum/maximum) were 9%/5%/19% for total choline, 10%/6%/20% for total creatine, 11%/7%/24% for glutamate, 10%/6%/19% for myo-inositol, and 9%/6%/19% for N-acetylaspartate. DISCUSSION: We defined the performance of 3D-CRT-based FID-MRSI for metabolite concentration estimate mapping, showing which metabolites could be robustly quantified in which ROIs with which inter-subject CVs expected. However, the basal brain regions and lesser-signal metabolites in particular remain as a challenge due susceptibility effects from the proximity to nasal and auditory cavities. Further improvement in quantification and the mitigation of B0 /B1 -field inhomogeneities will be necessary to achieve reliable whole-brain coverage.

Engineering Pichia pastoris for improved NADH regeneration: A novel chassis strain for whole-cell catalysis.

Many synthetically useful reactions are catalyzed by cofactor-dependent enzymes. As cofactors represent a major cost factor, methods for efficient cofactor regeneration are required especially for large-scale synthetic applications. In order to generate a novel and efficient host chassis for bioreductions, we engineered the methanol utilization pathway of Pichia pastoris for improved NADH regeneration. By deleting the genes coding for dihydroxyacetone synthase isoform 1 and 2 (DAS1 and DAS2), NADH regeneration via methanol oxidation (dissimilation) was increased significantly. The resulting Δdas1 Δdas2 strain performed better in butanediol dehydrogenase (BDH1) based whole-cell conversions. While the BDH1 catalyzed acetoin reduction stopped after 2 h reaching ~50% substrate conversion when performed in the wild type strain, full conversion after 6 h was obtained by employing the knock-out strain. These results suggest that the P. pastoris Δdas1 Δdas2 strain is capable of supplying the actual biocatalyst with the cofactor over a longer reaction period without the over-expression of an additional cofactor regeneration system. Thus, focusing the intrinsic carbon flux of this methylotrophic yeast on methanol oxidation to CO2 represents an efficient and easy-to-use strategy for NADH-dependent whole-cell conversions. At the same time methanol serves as co-solvent, inductor for catalyst and cofactor regeneration pathway expression and source of energy.

Prefrontal networks dynamically related to recovery from major depressive disorder: a longitudinal pharmacological fMRI study.

Due to lacking predictors of depression recovery, successful treatment of major depressive disorder (MDD) is frequently only achieved after therapeutic optimization leading to a prolonged suffering of patients. This study aimed to determine neural prognostic predictors identifying non-remitters prior or early after treatment initiation. Moreover, it intended to detect time-sensitive neural mediators indicating depression recovery. This longitudinal, interventional, single-arm, open-label, phase IV, pharmacological functional magnetic resonance imaging (fMRI) study comprised four scans at important stages prior (day 0) and after escitalopram treatment initiation (day 1, 28, and 56). Totally, 22 treatment-free MDD patients (age mean ± SD: 31.5 ± 7.7; females: 50%) suffering from a concurrent major depressive episode without any comorbid DSM-IV axis I diagnosis completed the study protocol. Primary outcome were neural prognostic predictors of depression recovery. Enhanced de-activation of anterior medial prefrontal cortex (amPFC, single neural mediator) indicated depression recovery correlating with MADRS score and working memory improvements. Strong dorsolateral PFC (dlPFC) activation and weak dlPFC-amPFC, dlPFC-posterior cingulate cortex (PCC), dlPFC-parietal lobe (PL) coupling (three prognostic predictors) hinted at depression recovery at day 0 and 1. Preresponse prediction of continuous (dlPFC-PL: R2day1 = 55.9%, 95% CI: 22.6-79%, P < 0.005) and dichotomous (specificity/sensitivity: SP/SNday1 = 0.91/0.82) recovery definitions remained significant after leave-one-out cross-validation. Identified prefrontal neural predictors might propel the future development of fMRI markers for clinical decision making, which could lead to increased response rates and adherence during acute phase treatment periods. Moreover, this study underscores the importance of the amPFC in depression recovery.