Extracellular signal-regulated kinase 1/2 plays a pro-life role in experimental brain stem death via MAPK signal-interacting kinase at rostral ventrolateral medulla

Background  

As the origin of a life-and-death signal detected from systemic arterial pressure, which sequentially increases (pro-life) and decreases (pro-death) to reflect progressive dysfunction of central cardiovascular regulation during the advancement towards brain stem death in critically ill patients, the rostral ventrolateral medulla (RVLM) is a suitable neural substrate for mechanistic delineation of this fatal phenomenon. The present study assessed the hypothesis that extracellular signal-regulated kinase 1/2 (ERK1/2), a member of the mitogen-activated protein kinases (MAPKs) that is important for cell survival and is activated specifically by MAPK kinase 1/2 (MEK1/2), plays a pro-life role in RVLM during brain stem death. We further delineated the participation of MAPK signal-interacting kinase (MNK), a novel substrate of ERK in this process.     

Depressive Symptoms in Crohn's Disease: Relationship with Immune Activation and Tryptophan Availability

Crohn''s disease (CD) is associated with immune activation and depressive symptoms. This study determines the impact of anti-tumor necrosis factor (TNF)-α treatment in CD patients on depressive symptoms and the degree to which tryptophan (TRP) availability and immune markers mediate this effect. Fifteen patients with CD, eligible for anti-TNF-α treatment were recruited. Disease activity (Harvey-Bradshaw Index (HBI), Crohn''s Disease Activity Index (CDAI)), fatigue (Multidimensional Fatigue Inventory (MFI)), quality of life (Inflammatory Bowel Disease Questionnaire (IBDQ)), symptoms of depression and anxiety (Symptom Checklist (SCL-90), Beck Depression Inventory (BDI), Hamilton Depression Rating Scale (HDRS)), immune activation (acute phase proteins (APP)), zinc and TRP availability were assessed before treatment and after 2, 4 and 8 weeks. Anti-TNF-α increased IBDQ scores and reduced all depression scores; however only SCL-90 depression scores remained decreased after correction for HBI. Positive APPs decreased, while negative APPs increased after treatment. After correction for HBI, both level and percentage of γ fraction were associated with SCL-90 depression scores over time. After correction for HBI, patients with current/past depressive disorder displayed higher levels of positive APPs and lower levels of negative APPs and zinc. TRP availability remained invariant over time and there was no association between SCL-90 depression scores and TRP availability. Inflammatory reactions in CD are more evident in patients with comorbid depression, regardless of disease activity. Anti-TNF-α treatment in CD reduces depressive symptoms, in part independently of disease activity; there was no evidence that this effect was mediated by immune-induced changes in TRP availability.     

Synthesis of 53 tissue and cell line expression QTL datasets reveals master eQTLs

Background

Gene expression genetic studies in human tissues and cells identify cis- and trans-acting expression quantitative trait loci (eQTLs). These eQTLs provide insights into regulatory mechanisms underlying disease risk. However, few studies systematically characterized eQTL results across cell and tissues types. We synthesized eQTL results from >50 datasets, including new primary data from human brain, peripheral plaque and kidney samples, in order to discover features of human eQTLs.

Results

We find a substantial number of robust cis-eQTLs and far fewer trans-eQTLs consistent across tissues. Analysis of 45 full human GWAS scans indicates eQTLs are enriched overall, and above nSNPs, among positive statistical signals in genetic mapping studies, and account for a significant fraction of the strongest human trait effects. Expression QTLs are enriched for gene centricity, higher population allele frequencies, in housekeeping genes, and for coincidence with regulatory features, though there is little evidence of 5′ or 3′ positional bias. Several regulatory categories are not enriched including microRNAs and their predicted binding sites and long, intergenic non-coding RNAs. Among the most tissue-ubiquitous cis-eQTLs, there is enrichment for genes involved in xenobiotic metabolism and mitochondrial function, suggesting these eQTLs may have adaptive origins. Several strong eQTLs (CDK5RAP2, NBPFs) coincide with regions of reported human lineage selection. The intersection of new kidney and plaque eQTLs with related GWAS suggest possible gene prioritization. For example, butyrophilins are now linked to arterial pathogenesis via multiple genetic and expression studies. Expression QTL and GWAS results are made available as a community resource through the NHLBI GRASP database [http://apps.nhlbi.nih.gov/grasp/].

Conclusions

Expression QTLs inform the interpretation of human trait variability, and may account for a greater fraction of phenotypic variability than protein-coding variants. The synthesis of available tissue eQTL data highlights many strong cis-eQTLs that may have important biologic roles and could serve as positive controls in future studies. Our results indicate some strong tissue-ubiquitous eQTLs may have adaptive origins in humans. Efforts to expand the genetic, splicing and tissue coverage of known eQTLs will provide further insights into human gene regulation.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-532) contains supplementary material, which is available to authorized users.     

Characterization of Pseudomonas aeruginosa fatty acid profiles in biofilms and batch planktonic cultures

The fatty acid composition of Pseudomonas aeruginosa PAO1 was compared between biofilm and batch planktonic cultures. Strain PAO1 biofilms were able to maintain a consistent fatty acid profile for up to 6 days, whereas strain PAO1 batch planktonic cultures showed a gradual loss of cis-monounsaturated fatty acids over 4 days. Biofilms exhibited a greater proportion of hydroxy fatty acids but a lower proportion of both cyclopropane fatty acids and saturated fatty acids (SAFAs). SAFAs with >=16 carbons, in particular, decreased in biofilms when compared with that in batch planktonic cultures. A reduced proportion of SAFAs and a decline in overall fatty acid chain length indicate more fluidic biophysical properties for cell membranes of P. aeruginosa in biofilms. Separating the biofilms into 2 partitions and comparing their fatty acid compositions revealed additional trends that were not observed in the whole biofilm: the shear-nonremovable layer consistently showed greater proportions of hydroxy fatty acid than the bulk liquid + shear-removable portion of the biofilm. The shear-nonremovable portion demonstrated a relatively immediate decline in the proportion of monounsaturated fatty acids between days 2 and 4; which was offset by an increase in the proportion of cyclopropane fatty acids, specifically 19:0cyc(11,12). Simultaneously, the shear-removable portion of the biofilm showed an increase in the proportion of trans-monounsaturated fatty acids and cyclopropane fatty acids.     

A mutant Pfu DNA polymerase designed for advanced uracil-excision DNA engineering

Background  

The combined use of restriction enzymes with PCR has revolutionized molecular cloning, but is inherently restricted by the content of the manipulated DNA sequences. Uracil-excision based cloning is ligase and sequence independent and allows seamless fusion of multiple DNA sequences in simple one-tube reactions, with higher accuracy than overlapping PCR.     

Discursive Shifts in Dutch River Management: ‘Deep’ Institutional Change or Adaptation Strategy?

This paper argues that a discursive shift is taking place in Dutch water policy, from ‘a battle against water’ to ‘living with water’ or ‘accommodating water’. Yet we ask ourselves whether this shift is just an adaptation strategy of the existing elite group of water managers, who pay lip-service to new management approaches in order to maintain their vested interests, as some authors claim, or whether it implies ‘deep’ institutional change, e.g. in terms of the emergence of new water institutions, power relations and procedures. While investigating this question, we make use of the ‘policy arrangement approach’, which pays attention to institutional and discursive aspects of policy making alike. Our conclusion is that we are currently observing institutional changes beyond ‘policy talk’, particularly in terms of new legislation and procedures. However, it is too early to speak of ‘deep’ institutional change in Dutch water management, because the former water institutions are still maintaining their power positions, despite the availability of additional resources for policy and research as well as the emergence of several new modes of governance.     

Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations

Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal cone-shaped epiphyses, chronic renal failure, and early-onset, severe retinal dystrophy. Through a combination of ciliome resequencing and Sanger sequencing, we identified IFT140 mutations in six MSS families and in a family with the clinically overlapping Jeune syndrome. IFT140 is one of the six currently known components of the intraflagellar transport complex A (IFT-A) that regulates retrograde protein transport in ciliated cells. Ciliary abundance and localization of anterograde IFTs were altered in fibroblasts of affected individuals, a result that supports the pivotal role of IFT140 in proper development and function of ciliated cells.