New specimens of the basal ornithischian dinosaur Lesothosaurus diagnosticus Galton, 1978 from the Early Jurassic of South Africa

We describe new specimens of the basal ornithischian dinosaur Lesothosaurus diagnosticus Galton, 1978 collected from a bonebed in the Fouriesburg district of the Free State, South Africa. The material was collected from the upper Elliot Formation (Early Jurassic) and represents the remains of at least three individuals. These individuals are larger in body size than those already known in museum collections and offer additional information on cranial ontogeny in the taxon. Moreover, they are similar in size to the sympatric taxon Stormbergia dangershoeki. The discovery of three individuals at this locality might imply group-living behaviour in this early ornithischian.Palaeontologia africana 2016. ©2016 Paul M. Barrett, Richard J. Butler, Adam M. Yates, Matthew G. Baron&Jonah N. Choiniere. This is an open-access article published under the Creative Commons Attribution 4.0 Unported License (CC BY4.0). To view a copy of the license, please visit http://creativecommons.org/licenses/by/4.0/. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This item is permanently archived at: http://wiredspace.wits.ac.za/handle/10539/19886. The attached file is the published version of the article

Complement C3 variant and the risk of age-related macular degeneration

Background: Age-related macular degeneration is the most common cause of blindness in Western populations. Susceptibility is influenced by age and by genetic and environmental factors. Complement activation is implicated in the pathogenesis.Methods: We tested for an association between age-related macular degeneration and 13 single-nucleotide polymorphisms (SNPs) spanning the complement genes C3 and C5 in case subjects and control subjects from the southeastern region of England. All subjects were examined by an ophthalmologist and had independent grading of fundus photographs to confirm their disease status. To test for replication of the most significant findings, we genotyped a set of Scottish cases and controls.Results: The common functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding to the electrophoretic variants C3S (slow) and C3F (fast), was strongly associated with age-related macular degeneration in both the English group (603 cases and 350 controls, P=5.9 x 10(sup -5)) and the Scottish group (244 cases and 351 controls, P=5.0 x 10(sup -5)). The odds ratio for age-related macular degeneration in C3 S/F heterozygotes as compared with S/S homozygotes was 1.7 (95% confidence interval [CI], 1.3 to 2.1); for F/F homozygotes, the odds ratio was 2.6 (95% CI, 1.6 to 4.1). The estimated population attributable risk for C3F was 22%.Conclusions: Complement C3 is important in the pathogenesis of age-related macular degeneration. This finding further underscores the influence of the complement pathway in the pathogenesis of this disease

Spatial heterogeneity and peptide availability determine CTL killing efficiency in vivo

The rate at which a cytotoxic T lymphocyte (CTL) can survey for infected cells is a key ingredient of models of vertebrate immune responses to intracellular pathogens. Estimates have been obtained using in vivo cytotoxicity assays in which peptide-pulsed splenocytes are killed by CTL in the spleens of immunised mice. However the spleen is a heterogeneous environment and splenocytes comprise multiple cell types. Are some cell types intrinsically more susceptible to lysis than others? Quantitatively, what impacts are made by the spatial distribution of targets and effectors, and the level of peptide-MHC on the target cell surface? To address these questions we revisited the splenocyte killing assay, using CTL specific for an epitope of influenza virus. We found that at the cell population level T cell targets were killed more rapidly than B cells. Using modeling, quantitative imaging and in vitro killing assays we conclude that this difference in vivo likely reflects different migratory patterns of targets within the spleen and a heterogeneous distribution of CTL, with no detectable difference in the intrinsic susceptibilities of the two populations to lysis. Modeling of the stages involved in the detection and killing of peptide-pulsed targets in vitro revealed that peptide dose influenced the ability of CTL to form conjugates with targets but had no detectable effect on the probability that conjugation resulted in lysis, and that T cell targets took longer to lyse than B cells. We also infer that incomplete killing in vivo of cells pulsed with low doses of peptide may be due to a combination of heterogeneity in peptide uptake and the dissociation, but not internalisation, of peptide-MHC complexes. Our analyses demonstrate how population-averaged parameters in models of immune responses can be dissected to account for both spatial and cellular heterogeneity

Mycobacterium tuberculosis Responds to Chloride and pH as Synergistic Cues to the Immune Status of its Host Cell

PubMed ID: 23592993This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Computational Cancer Biology: An Evolutionary Perspective

ISSN:1553-734XISSN:1553-735

Lower cardiorespiratory fitness contributes to increased insulin resistance and fasting glycaemia in middle-aged South Asian compared with European men living in the UK

AIMS/HYPOTHESIS: This study aimed to determine the extent to which increased insulin resistance and fasting glycaemia in South Asian men, compared with white European men, living in the UK, was due to lower cardiorespiratory fitness (maximal oxygen uptake [[Formula: see text]]) and physical activity. METHODS: One hundred South Asian and 100 age- and BMI-matched European men without diagnosed diabetes, aged 40–70 years, had fasted blood taken for measurement of glucose concentration, HOMA-estimated insulin resistance (HOMA(IR)), plus other risk factors, and underwent assessment of physical activity (using accelerometry), [Formula: see text], body size and composition, and demographic and other lifestyle factors. For 13 South Asian and one European man, HbA(1c) levels were >6.5% (>48 mmol/mol), indicating potential undiagnosed diabetes; these men were excluded from the analyses. Linear regression models were used to determine the extent to which body size and composition, fitness and physical activity variables explained differences in HOMA(IR) and fasting glucose between South Asian and European men. RESULTS: HOMA(IR) and fasting glucose were 67% (p < 0.001) and 3% (p < 0.018) higher, respectively, in South Asians than Europeans. Lower [Formula: see text], lower physical activity and greater total adiposity in South Asians individually explained 68% (95% CI 45%, 91%), 29% (11%, 46%) and 52% (30%, 80%), respectively, and together explained 83% (50%, 119%) (all p < 0.001) of the ethnic difference in HOMA(IR). Lower [Formula: see text] and greater total adiposity, respectively, explained 61% (9%, 111%) and 39% (9%, 76%) (combined effect 63% [8%, 115%]; all p < 0.05) of the ethnic difference in fasting glucose. CONCLUSIONS/INTERPRETATION: Lower cardiorespiratory fitness is a key factor associated with the excess insulin resistance and fasting glycaemia in middle-aged South Asian, compared with European, men living in the UK. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-013-2969-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users

A direct physical interaction between Nanog and Sox2 regulates embryonic stem cell self-renewal

Embryonic stem (ES) cell self-renewal efficiency is determined by the Nanog protein level. However, the protein partners of Nanog that function to direct self-renewal are unclear. Here, we identify a Nanog interactome of over 130 proteins including transcription factors, chromatin modifying complexes, phosphorylation and ubiquitination enzymes, basal transcriptional machinery members, and RNA processing factors. Sox2 was identified as a robust interacting partner of Nanog. The purified Nanog–Sox2 complex identified a DNA recognition sequence present in multiple overlapping Nanog/Sox2 ChIP-Seq data sets. The Nanog tryptophan repeat region is necessary and sufficient for interaction with Sox2, with tryptophan residues required. In Sox2, tyrosine to alanine mutations within a triple-repeat motif (S X T/S Y) abrogates the Nanog–Sox2 interaction, alters expression of genes associated with the Nanog-Sox2 cognate sequence, and reduces the ability of Sox2 to rescue ES cell differentiation induced by endogenous Sox2 deletion. Substitution of the tyrosines with phenylalanine rescues both the Sox2–Nanog interaction and efficient self-renewal. These results suggest that aromatic stacking of Nanog tryptophans and Sox2 tyrosines mediates an interaction central to ES cell self-renewal

Exposure of neonatal rats to maternal cafeteria feeding during suckling alters hepatic gene expression and DNA methylation in the insulin signalling pathway

Nutrition in early life is a determinant of lifelong physiological and metabolic function. Diseases that are associated with ageing may, therefore, have their antecedents in maternal nutrition during pregnancy and lactation. Rat mothers were fed either a standard laboratory chow diet (C) or a cafeteria diet (O) based upon a varied panel of highly palatable human foods, during lactation. Their offspring were then weaned onto chow or cafeteria diet giving four groups of animals (CC, CO, OC, OO n=9-10). Livers were harvested 10 weeks post-weaning for assessment of gene and protein expression, and DNA methylation. Cafeteria feeding post-weaning impaired glucose tolerance and was associated with sex-specific altered mRNA expression of peroxisome proliferator activated receptor gamma (PPARg) and components of the insulin-signalling pathway (Irs2, Akt1 and IrB). Exposure to the cafeteria diet during the suckling period modified the later response to the dietary challenge. Post-weaning cafeteria feeding only down-regulated IrB when associated with cafeteria feeding during suckling (group OO, interaction of diet in weaning and lactation P=0.041). Responses to cafeteria diet during both phases of the experiment varied between males and females. Global DNA methylation was altered in the liver following cafeteria feeding in the post-weaning period, in males but not females. Methylation of the IrB promoter was increased in group OC, but not OO (P=0.036). The findings of this study add to a growing evidence base that suggests tissue function across the lifespan a product of cumulative modifications to the epigenome and transcriptome, which may be both tissue and sex-specific

Arabinogalactan-protein and pectin epitopes in relation to an extracellular matrix surface network and somatic embryogenesis and callogenesis in Trifolium nigrescens Viv

The formation of an extracellular matrix surface network (ECMSN), and associated changes in the distribution of arabinogalactan-protein and pectin epitopes, have been studied during somatic embryogenesis (SE) and callogenesis of Trifolium nigrescens Viv. Scanning electron microscopy observations revealed the occurrence of an ECMSN on the surface of cotyledonary-staged somatic embryos as well as on the peripheral, non-regenerating callus cells. The occurrence of six AGP (JIM4, JIM8, JIM13, JIM16, LM2, MAC207) and four pectin (JIM5, JIM7, LM5, LM6) epitopes was analysed during early stages of SE, in cotyledonary-staged somatic embryos and in non-embryogenic callus using monoclonal antibodies. The JIM5 low methyl-esterified homogalacturonan (HG) epitope localized to ECMSN on the callus surface but none of the epitopes studied were found to localize to ECMSN over mature somatic embryos. The LM2 AGP epitope was detected during the development of somatic embryos and was also observed in the cell walls of meristematic cells from which SE was initiated. The pectic epitopes JIM5, JIM7, LM5 and LM6 were temporally regulated during SE. The LM6 arabinan epitope, carried by side chains of rhamnogalacturonan-I (RG-I), was detected predominantly in cells of embryogenic swellings, whilst the LM5 galactan epitope of RG-I was uniformly distributed throughout the ground tissue of cotyledonary-staged embryoids but not detected at the early stages of SE. Differences in the distribution patterns of low and high methyl-esterified HG were detected: low ester HG (JIM5 epitope) was most abundant during the early steps of embryo formation and highly methyl-esterified form of HG (JIM7 epitope) became prevalent during embryoid maturation

Informational entropy : a failure tolerance and reliability surrogate for water distribution networks

Evolutionary algorithms are used widely in optimization studies on water distribution networks. The optimization algorithms use simulation models that analyse the networks under various operating conditions. The solution process typically involves cost minimization along with reliability constraints that ensure reasonably satisfactory performance under abnormal operating conditions also. Flow entropy has been employed previously as a surrogate reliability measure. While a body of work exists for a single operating condition under steady state conditions, the effectiveness of flow entropy for systems with multiple operating conditions has received very little attention. This paper describes a multi-objective genetic algorithm that maximizes the flow entropy under multiple operating conditions for any given network. The new methodology proposed is consistent with the maximum entropy formalism that requires active consideration of all the relevant information. Furthermore, an alternative but equivalent flow entropy model that emphasizes the relative uniformity of the nodal demands is described. The flow entropy of water distribution networks under multiple operating conditions is discussed with reference to the joint entropy of multiple probability spaces, which provides the theoretical foundation for the optimization methodology proposed. Besides the rationale, results are included that show that the most robust or failure-tolerant solutions are achieved by maximizing the sum of the entropies