Shared common variants in prostate cancer and blood lipids

BACKGROUND: Epidemiological and clinical studies suggest comorbidity between prostate cancer (PCA) and cardiovascular disease (CVD) risk factors. However, the relationship between these two phenotypes is still not well understood. Here we sought to identify shared genetic loci between PCA and CVD risk factors.

METHODS: We applied a genetic epidemiology method based on conjunction false discovery rate (FDR) that combines summary statistics from different genome-wide association studies (GWAS), and allows identification of genetic overlap between two phenotypes. We evaluated summary statistics from large, multi-centre GWA studies of PCA (n=50 000) and CVD risk factors (n=200 000) [triglycerides (TG), low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol, systolic blood pressure, body mass index, waist-hip ratio and type 2 diabetes (T2D)]. Enrichment of single nucleotide polymorphisms (SNPs) associated with PCA and CVD risk factors was assessed with conditional quantile-quantile plots and the Anderson-Darling test. Moreover, we pinpointed shared loci using conjunction FDR.

RESULTS: We found the strongest enrichment of P-values in PCA was conditional on LDL and conditional on TG. In contrast, we found only weak enrichment conditional on HDL or conditional on the other traits investigated. Conjunction FDR identified altogether 17 loci; 10 loci were associated with PCA and LDL, 3 loci were associated with PCA and TG and additionally 4 loci were associated with PCA, LDL and TG jointly (conjunction FDR <0.01). For T2D, we detected one locus adjacent to HNF1B.

CONCLUSIONS: We found polygenic overlap between PCA predisposition and blood lipids, in particular LDL and TG, and identified 17 pleiotropic gene loci between PCA and LDL, and PCA and TG, respectively. These findings provide novel pathobiological insights and may have implications for trials using targeting lipid-lowering agents in a prevention or cancer setting.

COP and clathrin-coated vesicle budding:different pathways, common approaches

Vesicle and tubule transport containers move proteins and lipids from one membrane system to another. Newly forming transport containers frequently have electron-dense coats. Coats coordinate the accumulation of cargo and sculpt the membrane. Recent advances have shown that components of both COP1 and clathrin-adaptor coats share the same structure and the same motif-based cargo recognition and accessory factor recruitment mechanisms, which leads to insights on conserved aspects of coat recruitment, polymerisation and membrane deformation. These themes point to the way in which evolutionarily conserved features underpin these diverse pathways.

Association of common gene variants in the WNT/β-catenin pathway with colon cancer recurrence

Wnt/β-catenin signaling has a central role in the development and progression of most colon cancers (CCs). Germline variants in Wnt/β-catenin pathway genes may result in altered gene function and/or activity, thereby causing inter-individual differences in relation to tumor recurrence capacity and chemoresistance. We investigated germline polymorphisms in a comprehensive panel of Wnt/β-catenin pathway genes to predict time to tumor recurrence (TTR) in patients with stage III and high-risk stage II CC. A total of 234 patients treated with 5-fluorouracil-based chemotherapy were included in this study. Whole-blood samples were analyzed for putative functional germline polymorphisms in SFRP3, SFRP4, DKK2, DKK3, Axin2, APC, TCF7L2, WNT5B, CXXC4, NOTCH2 and GLI1 genes by PCR-based restriction fragment-length polymorphism or direct DNA sequencing. Polymorphisms with statistical significance were validated in an independent study cohort. The minor allele of WNT5B rs2010851 T>G was significantly associated with a shorter TTR (10.7 vs 4.9 years; hazard ratio: 2.48; 95% CI, 0.96-6.38; P=0.04) in high-risk stage II CC patients. This result remained significant in multivariate Cox's regression analysis. This study shows that the WNT5B germline variant rs2010851 was significantly identified as a stage-dependent prognostic marker for CC patients after 5-fluorouracil-based adjuvant therapy.

Common cancer stem cell gene variants predict colon cancer recurrence

PURPOSE: Recent evidence suggests that cancer stem cells (CSC) are responsible for key elements of colon cancer progression and recurrence. Germline variants in CSC genes may result in altered gene function and/or activity, thereby causing interindividual differences in a patient's tumor recurrence capacity and chemoresistance. We investigated germline polymorphisms in a comprehensive panel of CSC genes to predict time to tumor recurrence (TTR) in patients with stage III and high-risk stage II colon cancer.

EXPERIMENTAL DESIGN: A total of 234 patients treated with 5-fluorouracil-based chemotherapy at the University of Southern California were included in this study. Whole blood samples were analyzed for germline polymorphisms in genes that have been previously associated with colon CSC (CD44, Prominin-1, DPP4, EpCAM, ALCAM, Msi-1, ITGB1, CD24, LGR5, and ALDH1A1) by PCR-RFLP or direct DNA-sequencing.

RESULTS: The minor alleles of CD44 rs8193 C>T, ALCAM rs1157 G>A, and LGR5 rs17109924 T>C were significantly associated with increased TTR (9.4 vs. 5.4 years; HR, 0.51; 95% CI: 0.35-0.93; P = 0.022; 11.3 vs. 5.7 years; HR, 0.56; 95% CI: 0.33-0.94; P = 0.024, and 10.7 vs. 5.7 years; HR, 0.33; 95% CI: 0.12-0.90; P = 0.023, respectively) and remained significant in the multivariate analysis stratified by ethnicity. In recursive partitioning, a specific gene variant profile including LGR5 rs17109924, CD44 rs8193, and ALDH1A1 rs1342024 represented a high-risk subgroup with a median TTR of 1.7 years (HR, 6.71, 95% CI: 2.71-16.63, P < 0.001).

CONCLUSION: This is the first study identifying common germline variants in colon CSC genes as independent prognostic markers for stage III and high-risk stage II colon cancer patients.

ArnT proteins that catalyse the glycosylation of lipopolysaccharide share common features with bacterial N-oligosaccharyltransferases

ArnT is a glycosyltransferase that catalyses the addition of 4-amino-4-deoxy-L-arabinose (L-Ara4N) to the lipid A moiety of the lipopolysaccharide. This is a critical modification enabling bacteria to resist killing by antimicrobial peptides. ArnT is an integral inner membrane protein consisting of 13 predicted transmembrane helices and a large periplasmic C-terminal domain. We report here the identification of a functional motif with a canonical consensus sequence DEXRYAX(5)MX(3)GXWX(9)YFEKPX(4)W spanning the first periplasmic loop, which is highly conserved in all ArnT proteins examined. Site-directed mutagenesis demonstrated the contribution of this motif in ArnT function, suggesting that these proteins have a common mechanism. We also demonstrate that the Burkholderia cenocepacia and Salmonella enterica serovar Typhimurium ArnT C-terminal domain is required for polymyxin B resistance in vivo. Deletion of the C-terminal domain in B. cenocepacia ArnT resulted in a protein with significantly reduced in vitro binding to a lipid A fluorescent substrate and unable to catalyse lipid A modification with L-Ara4N. An in silico predicted structural model of ArnT strongly resembled the tertiary structure of Campylobacter lari PglB, a bacterial oligosaccharyltransferase involved in protein N-glycosylation. Therefore, distantly related oligosaccharyltransferases from ArnT and PglB families operating on lipid and polypeptide substrates, respectively, share unexpected structural similarity that could not be predicted from direct amino acid sequence comparisons. We propose that lipid A and protein glycosylation enzymes share a conserved catalytic mechanism despite their evolutionary divergence.

Repeal the HRA and Rely on the Common Law?

This piece contemplates whether the common law could fill the gaps in human rights protection if the UK's Human Rights Act 1998 were to be repealed. It looks at how the common law protected human rights before the Act came into force, what difference the Act has made, how the common law has become side-lined as a result, how in recent cases it has begun to play a more central role, and what more more needs to be done to develop it in ways which ensure that if the Human Rights Act were to be repealed it would not be particularly missed.

Turing’s Menagerie: Talking Lions, Virtual Bats, Electric Sheep and Analogical Peacocks: Common Ground and Common Interest are Necessary Components of Engagement

This theoretical paper attempts to define some of the key components and challenges required to create embodied conversational agents that can be genuinely interesting conversational partners. Wittgenstein’s argument concerning talking lions emphasizes the importance of having a shared common ground as a basis for conversational interactions. Virtual bats suggests that–for some people at least–it is important that there be a feeling of authenticity concerning a subjectively experiencing entity that can convey what it is like to be that entity. Electric sheep reminds us of the importance of empathy in human conversational interaction and that we should provide a full communicative repertoire of both verbal and non-verbal components if we are to create genuinely engaging interactions. Also we may be making the task more difficult rather than easy if we leave out non-verbal aspects of communication. Finally, analogical peacocks highlights the importance of between minds alignment and establishes a longer term goal of being interesting, creative, and humorous if an embodied conversational is to be truly an engaging conversational partner. Some potential directions and solutions to addressing these issues are suggested.

Common Themes in Multi-block Structured Quad/Hex Mesh Generation

The automatic generation of structured multi-block quadrilateral (quad) and hexahedral (hex) meshes has been researched for many years without definitive success. The core problem in quad / hex mesh generation is the placement of mesh singularities to give the desired mesh orientation and distribution [1]. It is argued herein that existing approaches (medial axis, paving / plastering, cross / frame fields) are actually alternative views of the same concept. Using the information provided by the different approaches provides additional insight into the problem.

Breaking and Entering: Examining the role of stress and aerial exposure in predator-prey relationships between the common shore crab (Carcinus maenas) and cultivated blue mussels (Mytilus edulis).

During benthic cultivation Mytilus edulis (blue mussels) are subject to predation pressure from a number of predators including Carcinus maenas (shore crabs). This predator can be responsible for substantial losses of mussels from the fishery and a full understanding of the predator–prey relationship between M. edulis and C. maenas is required to ensure attempts that reduce predatory pressure and subsequent commercial loss are successful. Whilst much work has examined the prey–predator size relationships between C. maenas and M. edulis, far less research has investigated how stress, such as periods of extended aerial exposure, may affect these relationships. We tested whether profit in terms of calories gained by crabs consuming mussels stressed by aerial exposure for 48 h differed from that of mussels at ambient conditions and whether being stressed affected the mussel's likelihood of predation. We also tested whether the size relationship between predators and their prey differed when mussels were stressed. We found that the profitability of prey (calories gained per second of handling time) did not vary between stressed and unstressed mussels. Handling times for stressed and unstressed mussels were similar, even when crabs were presented with mussels of the maximum size that they are able to consume. Small crabs were more likely to reject a mussel of preferred size if it was unstressed, suggesting that crabs may be able to assess that these mussels would require extra effort to break into and consume. Our findings suggest that the predator–prey relationship between mussels and crabs is not altered when mussels are stressed. C. maenas remains a voracious predator and regardless of the condition of mussels laid on commercial beds there is a need to control this predator in attempt to reduce losses in the benthic fishery.

Old World megadroughts and pluvials during the Common Era

Climate model projections suggestwidespread drying in the Mediterranean Basin and wetting in Fennoscandia in the coming decades largely as a consequence of greenhouse gas forcing of climate. To place these and other “Old World” climate projections into historical perspective based on more complete estimates of natural hydroclimatic variability, we have developed the “Old World Drought Atlas” (OWDA), a set of year-to-year maps of tree-ring reconstructed summer wetness and dryness over Europe and the Mediterranean Basin during the Common Era.
The OWDA matches historical accounts of severe drought and wetness with a spatial completeness not previously available. In addition, megadroughts reconstructed over north-central Europe in the 11th and mid-15th centuries
reinforce other evidence from North America and Asia that droughts were more severe, extensive, and prolonged over Northern Hemisphere land areas before the 20th century, with an inadequate understanding of their causes. The OWDA provides new data to determine the causes of Old World drought and wetness and attribute past climate variability to forced and/or internal variability.