Spatial distribution of intact polar lipids in North Sea surface waters: Relationship with environmental conditions and microbial community composition

We characterized and quantified the intact polar lipid (IPL) composition of the surface waters of the North Sea and investigated its relationships with environmental conditions, microbial abundances, and community composition. The total IPL pool comprised at least 600 different IPL species in seven main classes: the glycerophospholipids phosphatidylcholine (PC), phosphatidylglycerol (PG), and phosphatidylethanolamine (PE); the sulfur-bearing glycerolipid sulfoquinovosyldiacylglycerol (SQDG); and the nitrogen-bearing betaine lipids diacylglyceryl-trimethylhomoserine (DGTS), diacylglyceryl-hydroxymethyltrimethylalanine (DGTA), and diacylglyceryl-carboxy-hydroxymethylcholine (DGCC). Although no significant relationships were found between the IPL composition and environmental parameters, such as nutrient concentrations, distance-based ordination yielded distinct clusters of IPL species, which could in turn be tentatively correlated with the predominant microbial groups. SQDGs and PGs, as well as PC species containing saturated fatty acid moieties, were related to picoeukaryote abundances and PC species with polyunsaturated fatty acid (PUFA) moieties to nanoeukaryote abundances. The PEs were likely of mixed cyanobacterial-bacterial origin, whereas DGTA and DGCC species were mainly associated with cyanobacteria. DGTSs were likely derived from either pico-or nanoeukaryotes, although the DGTS species with PUFAs also showed some relationship with cyanobacterial abundances. Concentrations of the algal-derived IPLs showed strong positive correlations with chlorophyll a concentrations, indicating they may be used as biomarkers for living photosynthetic microbes. However, direct relationships between the IPLs and microbial groups were relatively weak, implying that the predominant IPLs in marine surface waters are not derived from single microbial groups and that direct inferences of microbial community compositions from IPL compositions should be considered with care

Complement component 4A protein levels are negatively related to frontal volumes in patients with schizophrenia spectrum disorders

Background: Excessive C4A-gene expression may result in increased microglia-mediated synaptic pruning. As C4A overexpression is observed in schizophrenia spectrum disorders (SSD), this mechanism may account for the altered brain morphology (i.e. reduced volume and cortical thickness) and cognitive symptoms that characterize SSD. Therefore, this study investigates the association of C4A serum protein levels with brain morphology and cognition, and in particular whether this association differs between recent-onset SSD (n = 69) and HC (n = 40). Methods: Serum C4A protein levels were compared between groups. Main outcomes included total gray matter volume, mean cortical thickness and cognitive performance. Regression analysis on these outcomes included C4A level, group (SSD vs. HC), and C4A*Group interactions. All statistical tests were corrected for age, sex, BMI, and antipsychotic medication dose. Follow-up analyses were performed on separate brain regions and scores on cognitive sub-tasks. Results: The group difference in C4A levels was not statistically significant (p = 0.86). The main outcomes did not show a significant interaction effect (p &gt; 0.13) or a C4A main effect (p &gt; 0.27). Follow-up analyses revealed significant interaction effects for the left medial orbitofrontal and left frontal pole volumes (p &lt; 0.001): C4A was negatively related to these volumes in SSD, but positively in HC. Conclusion: This study demonstrated that C4A was negatively related to – specifically – frontal brain volumes in SSD, but this relation was inverse for HC. The results support the hypothesis of complement-mediated brain volume reduction in SSD. The results also suggest that C4A has a differential association with brain morphology in SSD compared to HC.</p

Lower fractional anisotropy without evidence for neuro-inflammation in patients with early-phase schizophrenia spectrum disorders

Various lines of research suggest immune dysregulation as a potential therapeutic target for negative and cognitive symptoms in schizophrenia spectrum disorders (SSD). Immune dysregulation would lead to higher extracellular free-water (EFW) in cerebral white matter (WM), which may partially underlie the frequently reported lower fractional anisotropy (FA) in SSD. We aim to investigate differences in EFW concentrations – a presumed proxy for neuro-inflammation – between early-phase SSD patients (n = 55) and healthy controls (HC; n = 37), and to explore immunological and cognitive correlates. To increase specificity for EFW, we study several complementary magnetic resonance imaging contrasts that are sensitive to EFW. FA, mean diffusivity (MD), magnetization transfer ratio (MTR), myelin water fraction (MWF) and quantitative T1 and T2 were calculated from diffusion-weighted imaging (DWI), magnetization transfer imaging (MTI) and multicomponent driven equilibrium single-pulse observation of T1/T2 (mcDESPOT). For each measure, WM skeletons were constructed with tract-based spatial statistics. Multivariate SSD-HC comparisons with WM skeletons and their average values (i.e. global WM) were not statistically significant. In voxel-wise analyses, FA was significantly lower in SSD in the genu of the corpus callosum and in the left superior longitudinal fasciculus (p < 0.04). Global WM measures did not correlate with immunological markers (i.e. IL1-RA, IL-6, IL-8, IL-10 and CRP) or cognition in HC and SSD after corrections for multiple comparisons. We confirmed lower FA in early-phase SSD patients. However, non–FA measures did not provide additional evidence for immune dysregulation or for higher EFW as the primary mechanism underlying the reported lower FA values in SSD

High-power operation of coherently coupled tapered laser diodes in an external cavity

We demonstrate a rear-side phase-locking architecture with two high-brightness diode lasers. This technique is based on the passive phase-locking of emitters in an external cavity on their rear facet, and their coherent combination on the front facet. Two high-brightness high-power tapered laser diodes are coherently combined using a Michelson-based cavity. The combining efficiency is above 80% and results in an output power of 6.7 W in a nearly diffraction-limited beam. The rear-side architecture is then used with a laser bar of 5 tapered emitters using an interferometric extended cavity, based on a diffractive optical element. We describe the experimental evaluation of the diffractive optical element, and the phase-locked operation of the laser bar

Resequencing three candidate genes for major depressive disorder in a Dutch cohort

Major depressive disorder (MDD) is a psychiatric disorder, characterized by periods of low mood of more than two weeks, loss of interest in normally enjoyable activities and behavioral changes. MDD is a complex disorder and does not have a single genetic cause. In 2009 a genome wide association study (GWAS) was performed on the Dutch GAIN-MDD cohort. Many of the top signals of this GWAS mapped to a region spanning the gene PCLO, and the non-synonymous coding single nucleotide polymorphism (SNP) rs2522833 in the PCLO gene became genome wide significant after post-hoc analysis. We performed resequencing of PCLO, GRM7, and SLC6A4 in 50 control samples from the GAIN-MDD cohort, to detect new genomic variants. Subsequently, we genotyped these variants in the entire GAIN-MDD cohort and performed association analysis to investigate if rs2522833 is the causal variant or simply in linkage disequilibrium with a more associated variant. GRM7 and SLC6A4 are both candidate genes for MDD from literature. We aimed to gather more evidence that rs2522833 is indeed the causal variant in the GAIN-MDD cohort or to find a previously undetected common variant in either PCLO, GRM7, or SLC6A4 with a higher association in this cohort. After next generation sequencing and association analysis we excluded the possibility of an undetected common variant to be more associated. For neither PCLO nor GRM7 we found a more associated variant. For SLC6A4, we found a new SNP that showed a lower P-value (P = 0.07) than in the GAIN-MDD GWAS (P = 0.09). However, no evidence for genome-wide significance was found. Although we did not take into account rare variants, we conclude that our results provide further support for the hypothesis that the non-synonymous coding SNP rs2522833 in the PCLO gene is indeed likely to be the causal variant in the GAIN-MDD cohort

Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients.

INTRODUCTION\nDrug-target binding kinetics are major determinants of the time course of drug action for several drugs, as clearly described for the irreversible binders omeprazole and aspirin. This supports the increasing interest to incorporate newly developed high-throughput assays for drug-target binding kinetics in drug discovery. A meaningful application of in vitro drug-target binding kinetics in drug discovery requires insight into the relation between in vivo drug effect and in vitro measured drug-target binding kinetics.\nAREAS COVERED\nIn this review, the authors discuss both the relation between in vitro and in vivo measured binding kinetics and the relation between in vivo binding kinetics, target occupancy and effect profiles.\nEXPERT OPINION\nMore scientific evidence is required for the rational selection and development of drug-candidates on the basis of in vitro estimates of drug-target binding kinetics. To elucidate the value of in vitro binding kinetics measurements, it is necessary to obtain information on system-specific properties which influence the kinetics of target occupancy and drug effect. Mathematical integration of this information enables the identification of drug-specific properties which lead to optimal target occupancy and drug effect in patients.Pharmacolog

Honeybees balance essential fatty acids and suffer cognitively from deficiency

Abstract Background and aims. Epidemiological data on autoimmune hepatitis (AIH) are scarce. In this study, we determined the clinical and epidemiological characteristics of AIH patients in the Netherlands (16.7 million inhabitants). Methods. Clinical characteristics were collected from 1313 AIH patients (78% females) from 31 centers, including all eight academic centers in the Netherlands. Additional data on ethnicity, family history and symptoms were obtained by the use of a questionnaire. Results. The prevalence of AIH was 18.3 (95% confidential interval [CI]: 17.3-19.4) per 100,000 with an annual incidence of 1.1 (95% CI: 0.5-2) in adults. An incidence peak was found in middle-aged women. At diagnosis, 56% of patients had fibrosis and 12% cirrhosis in liver biopsy. Overall, 1% of patients developed HCC and 3% of patients underwent liver transplantation. Overlap with primary biliary cirrhosis and primary sclerosing cholangitis was found in 9% and 6%, respectively. The clinical course did not differ between Caucasian and non-Caucasian patients. Other autoimmune diseases were found in 26% of patients. Half of the patients reported persistent AIH-related symptoms despite treatment with a median treatment period of 8 years (range 1-44 years). Familial occurrence was reported in three cases. Conclusion. This is the largest epidemiological study of AIH in a geographically defined region and demonstrates that the prevalence of AIH in the Netherlands is uncommon. Although familial occurrence of AIH is extremely rare, our twin data may point towards a genetic predisposition. The high percentage of patients with cirrhosis or fibrosis at diagnosis urges the need of more awareness for AIH

The Structure of a Rigorously Conserved RNA Element within the SARS Virus Genome

We have solved the three-dimensional crystal structure of the stem-loop II motif (s2m) RNA element of the SARS virus genome to 2.7-Å resolution. SARS and related coronaviruses and astroviruses all possess a motif at the 3′ end of their RNA genomes, called the s2m, whose pathogenic importance is inferred from its rigorous sequence conservation in an otherwise rapidly mutable RNA genome. We find that this extreme conservation is clearly explained by the requirement to form a highly structured RNA whose unique tertiary structure includes a sharp 90° kink of the helix axis and several novel longer-range tertiary interactions. The tertiary base interactions create a tunnel that runs perpendicular to the main helical axis whose interior is negatively charged and binds two magnesium ions. These unusual features likely form interaction surfaces with conserved host cell components or other reactive sites required for virus function. Based on its conservation in viral pathogen genomes and its absence in the human genome, we suggest that these unusual structural features in the s2m RNA element are attractive targets for the design of anti-viral therapeutic agents. Structural genomics has sought to deduce protein function based on three-dimensional homology. Here we have extended this approach to RNA by proposing potential functions for a rigorously conserved set of RNA tertiary structural interactions that occur within the SARS RNA genome itself. Based on tertiary structural comparisons, we propose the s2m RNA binds one or more proteins possessing an oligomer-binding-like fold, and we suggest a possible mechanism for SARS viral RNA hijacking of host protein synthesis, both based upon observed s2m RNA macromolecular mimicry of a relevant ribosomal RNA fold