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.

Home-range size in juveniles of the temperate reef fish, the common triplefin (Forsterygion lapillum)

An organism’s home range dictates the spatial scale on which important processes occur (e.g. competition and predation) and directly affects the relationship between individual fitness and local habitat quality. Many reef fish species have very restricted home ranges after settlement and, here, we quantify home-range size in juveniles of a widespread and abundant reef fish in New Zealand, the common triplefin (Forsterygion lapillum). We conducted visual observations on 49 juveniles (mean size = 35-mm total length) within the Wellington harbour, New Zealand. Home ranges were extremely small, 0.053 m2 ± 0.029 (mean ± s.d.) and were unaffected by adult density, body size or substrate composition. A regression tree indicated that home-range size sharply decreased ~4.5 juveniles m–2 and a linear mixed model confirmed that home-range sizes in high-density areas (>4.5 juveniles m–2) were significantly smaller (34%) than those in low-density areas (after accounting for a significant effect of fish movement on our home-range estimates). Our results suggest that conspecific density may have negative and non-linear effects on home-range size, which could shape the spatial distribution of juveniles within a population, as well as influence individual fitness across local density gradients.

Preparing assessments and examinations. Common errors and good practice.

Assessment forms an important part of the student learning experience and students place a high value on the quality of feedback that they receive from academic staff on where they might improve on their examinations or assignments. However while feedback is important the quality of the actual assessment itself before students undertake an examination or commence writing an assignment is also important. It is imperative that students are clear in their understanding of what is expected of them in order to achieve a particular grade and that there is lack of ambiguity in examinations or assignments. Biggs (2003) highlighted the importance of clarity in what students are expected to be able to do at the end of a unit of study, and that intended learning outcomes should be clearly aligned to the assessment and communicated to students so that they can structure their learning activities to optimize their assessment performance. However as Rust (2002) highlighted there are often inconsistencies in assessment practices ranging from a mis-match of assessment and learning outcomes to the inclusion of additional learning criteria and lack of clarity in the instructions. Such inconsistencies and unacceptable errors in examination papers can undermine student confidence in the assessment process
In order to try and minimise such inconsistencies an internal assessment group was set up October 2013 within the School of Nursing and Midwifery at Queens University Belfast, consisting of representative academic staff from across the range of undergraduate and post graduate courses in nursing and midwifery. The assessment group was to be a point of reference for all school examinations with a particular remit to develop an assessment strategy for all nursing and midwifery programmes and to ensure that all assessments comply with current best practice and with Nursing and Midwifery Council (NMC) requirements.
Aim
This paper aims to highlight some examples of good practice and common errors that were found in assignments and examinations that were submitted to the assessment group for review.
References

Biggs. J. (2003) Teaching for Quality Learning at University – What the Student Does 2nd Edition SRHE / Open University Press, Buckingham.
Rust, C.( 2002) The impact of assessment on student learning, Active Learning in Higher education Vol3(2):145-158

The common vaginal commensal bacterium Ureaplasma parvum is associated with chorioamnionitis in extreme preterm labour

OBJECTIVE: To assess the association of vaginal commensal and low grade pathogenic bacteria including Ureaplasma parvum, Ureaplasma urealyticum, Mycoplasma hominis, Mycoplasma genitalium, Group B Streptococcus (GBS), and Gardnerella vaginalis, in women who delivered preterm at less than 37 weeks gestation in the presence or absence of inflammation of the chorioamnionitic membranes.

METHODS: A case control study involving women who delivered before 37 weeks gestation with and without inflammation of chorioamnionitic membranes. A total of 57 placental samples were histologically examined for polymorphonuclear leukocyte infiltration of placental tissue for evidence of chorioamnionitis, and by type-specific nucleic acid amplification for evidence of infection with one or more of the target bacteria. Demographic data was collected for each mother.

RESULTS: Amongst the 57 placental samples, 42.1% had chorioamnionitis and 24.6% delivered in the second trimester of pregnancy; U. parvum, U. urealyticum, G. vaginalis and GBS were all detected in the study with respective prevalence of 19.3%, 3.5%, 17.5% and 15.8%; M.genitalium and M. hominis were not detected. U. parvum was significantly associated with chorioamnionitis (p value = 0.02; OR 5.0; (95% CI 1.2-21.5) and was more common in women who delivered in the second (35.7%) compared to the third trimester of pregnancy (13.9%). None of the other bacteria were associated with chorioamnionitis or earlier delivery and all G.vaginalis positive women delivered in the third trimester of pregnancy (p value 0.04).

CONCLUSIONS: The detection of U. parvum in placental tissue was significantly associated with acute chorioamnionitis in women presenting in extreme preterm labour.

Patterns of co‑occurrence and interactions between age classes of the common triplefin, Forsterygion lapillum

Many marine organisms have pelagic larval stages that settle into benthic habitats occupied by older individuals; however, a mechanistic understanding of inter cohort interactions remains elusive for most species. Patterns of spatial covariation in the densities of juvenile and adult age classes of a small temperate reef fish, the common triplefin (Forsterygion lapillum), were evaluated during the recruitment season (Feb–Mar, 2011) in Wellington, New Zealand (41°17′S, 174°46′E). The relationship between juvenile and adult density among sites was best approximated by a dome-shaped curve, with a negative correlation between densities of juveniles and adults at higher adult densities. The curve shape was temporally variable, but was unaffected by settlement habitat type (algal species). A laboratory experiment using a “multiple-predator effects”design tested the hypothesis that increased settler mortality in the presence of adults (via enhanced predation risk or cannibalism) contributed to the observed negative relationship between juveniles and adults. Settler mortality did not differ between controls and treatments that contained either one (p = 0.08) or two (p = 0.09) adults. However, post hoca analyses revealed a significant positive correlation between the mean length of juveniles used in experimental trials and survival of juveniles in these treatments, suggesting that smaller juveniles may be vulnerable to cannibalism. There was no evidence for risk enhancement or predator interference when adults were present alongside a hetero specific predator (F. varium). These results highlight the complex nature of intercohort relationships in shaping recruitment patterns and add to the growing body of literature recognizing the importance of age class interactions.

Gramsci, austerity common sense and the attacks on the welfare state: The need to understand and resist the imposition of the global neoliberal agenda and the role of the social work profession.

During the last 30 years governments almost everywhere in the world are furthering a global neoliberal agenda by withdrawing the state from the delivery of services, decreasing social spending and lowering corporate taxation etc. This restructuring has led to a massive transfer of wealth from the welfare state and working class people into capital. In order to legitimize this restructuring conservative governments engage in collective blaming towards their denizens. This presentation will examine some of the well circulated phrases that have been used by the dominant elite in some countries during the last year to legitimize the imposition of austerity measures. Phrases such as, ‘We all partied’ used by the Irish finance minister, Brian Lenihan, to explain the Irish crisis and collectively blame all Irish people, ‘We must all share the pain’, deployed by another Irish Minister Gilmore and the UK coalition administration’s sound bite ‘We are all in this together’, legitimize the imposition of austerity measures. Utilizing the Gramscian concept of common sense (Gramsci, 1971), I call these phrases ‘austerity common sense’. They are austerity common sense because they both reflect and legitimate the austerity agenda. By deploying these phrases, the ruling economic and political elite seek to influence the perception of the people and pre-empt any intention of resistance. The dominant theme of these phrases is that there is no alternative and that austerity measures are somehow self-inflicted and, as such, should not be challenged because we are all to blame. The purpose of this presentation is to explore the “austerity common sense” theme from a Gramscian approach, focus on its implications for the social work profession and discuss the ways to resist the imposition of the global neoliberal agenda.

Parameter Optimisation for Woodwind Single-Reed Models

Time-domain modelling of single-reed woodwind instruments usually involves a lumped model of the excitation mechanism. The parameters of this lumped model have to be estimated for use in numerical simulations. Several attempts have been made to estimate these parameters, including observations of the mechanics of isolated reeds, measurements under artificial or real playing conditions and estimations based on numerical simulations. In this study an optimisation routine is presented, that can estimate reed-model parameters, given the pressure and flow signals in the mouthpiece. The method is validated, tested on a series of numerically synthesised data. In order to incorporate the actions of the player in the parameter estimation process, the optimisation routine has to be applied to signals obtained under real playing conditions. The estimated parameters can then be used to resynthesise the pressure and flow signals in the mouthpiece. In the case of measured data, as opposed to numerically synthesised data, special care needs to be taken while modelling the bore of the instrument. In fact, a careful study of various experimental datasets revealed that for resynthesis to work, the bore termination impedance should be known very precisely from theory. An example is given, where the above requirement is satisfied, and the resynthesised signals closely match the original signals generated by the player.