The Majority of Active Rhodobacteraceae in Marine Sediments Belong to Uncultured Genera: A Molecular Approach to Link Their Distribution to Environmental Conditions

General studies on benthic microbial communities focus on fundamental biogeochemical processes or the most abundant constituents. Thereby, minor fractions such as the Rhodobacteraceae are frequently neglected. Even though this family belongs to the most widely distributed bacteria in the marine environment, their proportion on benthic microbial communities is usually within or below the single digit range. Thus, knowledge on these community members is limited, even though their absolute numbers might exceed those from the pelagic zone by orders of magnitudes. To unravel the distribution and diversity of benthic, metabolically active Rhodobacteraceae, we have now analyzed an already existing library of bacterial 16S rRNA transcripts. The dataset originated from 154 individual sediment samples comprising seven oceanic regions and a broad variety of environmental conditions. Across all samples, a total of 0.7% of all 16S rRNA transcripts was annotated as Rhodobacteraceae. Among those, Sulfitobacter, Paracoccus, and Phaeomarinomonas were the most abundant cultured representatives, but the majority (78%) was affiliated to uncultured family members. To define them, the 45 most abundant Rhodobacteraceae-OTUs assigned as “uncultured” were phylogenetically assembled in new clusters. Their next relatives particularly belonged to different subgroups other than the Roseobacter group, reflecting a large part of the hidden diversity within the benthic Rhodobacteraceae with unknown functions. The general composition of active Rhodobacteraceae communities was found to be specific for the geographical location, exhibiting a decreasing richness with sediment depth. One-third of the Rhodobacteraceae-OTUs significantly responded to the prevailing redox regime, suggesting an adaption to anoxic conditions. A possible approach to predict their physiological properties is to identify the metabolic capabilities of their nearest relatives. Those need to be proven by physiological experiments, as soon an isolate is available. Because many uncultured members of these subgroups likely thrive under anoxic conditions, in future research, a molecular-guided cultivation strategy can be pursued to isolate novel Rhodobacteraceae from sediments

Expression quantitative trait loci are highly sensitive to cellular differentiation state

Blood cell development from multipotent hematopoietic stem cells to specialized blood cells is accompanied by drastic changes in gene expression for which the triggers remain mostly unknown. Genetical genomics is an approach linking natural genetic variation to gene expression variation, thereby allowing the identification of genomic loci containing gene expression modulators (eQTLs). In this paper, we used a genetical genomics approach to analyze gene expression across four developmentally close blood cell types collected from a large number of genetically different but related mouse strains. We found that, while a significant number of eQTLs (365) had a consistent “static” regulatory effect on gene expression, an even larger number were found to be very sensitive to cell stage. As many as 1,283 eQTLs exhibited a “dynamic” behavior across cell types. By looking more closely at these dynamic eQTLs, we show that the sensitivity of eQTLs to cell stage is largely associated with gene expression changes in target genes. These results stress the importance of studying gene expression variation in well-defined cell populations. Only such studies will be able to reveal the important differences in gene regulation between different ce

Clinical benefit of a precision medicine based approach for guiding treatment of refractory cancers

Patients and methods: Patients with metastatic solid tumors who had progressed on at least one line of standard of care therapy were referred to the Indiana University Health Precision Genomics Program. Tumor samples were submitted for DNA & RNA next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry for actionable targets. A multi-disciplinary tumor board reviewed all results. For each patient, the ratio of progression-free survival (PFS) of the genomically guided line of therapy divided by the PFS of their prior line was calculated. Patients whose PFS ratio was ≥ 1.3 were deemed to have a meaningful improvement in PFS. Results: From April 2014-October 2015, 168 patients were evaluated and 101 patients achieved adequate clinical follow-up for analysis. 19 of 44 (43.2%) patients treated with genomically guided therapy attained a PFS ratio ≥ 1.3 vs. 3 of 57 (5.3%) treated with non-genomically guided therapy (p < 0.0001). Similarly, overall PFS ratios (irrespective of cutoff) were higher for patients with genomically guided therapy vs non-genomically guided therapy (p = 0.05). Further, patients treated with genomically guided therapy had a superior median PFS compared to those treated with non-genomically guided therapy (86 days vs. 49 days, p = 0.005, H.R. = 0.55, 95% C.I.:0.37-0.84). Conclusion: Patients with refractory metastatic cancer who receive genomically guided therapy have improved PFS ratios and longer median PFS compared to patients who do not receive genomically guided therapy

16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65 046 European population controls (5/393 cases versus 32/65 046 controls; Fisher's exact test P = 2.83 × 10−6, odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10−4). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical R

Potential seigniorage in Europe: the effects of the EMU

SIGLEAvailable from Bibliothek des Instituts fuer Weltwirtschaft, ZBW, Duesternbrook Weg 120, D-24105 Kiel C 196383 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Matching the proteome to the genome: the microbody of penicillin-producing Penicillium chrysogenum cells

In the filamentous fungus Penicillium chrysogenum, microbodies are essential for penicillin biosynthesis. To better understand the role of these organelles in antibiotics production, we determined the matrix enzyme contents of P. chrysogenum microbodies. Using a novel in silico approach, we first obtained a catalogue of 200 P. chrysogenum proteins with putative microbody targeting signals (PTSs). This included two orthologs of proteins involved in cephalosporin biosynthesis, which we demonstrate to be bona fide microbody matrix constituents. Subsequently, we performed a proteomics based inventory of P. chrysogenum microbody matrix proteins using nano-LC-MS/MS analysis. We identified 89 microbody proteins, 79 with a PTS, including the two known microbody-borne penicillin biosynthesis enzymes, isopenicillin N:acyl CoA acyltransferase and phenylacetyl-CoA ligase. Comparative analysis revealed that 69 out of 79 PTS proteins identified experimentally were in the reference list. A prominent microbody protein was identified as a novel fumarate reductase-cytochrome b5 fusion protein, which contains an internal PTS2 between the two functional domains. We show that this protein indeed localizes to P. chrysogenum microbodies.

Large common deletions associate with mortality at old age

Copy-number variants (CNVs) are a source of genetic variation that increasingly are associated with human disease. However, the role of CNVs in human lifespan is to date unknown. To identify CNVs that influence mortality at old age, we analyzed genome-wide CNV data in 5178 participants of Rotterdam Study (RS1) and positive findings were evaluated in 1714 participants of the second cohort of the Rotterdam Study (RS2) and in 4550 participants of Framingham Heart Study (FHS). First, we assessed the total burden of rare (frequency 1%) CNVs for association with mortality during follow-up. These analyses were repeated by stratifying CNVs by type and size. Secondly, we assessed individual common CNV regions (CNVR) for association with mortality. We observed that the burden of common but not of rare CNVs influences mortality. A higher burden of large (>= 500 kb) common deletions associated with 4% higher mortality [hazard ratio (HR) per CNV 1.04, 95% confidence interval (CI) 1.02-1.07, P = 5.82 x 10(-5)] in the 11 442 participants of RS1, RS2 and FHS. In the analysis of 312 individual common CNVRs, we identified two regions (11p15.5; 14q21.3) that associated with higher mortality in these cohorts. The 11p15.5 region (combined HR 1.59, 95% CI 1.31-1.93, P = 2.87 x 10(-6)) encompasses 41 genes, of which some have previously been related to longevity, whereas the 14q21.3 region (combined HR 1.57, 95% CI 1.19-2.07, P = 1.53 x 10(-3)) does not encompass any genes. In conclusion, the burden of large common deletions, as well as common CNVs in 11p15.5 and 14q21.3 region, associate with higher mortality