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1.  Is the mothers’ country of birth associated with the sex of their offspring in England and Wales from 2007 to 2011? 
Preference for sons in India has resulted in a skewed sex ratio at live birth, probably as a consequence of female feticide. However, it is unclear if these cultural preferences are also currently present in communities who have emigrated from India to England and Wales.
Data of all live births in England and Wales from 2007–2011 were obtained from the Office of National Statistics. A logistic regression analysis was used to compare the probability of having a male infant in mothers born inside the United Kingdom (UK) to those born outside the UK, stratified by mothers’ region and country of birth.
Mothers born in India were not observed to be giving birth to disproportionately more boys than mothers that were born in the UK (Odds Ratio OR: 1.00, 95% Confidence Interval CI: 0.98 - 1.02), although an excess of male births were observed in mothers born in South-East Asia (OR 1.03; 95% CI: 1.01-1.05, p = 0.005), the Middle East (OR 1.02; 95% CI: 1.00-1.05, p = 0.047), and South America (1.04; 95% CI: 1.00-1.07, p = 0.025). Mothers who were born in Africa were found to be less likely to give birth to boys than girls when compared to mothers born in the UK (OR: 0.98, 95% CI: 0.97–0.99), and this observation was attributable to women born in East and West Africa.
There was no evidence of an excess of males born to women from India in England and Wales. An excess of males were observed in mothers born in South-East Asia, the Middle East and South America. Women born in Africa are less likely to give birth to boys than UK born mothers, an observation that is consistent with previous data.
PMCID: PMC4183769  PMID: 25252884
Sex ratio; India; England and Wales; Africa
2.  An efficient procedure for the preparation of natural products bearing the 2-(2-phenylethyl)chromone skeleton 
Tetrahedron letters  2013;54(32):4292-4295.
Several 2-(2-phenylethyl)chromones have been shown to possess neuroprotective activity. However, limited synthetic methods have been disclosed to construct the 2-(2-phenylethyl)chromone skeleton. Herein we report a straightforward 3-step preparation of five naturally occurring 2-(2-phenylethyl)chromones utilizing the Claisen condensation as the key step.
PMCID: PMC3735228  PMID: 23935224
2-(2-phenylethyl)chromones; Claisen condensation; Neuroprotection; Chromenes
3.  The MutSβ complex is a modulator of p53-driven tumorigenesis through its functions in both DNA double strand break repair and mismatch repair 
Oncogene  2013;33(30):3939-3946.
Loss of the DNA mismatch repair protein MSH3 leads to the development of a variety of tumors in mice without significantly affecting survival rates, suggesting a modulating role for the MutSβ (MSH2-MSH3) complex in late onset tumorigenesis. To better study the role of MSH3 in tumor progression, we crossed Msh3−/− mice onto a tumor predisposing p53-deficient background. Survival of Msh3/p53 mice was not reduced compared to single p53 mutant mice; however, the tumor spectrum changed significantly from lymphoma to sarcoma, indicating MSH3 as a potent modulator of p53-driven tumorigenesis. Interestingly, Msh3−/− mouse embryonic fibroblasts displayed increased chromatid breaks and persistence of γH2AX foci following ionizing radiation, indicating a defect in DNA double strand break repair. Msh3/p53 tumors showed increased loss of heterozygosity, elevated genome-wide copy number variation, and a moderate microsatellite instability phenotype compared to Msh2/p53 tumors, revealing that MSH2-MSH3 suppresses tumorigenesis by maintaining chromosomal stability. Our results show that the MSH2-MSH3 complex is important for the suppression of late onset tumors due to its role in DNA double strand break repair as well as in DNA mismatch repair. Furthermore, they demonstrate that MSH2-MSH3 suppresses chromosomal instability and modulates the tumor spectrum in p53-deficient tumorigenesis, and possibly plays a role in other chromosomally unstable tumors as well.
PMCID: PMC3961563  PMID: 24013230
DNA mismatch repair; MSH2-MSH3; DNA double strand break repair; chromosomal instability; p53; sarcomagenesis
4.  Disease-enhancing antibodies improve the efficacy of bacterial toxin-neutralizing antibodies 
Cell host & microbe  2013;13(4):417-428.
During infection, humoral immunity produces a polyclonal response with various immunoglobulins recognizing different epitopes within the microbe or toxin. Despite this diverse response, the biological activity of an antibody (Ab) is usually assessed by the action of a monoclonal population. We demonstrate that a combination of monoclonal antibodies (mAbs) that are individually disease-enhancing or neutralizing to Bacillus anthracis protective antigen (PA), a component of anthrax toxin, results in significantly augmented protection against the toxin. This boosted protection is Fc gamma receptor (FcγR)-dependent and involves the formation of stoichiometrically defined mAb-PA complexes that requires immunoglobulin bivalence and simultaneous interaction between PA and the two mAbs. The formation of these mAb-PA complexes inhibits PA oligomerization, resulting in protection. These data suggest that functional assessments of single Abs may inaccurately predict how the same Abs will operate in polyclonal preparations and imply that potentially therapeutic mAbs may be overlooked in single Ab screens.
PMCID: PMC3633089  PMID: 23601104
5.  Efficient Excitation of Channel Plasmons in Tailored, UV-Lithography-Defined V-Grooves 
Nano Letters  2014;14(3):1659-1664.
We demonstrate the highly efficient (>50%) conversion of freely propagating light to channel plasmon-polaritons (CPPs) in gold V-groove waveguides using compact 1.6 μm long waveguide-termination coupling mirrors. Our straightforward fabrication process, involving UV-lithography and crystallographic silicon etching, forms the coupling mirrors innately and ensures exceptional-quality, wafer-scale device production. We tailor the V-shaped profiles by thermal silicon oxidation in order to shift initially wedge-located modes downward into the V-grooves, resulting in well-confined CPPs suitable for nanophotonic applications.
PMCID: PMC3964729  PMID: 24524631
Channel plasmon polariton; V-groove; termination mirror; plasmonic coupler; UV lithography
6.  Fungal Virulence in a Lepidopteran Model Is an Emergent Property with Deterministic Features 
mBio  2013;4(3):e00100-13.
Virulence has been proposed to be an emergent property, which by definition implies that it is not reducible to its components, but this application of a philosophical concept to the host-microbe interaction has not been experimentally tested. The goals of our study were to analyze the correlation of the phenotype with the ability to cause disease and to determine the dynamics of an experimental cryptococcal infection in Galleria mellonella and Acanthamoeba castellanii. By studying the outcome of infection as host death, we showed that the dynamics of virulence in the G. mellonella/Cryptococcus neoformans interaction follow a predictable pattern. We also found that the experimental temperature and not the presence of virulence factors was a critical parameter defining the pathogenic potential of cryptococcal species. Our results established that cryptococcal species not considered pathogenic could be pathogens given suitable conditions. Our results support the idea that virulence is an emergent property that cannot be easily predicted by a reductionist approach and yet it behaves as a deterministic system in a lepidopteran cryptococcal infection. These findings provide a road map for evaluating whether host-microbe interactions in other systems are chaotic, deterministic, or stochastic, including those with public health importance.
Virulence is a complex phenotype that cannot be easily studied by analyzing its individual components in isolation. By studying the outcome of infection as the death of the host, we found that a given microbial phenotype does not necessarily correlate with its ability to cause disease and that the presence of so-called virulence factors does not predict pathogenicity, consistent with the notion that virulence is an emergent property. This paper reports that the dynamics of virulence in Galleria mellonella larvae infected with the fungus Cryptococcus neoformans follows a predictable pattern. Establishing that virulence is an emergent property is important because it implies that it is not reducible to its components, and consequently, this phenomenon needs to be studied by a holistic approach.
PMCID: PMC3648900  PMID: 23631914
7.  Impact of gastro-oesophageal reflux on microRNA expression, location and function 
BMC Gastroenterology  2013;13:4.
Ulceration of the oesophageal squamous mucosa (ulcerative oesophagitis) is a pathological manifestation of gastro-oesophageal reflux disease, and is a major risk factor for the development of Barrett’s oesophagus. Barrett’s oesophagus is characterised by replacement of reflux-damaged oesophageal squamous epithelium with a columnar intestinal-like epithelium. We previously reported discovery of microRNAs that are differentially expressed between oesophageal squamous mucosa and Barrett’s oesophagus mucosa. Now, to better understand early steps in the initiation of Barrett’s oesophagus, we assessed the expression, location and function of these microRNAs in oesophageal squamous mucosa from individuals with ulcerative oesophagitis.
Quantitative real-time PCR was used to compare miR-21, 143, 145, 194, 203, 205 and 215 expression levels in oesophageal mucosa from individuals without pathological gastro-oesophageal reflux to individuals with ulcerative oesophagitis. Correlations between microRNA expression and messenger RNA differentiation markers BMP-4, CK8 and CK14 were analyzed. The cellular localisation of microRNAs within the oesophageal mucosa was determined using in-situ hybridisation. microRNA involvement in proliferation and apoptosis was assessed following transfection of a human squamous oesophageal mucosal cell line (Het-1A).
miR-143, miR-145 and miR-205 levels were significantly higher in gastro-oesophageal reflux compared with controls. Elevated miR-143 expression correlated with BMP-4 and CK8 expression, and elevated miR-205 expression correlated negatively with CK14 expression. Endogenous miR-143, miR-145 and miR-205 expression was localised to the basal layer of the oesophageal epithelium. Transfection of miR-143, 145 and 205 mimics into Het-1A cells resulted in increased apoptosis and decreased proliferation.
Elevated miR-143, miR-145 and miR-205 expression was observed in oesophageal squamous mucosa of individuals with ulcerative oesophagitis. These miRNAs localised to the basal layer of the oesophageal epithelium. They reduced proliferation and increased apoptosis, and may play roles in regulating epithelial restoration in response to injury caused by gastro-oesophageal reflux.
PMCID: PMC3553039  PMID: 23297865
microRNA; Gastro-oesophageal reflux disease; Ulcerative oesophagitis; Apoptosis; Proliferation; Barrett’s oesophagus
8.  Producing High-Accuracy Lattice Models from Protein Atomic Coordinates Including Side Chains 
Advances in Bioinformatics  2012;2012:148045.
Lattice models are a common abstraction used in the study of protein structure, folding, and refinement. They are advantageous because the discretisation of space can make extensive protein evaluations computationally feasible. Various approaches to the protein chain lattice fitting problem have been suggested but only a single backbone-only tool is available currently. We introduce LatFit, a new tool to produce high-accuracy lattice protein models. It generates both backbone-only and backbone-side-chain models in any user defined lattice. LatFit implements a new distance RMSD-optimisation fitting procedure in addition to the known coordinate RMSD method. We tested LatFit's accuracy and speed using a large nonredundant set of high resolution proteins (SCOP database) on three commonly used lattices: 3D cubic, face-centred cubic, and knight's walk. Fitting speed compared favourably to other methods and both backbone-only and backbone-side-chain models show low deviation from the original data (~1.5 Å RMSD in the FCC lattice). To our knowledge this represents the first comprehensive study of lattice quality for on-lattice protein models including side chains while LatFit is the only available tool for such models.
PMCID: PMC3426164  PMID: 22934109
9.  Pt-Catalyzed Cyclization/1,2-Migration for the Synthesis of Indolizines, Pyrrolones, and Indolizinones 
Organic Letters  2007;9(6):1169-1171.
Indolizine, pyrrolone, and indolizinone heterocycles are easily accessed via the Pt(II)-catalyzed cycloisomerization or a tandem cyclization/1,2-migration of pyridine propargylic alcohols and derivatives. This method provides an efficient synthesis of highly functionalized heterocycles from readily available substrates.
PMCID: PMC3384527  PMID: 17309277
10.  Pt-catalyzed cyclization/migration of propargylic alcohols for the synthesis of 3(2H)-furanones, pyrrolones, indolizines, and indolizinones 
Tetrahedron  2008;64(29):7008-7014.
Several heterocycles such as furanones, pyrrolones, and indolizines, which are of pharmacological importance, are easily accessed via the Pt(II)-catalyzed heterocyclization/1,2-migration of propargylic ketols or hydroxy imine derivatives. This method sidesteps the challenges of traditional heteroaromatic oxygenation strategies such as regioselectivity and functional group tolerance in the syntheses of these heterocycles.
PMCID: PMC3351138  PMID: 22593605
11.  miR-200 family expression is downregulated upon neoplastic progression of Barrett’s esophagus 
AIM: To investigate miR-200 family expression in Barrett’s epithelium, gastric and duodenal epithelia, and esophageal adenocarcinoma.
METHODS: Real-time reverse transcriptase-polymerase chain reaction was used to measure miR-200, ZEB1 and ZEB2 expression. Ingenuity Pathway Analysis of miR-200 targets was used to predict biological outcomes.
RESULTS: Barrett’s epithelium expressed lower levels of miR-141 and miR-200c than did gastric and duodenal epithelia (P < 0.001). In silico analysis indicated roles for the miR-200 family in molecular pathways that distinguish Barrett’s epithelium from gastric and duodenal epithelia, and which control apoptosis and proliferation. All miR-200 members were downregulated in adenocarcinoma (P < 0.02), and miR-200c expression was also downregulated in non-invasive epithelium adjacent to adenocarcinoma (P < 0.02). The expression of all miR-200 members was lower in Barrett’s epithelium derived high-grade dysplastic cell lines than in a cell line derived from benign Barrett’s epithelium. We observed significant inverse correlations between miR-200 family expression and ZEB1 and ZEB2 expression in Barrett’s epithelium and esophageal adenocarcinoma (P < 0.05).
CONCLUSION: miR-200 expression might contribute to the anti-apoptotic and proliferative phenotype of Barrett’s epithelium and regulate key neoplastic processes in this epithelium.
PMCID: PMC3057147  PMID: 21448356
miRNA; Barrett’s esophagus; Esophageal adenocarcinoma; miR-200; Epithelial to mesenchymal transition; Apoptosis; Proliferation; Epithelium
12.  Oscillations by Minimal Bacterial Suicide Circuits Reveal Hidden Facets of Host-Circuit Physiology 
PLoS ONE  2010;5(7):e11909.
Synthetic biology seeks to enable programmed control of cellular behavior though engineered biological systems. These systems typically consist of synthetic circuits that function inside, and interact with, complex host cells possessing pre-existing metabolic and regulatory networks. Nevertheless, while designing systems, a simple well-defined interface between the synthetic gene circuit and the host is frequently assumed. We describe the generation of robust but unexpected oscillations in the densities of bacterium Escherichia coli populations by simple synthetic suicide circuits containing quorum components and a lysis gene. Contrary to design expectations, oscillations required neither the quorum sensing genes (luxR and luxI) nor known regulatory elements in the PluxI promoter. Instead, oscillations were likely due to density-dependent plasmid amplification that established a population-level negative feedback. A mathematical model based on this mechanism captures the key characteristics of oscillations, and model predictions regarding perturbations to plasmid amplification were experimentally validated. Our results underscore the importance of plasmid copy number and potential impact of “hidden interactions” on the behavior of engineered gene circuits - a major challenge for standardizing biological parts. As synthetic biology grows as a discipline, increasing value may be derived from tools that enable the assessment of parts in their final context.
PMCID: PMC2912849  PMID: 20689598
13.  Freiburg RNA Tools: a web server integrating IntaRNA, ExpaRNA and LocARNA 
Nucleic Acids Research  2010;38(Web Server issue):W373-W377.
The Freiburg RNA tools web server integrates three tools for the advanced analysis of RNA in a common web-based user interface. The tools IntaRNA, ExpaRNA and LocARNA support the prediction of RNA–RNA interaction, exact RNA matching and alignment of RNA, respectively. The Freiburg RNA tools web server and the software packages of the stand-alone tools are freely accessible at
PMCID: PMC2896085  PMID: 20444875
14.  MicroRNAs, development of Barrett’s esophagus, and progression to esophageal adenocarcinoma 
Barrett’s esophagus is a premalignant condition caused by gastroesophageal reflux. Once developed, it can progress through varying grades of dysplasia to esophageal adenocarcinoma. Whilst it is well accepted that Barrett’s esophagus is caused by gastroesophageal reflux, the molecular mechanisms of its pathogenesis and progression to cancer remain unclear. MicroRNAs (miRNAs) are short segments of RNA that have been shown to control the expression of many human genes. They have been implicated in most cellular processes, and the role of miRNAs in disease development is becoming increasingly evident. Understanding altered miRNA expression is likely to help unravel the molecular mechanisms that underpin the development of Barrett’s esophagus and its progression to cancer.
PMCID: PMC2816263  PMID: 20128019
Barrett’s esophagus; MicroRNA; Esophageal adenocarcinoma; Transdifferentiation; Tumour suppressor
15.  Signal discrimination by differential regulation of protein stability in quorum sensing 
Journal of molecular biology  2008;382(5):1290-1297.
Quorum sensing (QS) is a communication mechanism exploited by a large variety of bacteria to coordinate gene expression at the population level. In gram-negative bacteria, QS occurs via synthesis and detection of small chemical signals, most of which belong to the acyl-homoserine lactone (AHL) class. In such a system, binding of an AHL signal to its cognate transcriptional regulator (R-protein) often induces stabilization and subsequent dimerization of the R-protein, which results in the regulation of downstream gene expression. Existence of diverse QS systems within and among species of bacteria indicates that each bacterium needs to distinguish among a myriad of structurally similar chemical signals. We show, using a mathematical model, that fast degradation of an R-protein monomer can facilitate discrimination of signals that differentially stabilize it. Furthermore, our results suggest an inverse correlation between the stability of an R-protein and the achievable limits of fidelity in signal discrimination. In particular, an unstable R-protein tends to be more specific to its cognate signal, whereas a stable R-protein tends to be more promiscuous. These predictions are consistent with experimental data on well-studied natural and engineered R-proteins, and thus have implications for understanding the functional design of QS systems.
PMCID: PMC2573026  PMID: 18721812
gene regulation; quorum sensing; kinetic proofreading; systems biology
16.  CPSP-web-tools: a server for 3D lattice protein studies 
Bioinformatics  2009;25(5):676-677.
Summary: Studies on proteins are often restricted to highly simplified models to face the immense computational complexity of the associated problems. Constraint-based protein structure prediction (CPSP) tools is a package of very fast algorithms for ab initio optimal structure prediction and related problems in 3D HP-models [cubic and face centered cubic (FCC)]. Here, we present CPSP-web-tools, an interactive online interface of these programs for their immediate use. They include the first method for the direct prediction of optimal energies and structures in 3D HP side-chain models. This newest extension of the CPSP approach is described here for the first time.
Availability and Implementation: Free access at
PMCID: PMC2647832  PMID: 19151096

Results 1-16 (16)