Problems of Rehousing

The purpose of this thesis was to investigate the changing circumstances of a group of families rehoused by the Glasgow Local Authority. The families came mostly from central areas of the city and were rehoused in Drumchapel on the western periphery of Glasgow. The gains of moving to new houses were thus offset by separation from friends and relatives, and increased travelling times to work and shops. Fresh air and clean surroundings were accompanied by higher rates and rents, higher bus fares and the expense of fitting out new and larger houses. A total of 421 families were seen in their old houses immediately before being rehoused by the local authority. Three hundred and ninety-seven of these families were seen after six months in their new houses and 387 after one year. Most of the families had been on the local authority housing list for over ten years and the average age of the tenants at the time of rehousing was over 38 years. Nine out of ten of the old houses were tenements dating back to the nineteenth century. Nine out of ten of the new houses were also tenements, and the majority of these were of three apartments (Two bedrooms and living-dining room). The numbers of new four and five apartment houses available were inadequate and led to overcrowding in over one fifth of the three-apartment houses. The number of smaller houses available was also inadequate, making it necessary in several cases to accommodate couples and single persons in three-apartment houses. Nevertheless overcrowding was far less common after rehousing, and overcrowding of sleeping accommodation was abolished. Almost one half of the old houses had shared toilet accommodation. In such cases the toilet was usually situated on the stairhead and shared by two to five families. Less than one fifth of the houses had baths or running hot water. All of the new houses had toilets, baths and running hot water. Most of the tenants were engaged in skilled or semi-skilled work, but the tenants transferred from houses due for demolition and the tenants who had kept their old houses in an unsatisfactory state, showed an excess of unskilled workers. Further, the men drawn from these very decrepit and ill-kept houses showed a relatively poor work record in terms of continuity of employment over the two years before rehousing. Over one half of the tenants had liked their old districts, but most of them preferred Drumchapel. Those tenants transferred from older local authority houses often saw little improvement in Drumchapel over their old conditions. They were glad to move to a home of their own, but often sighed for the semi-detached, or terraced type of house they had left. The rents and rates of the old houses averaged 15/4[d] weekly, those of the new houses averaged 25/5[d] weekly. The increase was considered worthwhile by most tenants when they took into account the improved facilities of the new houses. (Abstract shortened by ProQuest.)

Comparative transcriptional profiling analysis of developing melon (Cucumis melo L.) fruit from climacteric and non-climacteric varieties

[EN] Background: In climacteric fruit-bearing species, the onset of fruit ripening is marked by a transient rise in respiration rate and autocatalytic ethylene production, followed by rapid deterioration in fruit quality. In non-climacteric species, there is no increase in respiration or ethylene production at the beginning or during fruit ripening. Melon is unusual in having climacteric and non-climacteric varieties, providing an interesting model system to compare both ripening types. Transcriptomic analysis of developing melon fruits from Védrantais and Dulce (climacteric) and Piel de sapo and PI 161375 (non-climacteric) varieties was performed to understand the molecular mechanisms that differentiate the two fruit ripening types. Results: Fruits were harvested at 15, 25, 35 days after pollination and at fruit maturity. Transcript profiling was performed using an oligo-based microarray with 75 K probes. Genes linked to characteristic traits of fruit ripening were differentially expressed between climacteric and non-climacteric types, as well as several transcription factor genes and genes encoding enzymes involved in sucrose catabolism. The expression patterns of some genes in PI 161375 fruits were either intermediate between. Piel de sapo and the climacteric varieties, or more similar to the latter. PI 161375 fruits also accumulated some carotenoids, a characteristic trait of climacteric varieties. Conclusions: Simultaneous changes in transcript abundance indicate that there is coordinated reprogramming of gene expression during fruit development and at the onset of ripening in both climacteric and non-climacteric fruits. The expression patterns of genes related to ethylene metabolism, carotenoid accumulation, cell wall integrity and transcriptional regulation varied between genotypes and was consistent with the differences in their fruit ripening characteristics. There were differences between climacteric and non-climacteric varieties in the expression of genes related to sugar metabolism suggesting that they may be potential determinants of sucrose content and post-harvest stability of sucrose levels in fruit. Several transcription factor genes were also identified that were differentially expressed in both types, implicating them in regulation of ripening behaviour. The intermediate nature of PI 161375 suggested that classification of melon fruit ripening behaviour into just two distinct types is an over-simplification, and that in reality there is a continuous spectrum of fruit ripening behaviourWe wish to thank Marta Casado for assistance with qRT-PCR analysis, Anna Orozco and Rosa Rodriguez for help with carotenoid measurements, Kostas Alexiou for uploading the microarray data at GEO and Walter Sanseverino for obtaining the correspondence of the microarray contigs with the melon annotated genes. We thank Beatrice Encke and Nicole Krohn for technical help with the sugar analysis. We also thank Laura Pascual for a critical reading of the manuscript. MSa was supported by a JAE-Doc grant from the Spanish Ministry of Science. This work was supported by the Spanish Ministry of Science and Innovation (MICINN project GEN2006-27773-C2-1-E to JGM) and the German Federal Ministry of Education and Research (BMBF project 0313987 to MSt) within the framework of the EU Framework 6 ERA-NET Plant Genomics programme.Saladie, M.; Cañizares Sales, J.; Michael A. Phillips; Rodriguez Concepcion, M.; Larrigaudière, C.; Gibon, Y.; Stitt, M.... (2015). Comparative transcriptional profiling analysis of developing melon (Cucumis melo L.) fruit from climacteric and non-climacteric varieties. BMC Genomics. 16(440):1-20. https://doi.org/10.1186/s12864-015-1649-3S12016440McMurchie EJ, McGlasson WB, Eaks IL. Treatment of fruit with propylene gives information about the biogenesis of ethylene. Nature. 1972;237:235–6.Giovannoni JJ. Genetic regulation of fruit development and ripening. Plant Cell. 2004;16:S170–80.Yamaguchi M, Hughes DL, Yabumoto K, Jennings WG. Quality of cantaloupe muskmelons: Variability and attributes. Scientia Hort. 1977;6:59–70.Seymour GB, McGlasson WB. Melons. In: Seymour GB, Taylor JE, Tucker GA, editors. Biochemistry of fruit ripening. London: Chapman & Hall; 1993. p. 273-290.Pech JC, Balague C, Latché A, Bouzayen M. Post-harvest physiology of climacteric fruits: recent developments in the biosynthesis and action of ethylene. Sci Aliments. 1994;14:3–15.Latché A, Ayub RA, Martinez G, Guis M, Ben Amor M, Rombaldi CV, et al. Biosynthèse et mode d’action de l’hormone végétale éthylène. Fruits. 1995;50:379–96.Moore S, Payton P, Wright M, Tanksley S, Giovannoni J. Utilization of tomato microarrays for comparative gene expression analysis in the Solanaceae. J Exp Bot. 2005;56:2885–95.Giovannoni JJ. Fruit ripening mutants yield insights into ripening control. Curr Opin Plant Biol. 2007;10:283–9.Saladié M, Rose JKC, Cosgrove DJ, Catalá C. Characterization of a new xyloglucan endotransglucosylase/hydrolase (XTH) from ripening tomato fruit and implications for the diverse modes of enzymic action. Plant J. 2006;47:282–95.Stepanova AN, Alonso JM. Ethylene signalling and response: where different regulatory modules meet. Curr Opin Plant Sci. 2009;12:548–55.Alexander L, Grierson D. Ethylene biosynthesis and action in tomato: a model for climacteric fruit ripening. J Exp Bot. 2002;53:2039–55.Klee HJ. Ethylene signal transduction. Moving beyond Arabidopsis. Plant Physiol. 2004;135:660–7.Adams-Phillips L, Barry C, Giovannoni J. Signal transduction systems regulating fruit ripening. Trends Plant Sci. 2004;9:331–8.Vrebalov J, Ruezinsky D, Padmanabhan V, White R, Medrano D, Drake R, et al. A MADS-box gene necessary for fruit ripening at the tomato ripening-inhibitor (rin) locus. Science. 2002;296:343–6.Giovannoni JJ, Tanksley S, Vrebalov J, Noensie F. NOR gene compositions and methods for use thereof. US Patent 6762347_B1. July 13, 2004.Manning K, Tor M, Poole M, Hong Y, Thompson AJ, King GJ, et al. A naturally occurring epigenetic mutation in a gene encoding an SBP-box transcription factor inhibits tomato fruit ripening. Nat Genet. 2006;38:948–52.Itkin M, Seybold H, Breitel D, Rogachev I, Meir S, Aharoni A. TOMATO AGAMOUS-LIKE 1 is a component of the fruit ripening regulatory network. Plant J. 2009;60:1081–95.Lin Z, Hong Y, Yin M, Li C, Zhang K, Grierson D. A tomato HD-Zip homeobox protein, LeHB-1, plays an important role in floral organogenesis and ripening. Plant J. 2008;55:301–10.Chung M-Y, Vrebalov J, Alba R, Lee JM, McQuinn R, Chung J-D, et al. A tomato (Solanum lycopersicum) APETALA2/ERF gene, SlAP2a, is a negative regulator of fruit ripening. Plant J. 2011;64:936–47.Karlova R, Rosin FM, Busscher-Lange J, Parapunova V, Do PT, Fernie AR, et al. Transcriptome and metabolite profiling show that APETALA2a is a major regulator of tomato fruit ripening. Plant Cell. 2011;23:923–41.Seymour GB, Chapman NH, Chew BL, Rose JKC. Regulation of ripening and opportunities for control in tomato and other fruits. Plant Biotechnol J. 2013;11:269–78.Klee HJ, Giovannoni JJ. Genetics and control of tomato fruit ripening and quality attributes. Annu Rev Genet. 2011;45:41–59.Bemer M, Karlova R, Ballester AR, Tikunov YM, Bovy AG, Wolters-Arts M, et al. The tomato FRUITFUL homologs TDR4/FUL1 and MBP7/FUL2 regulate ethylene-Independent aspects of fruit ripening. Plant Cell. 2012;24:4437–51.Fujisawa M, Shima Y, Higuchi N, Nakano T, Koyama Y, Kasumi T, et al. Direct targets of the tomato-ripening regulator RIN identified by transcriptome and chromatin immunoprecipitation analyses. Planta. 2012;235:1107–22.Kumar R, Sharma MK, Kapoor S, Tyagi AK, Sharma A. Transcriptome analysis of rin mutant fruit and in silico analysis of promoters of differentially regulated genes provides insight into LeMADS-RIN-regulated ethylene-dependent as well as ethylene-independent aspects of ripening in tomato. Mol Genet Genom. 2012;287:189–203.Zhong S, Fei Z, Chen Y-R, Zheng Y, Huang M, Vrebalov J, et al. Single-base resolution methylomes of tomato fruit development reveal epigenome modifications associated with ripening. Nat Biotechnol. 2013;31:154–9.Wilkinson JQ, Lanahan MB, Conner TW, Klee HJ. Identification of mRNAs with enhanced expression in ripening strawberry fruit using polymerase chain reaction differential display. Plant Mol Biol. 1995;27:1097–108.Manning K. Isolation of a set of ripening-related genes from strawberry: Their identification and possible relationship to fruit quality traits. Planta. 1998;205:622–31.Aharoni A, Keizer LC, Bouwmeester HJ, Sun Z, Alvarez-Huerta M, Verhoeven HA, et al. Identification of the SAAT gene involved in strawberry flavor biogenesis by use of DNA microarrays. Plant Cell. 2000;12:647–62.Osorio S, Alba R, Nikoloski Z, Kochevenko A, Fernie AR, Giovannoni JJ. Integrative comparative analyses of transcript and metabolite profiles from pepper and tomato ripening and development stages uncovers species-specific patterns of network regulatory behavior. Plant Physiol. 2012;159:1713–29.Ezura H, Owino WO. Melon ripening and ethylene. Plant Sci. 2008;175:121–9.Pech JC, Bouzayen M, Latché A. Climacteric fruit ripening: ethylene-dependent and independent regulation of ripening pathways in melon fruit. Plant Sci. 2008;175:114–20.Vegas J, Garcia-Mas J, Monforte AJ. Interaction between QTLs induces an advance in ethylene biosynthesis during melon fruit ripening. Theor Appl Genet. 2013;126:1531–44.Lyons JM, Pratt HK, McGlasson WB. Ethylene production, respiration, and internal gas concentrations in cantaloupe fruits at various stages of maturity. Plant Physiol. 1962;37:31–26.Hadfield KA, Dang T, Guis M, Pech JC, Bouzayen M, Bennett AB. Characterization of ripening-regulated cDNAs and their expression in ethylene-suppressed Charentais melon fruit. Plant Physiol. 2000;122:977–83.Ayub R, Guis M, Ben Amor M, Gillot L, Roustan JP, Latché A, et al. Expression of ACC oxidase antisense gene inhibits ripening of cantaloupe melon fruits. Nat Biotechnol. 1996;14:862–6.Monforte AJ, Oliver M, Gonzalo MJ, Alvarez JM, Dolcet-Sanjuan R, Arus P. Identification of quantitative trait loci involved in fruit quality traits in melon (Cucumis melo L.). Theor Appl Genet. 2004;108:750–8.Cuevas HE, Staub JE, Simon PW, Zalapa JE. A consensus linkage map identifies genomic regions controlling fruit maturity and beta-carotene-associated flesh color in melon (Cucumis melo L.). Theor Appl Genet. 2009;119:741–56.Bian W, Barsan C, Egea I, Purgatto E, Chervin C, Zouine M, et al. Metabolic and molecular events occurring during chromoplast biogenesis. J Bot. 2011;10:1–13.Pratt HK, Goeschl JD, Martin FW. Fruit growth and development, ripening, and role of ethylene in honey dew muskmelon. J Am Soc Hortic Sci. 1977;102:203–10.Lester GE, Dunlap JR. Physiological-changes during development and ripening of perlita muskmelon fruits. Sci Hortic. 1985;26:323–31.Rose JKC, Hadfield KA, Labavitch JM, Bennett AB. Temporal sequence of cell wall disassembly in rapidly ripening melon fruit. Plant Physiol. 1998;117:345–61.Nishiyama K, Guis M, Rose JK, Kubo Y, Bennett KA, Wangjin L, et al. Ethylene regulation of fruit softening and cell wall disassembly in Charentais melon. J Exp Bot. 2007;58:1281–90.Portnoy V, Diber A, Pollock S, Karchi H, Lev S, Tzuri G, et al. Use of non-normalized, non-amplified cDNA for 454-based RNA sequencing of fleshy melon fruit. Plant Genome. 2011;4:1.Dai N, Cohen S, Portnoy V, Tzuri G, Harel-Beja R, Pompan-Lotan M, et al. Metabolism of soluble sugars in developing melon fruit: a global transcriptional view of the metabolic transition to sucrose accumulation. Plant Mol Biol. 2011;76:1–18.Corbacho J, Romojaro F, Pech JC, Latché A, Gomez-Jimenez MC. Transcriptomic events involved in melon mature-fruit abscission comprise the sequential induction of cell-wall degrading genes coupled to a stimulation of endo and exocytosis. PLoS One. 2013;8:e58363.Mascarell-Creus A, Cañizares J, Vilarrasa-Blasi J, Mora-García S, Blanca J, Gonzalez-Ibeas D, et al. An oligo-based microarray offers novel transcriptomic approaches for the analysis of pathogen resistance and fruit quality traits in melon (Cucumis melo L). BMC Genomics. 2009;10:e467.Garcia-Mas J, Benjak A, Sanseverino W, Bourgeois M, Mir G, Gonzalez VM, et al. The genome of melon (Cucumis melo L.). Proc Natl Acad Sci U S A. 2012;109:11872–7.Gonzalez-Ibeas D, Cañizares J, Aranda MA. Microarray analysis shows that recessive resistance to Watermelon mosaic virus in melon is associated with the induction of defense response genes. Mol Plant Microbe Interact. 2012;25:107–18.Roig C, Fita A, Ríos G, Hammond JP, Nuez F, Picó B. Root transcriptional responses of two melon genotypes with contrasting resistance to Monosporascus cannonballus (Pollack et Uecker) infection. BMC Genomics. 2012;13:601–12.Conesa A, Nueda MJ, Ferrer A, Talón M. MaSigPro: a method to identify significantly differential expression profiles in time-course microarray experiments. Bioinformatics. 2006;22:1096–102.Al-Shahrour F, Díaz-Uriarte R, Dopazo J. FatiGO: a web tool for finding significant associations of Gene Ontology terms with groups of genes. Bioinformatics. 2004;20:578–80.Pilati S, Perazzolli M, Malossini A, Cestaro A, Demattè L, Fontana P, et al. Genome-wide transcriptional analysis of grapevine berry ripening reveals a set of genes similarly modulated during three seasons and the occurrence of an oxidative burst at vèraison. BMC Genomics. 2007;8:428.Miki T, Yamamoto M, Nakagawa H, Ogura N, Mori H, Imaseki H, et al. Nucleotide sequence of a cDNA for 1-aminocyclopropane-1-carboxylate synthase from melon fruits. Plant Physiol. 1995;107:297–8.Yamamoto M, Miki T, Ishiki Y, Fujinami K, Yanagisawa Y, Nakagawa H, et al. The synthesis of ethylene in melon fruit during the early stage of ripening. Plant Cell Physiol. 1995;36:591–59.Lehman A, Black R, Ecker JR. HOOKLESS1, an ethylene response gene, is required for differential cell elongation in the Arabidopsis hypocotyl. Cell. 1996;85:183–94.Elitzur T, Vrebalov J, Giovannoni JJ, Goldschmidt EE, Friedman H. The regulation of MADS-box gene expression during ripening of banana and their regulatory interaction with ethylene. J Exp Bot. 2010;61(5):1523–35.Yang Y, Wu Y, Pirrello J, Regad F, Bouzayen M, Deng W, et al. Silencing Sl-EBF1 and Sl-EBF2 expression causes constitutive ethylene response phenotype, accelerated plant senescence, and fruit ripening in tomato. J Exp Bot. 2010;61(3):697–708.Tanaka R, Oster U, Kruse E, Rudiger W, Grimm B. Reduced activity of geranylgeranyl reductase leads to loss of chlorophyll and tocopherol and to partially geranylgeranylated chlorophyll in transgenic tobacco plants expressing antisense RNA for geranylgeranyl reductase. Plant Physiol. 1999;120:695–704.Kim J, DellaPenna D. Defining the primary route for lutein synthesis in plants: the role of Arabidopsis carotenoid beta-ring hydroxylase CYP97A3. Proc Natl Acad Sci U S A. 2006;103:3474–9.Welsch R, Maass D, Voegel T, Dellapenna D, Beyer P. Transcription factor RAP2.2 and its interacting partner SINAT2: stable elements in the carotenogenesis of Arabidopsis leaves. Plant Physiol. 2007;145:1073–85.Neta-Sharir I, Isaacson T, Lurie S, Weiss D. Dual role for tomato heat shock protein 21: protecting photosystem II from oxidative stress and promoting color changes during fruit maturation. Plant Cell. 2005;17:1829–38.Li L, Paolillo DJ, Parthasarathy MV, Dimuzio EM, Garvin DF. A novel gene mutation that confers abnormal patterns of beta-carotene accumulation in cauliflower (Brassica oleracea var. botrytis). Plant J. 2001;26:59–67.Lu S, Van Eck J, Zhou X, Lopez AB, Halloran DM, Cosman KM, et al. The cauliflower Or gene encodes a DnaJ cysteine-rich domain-containing protein that mediates high levels of beta-carotene accumulation. Plant Cell. 2006;18:3594–605.Akhtar MS, Goldschmidt EE, John I, Rodoni S, Matile P, Grierson D. Altered patterns of senescence and ripening in gf, a stay-green mutant of tomato. J Exp Bot. 1999;50(336):1115–22.Saeed AI, Sharov V, White J, Li J, Liang W, Bhagabati N, et al. TM4: a free, open-source system for microarray data management and analysis. Biotechniques. 2003;34:374–8.Lohse M, Nunes-Nesi A, Krüger P, Nagel A, Hannemann J, Giorgi FM, et al. Robin: an intuitive wizard application for R-based expression microarray quality assessment and analysis. Plant Physiol. 2010;153:642–51.Thimm O, Bläsing O, Gibon Y, Nagel A, Meyer S, Krüger P, et al. MapMan: a user-driven tool to display genomics data sets onto diagrams of metabolic pathways and other biological processes. Plant J. 2004;37:914–39.Usadel B, Poree F, Nagel A, Lohse M, Czedik-Eysenberg A, Stitt M. A guide to using MapMan to visualize and compare omics data in plants: a case study in the crop species, maize. Plant Cell Environ. 2009;32:1211–29.Costa F, Alba R, Schouten H, Soglio V, Gianfranceschi L, Serra S, et al. Use of homologous and heterologous gene expression profiling tools to characterize transcription dynamics during apple fruit maturation and ripening. BMC Plant Biol. 2010;10:229.Zhang C, Yu X, Ayre BG, Turgeon R. The origin and composition of cucurbit “phloem” exudate. Plant Physiol. 2012;158:1873–82.Rose JKC, Saladié M, Catalá C. The plot thickens: new perspectives of primary cell wall modification. Current Opin Plant Biol. 2004;7:296–301.Manning K. Changes in gene-expression during strawberry fruit ripening and their regulation by auxin. Planta. 1994;194:62–8.Saladié M, Wright LP, Garcia-Mas J, Rodriguez-Concepcion M, Phillips MA. The 2-C-methylerithritol 4-phosphate pathway in melon is regulated by specialized isoforms for the first and last steps. J Exp Bot. 2014;65:5077–92.Périn C, Gomez-Jimenez M, Hagen L, Dogimont C, Pech JC, Latché A, et al. Molecular and genetic characterization of a non-climacteric phenotype in melon reveals two loci conferring altered ethylene response in fruit. Plant Physiol. 2002;129:300–9.Eduardo I, Arús P, Monforte AJ. Development of a genomic library of near isogenic lines (NILs) in melon (Cucumis melo L.) from the exotic accession PI161375. Theor Appl Genet. 2005;112:139–48.Stitt M, McLilley R, Gerhardt R, Heldt HW. Metabolite levels in specific cells and subcellular compartments of plant leaves. Meth Enzymol. 1989;174:518–52.Ibdah M, Azulay Y, Portnoy V, Wasserman B, Bar E, Meir A, et al. Functional characterization of CmCCD1, a carotenoid cleavage dioxygenase from melon. Phytochemistry. 2006;67:1579–89.Rodriguez-Concepcion M, Fores O, Martinez-Garcia JF, Gonzalez V, Phillips MA, Ferrer A, et al. Distinct light-mediated pathways regulate the biosynthesis and exchange of isoprenoid precursors during Arabidopsis seedling development. Plant Cell. 2004;16:144–56.Fraser PD, Pinto MES, Holloway DE, Bramley PM. Application of high-performance liquid chromatography with photodiode array detection to the metabolic profiling of plant isoprenoids. Plant J. 2000;24:551–8.Burns J, Fraser PD, Bramley PM. Identification and quantification of carotenoids, tocopherols and chlorophylls in commonly consumed fruits and vegetables. Phytochemistry. 2003;62:939–47.Taylor KL, Brackenridge AE, Vivier MA, Oberholster A. High-performance liquid chromatography profiling of the major carotenoids in Arabidopsis thaliana leaf tissue. J Chromatogr A. 2006;1121:83–91.Hartigan JA, Wong MA. A k-means clustering algorithm. Appl Stat. 1979;28:100–8.Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000;25:25–9.Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3:0034.1.Pfaffl MW, Tichopad A, Prgomet C, Neuvians TP. Determination of stable housekeeping genes, differentially regulated target genes and sample integrity: BestKeeper - Excel-based tool using pair-wise correlations. Biotechnol Lett. 2004;26:509–15.Gonzalez-Ibeas D, Blanca J, Roig C, González-To M, Picó B, Truniger V, et al. MELOGEN: An EST database for melon functional genomics. BMC Genomics. 2007;8:306.Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001;29:e45.Masoudi-Nejad A, Goto S, Jauregui R, Ito M, Kawashima S, Moriya Y, et al. EGENES: transcriptome-based plant database of genes with metabolic pathway information and expressed sequence tag indices in KEGG. Plant Physiol. 2007;144:857–66.Usadel B, Nagel A, Thimm O, Redestig H, Blaesing OE, Palacios-Rojas N, et al. Extension of the visualisation tool MapMan to allow statistical analysis of arrays, display of corresponding genes and comparison with known responses. Plant Physiol. 2005;138:1195–204.Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Stat Methodol. 1995;57:289–300

Discovery of sisunatovir (RV521), an inhibitor of respiratory syncytial virus fusion

RV521 is an orally bioavailable inhibitor of respiratory syncytial virus (RSV) fusion that was identified after a lead optimization process based upon hits that originated from a physical property directed hit profiling exercise at Reviral. This exercise encompassed collaborations with a number of contract organizations with collaborative medicinal chemistry and virology during the optimization phase in addition to those utilized as the compound proceeded through preclinical and clinical evaluation. RV521 exhibited a mean IC50 of 1.2 nM against a panel of RSV A and B laboratory strains and clinical isolates with antiviral efficacy in the Balb/C mouse model of RSV infection. Oral bioavailability in preclinical species ranged from 42 to >100% with evidence of highly efficient penetration into lung tissue. In healthy adult human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a significant reduction in viral load and symptoms compared to placebo

Ecology and Transmission of Buruli Ulcer Disease: A Systematic Review

Buruli ulcer is a neglected emerging disease that has recently been reported in some countries as the second most frequent mycobacterial disease in humans after tuberculosis. Cases have been reported from at least 32 countries in Africa (mainly west), Australia, Southeast Asia, China, Central and South America, and the Western Pacific. Large lesions often result in scarring, contractual deformities, amputations, and disabilities, and in Africa, most cases of the disease occur in children between the ages of 4–15 years. This environmental mycobacterium, Mycobacterium ulcerans, is found in communities associated with rivers, swamps, wetlands, and human-linked changes in the aquatic environment, particularly those created as a result of environmental disturbance such as deforestation, dam construction, and agriculture. Buruli ulcer disease is often referred to as the “mysterious disease” because the mode of transmission remains unclear, although several hypotheses have been proposed. The above review reveals that various routes of transmission may occur, varying amongst epidemiological setting and geographic region, and that there may be some role for living agents as reservoirs and as vectors of M. ulcerans, in particular aquatic insects, adult mosquitoes or other biting arthropods. We discuss traditional and non-traditional methods for indicting the roles of living agents as biologically significant reservoirs and/or vectors of pathogens, and suggest an intellectual framework for establishing criteria for transmission. The application of these criteria to the transmission of M. ulcerans presents a significant challenge

The seeds of divergence: the economy of French North America, 1688 to 1760

Generally, Canada has been ignored in the literature on the colonial origins of divergence with most of the attention going to the United States. Late nineteenth century estimates of income per capita show that Canada was relatively poorer than the United States and that within Canada, the French and Catholic population of Quebec was considerably poorer. Was this gap long standing? Some evidence has been advanced for earlier periods, but it is quite limited and not well-suited for comparison with other societies. This thesis aims to contribute both to Canadian economic history and to comparative work on inequality across nations during the early modern period. With the use of novel prices and wages from Quebec—which was then the largest settlement in Canada and under French rule—a price index, a series of real wages and a measurement of Gross Domestic Product (GDP) are constructed. They are used to shed light both on the course of economic development until the French were defeated by the British in 1760 and on standards of living in that colony relative to the mother country, France, as well as the American colonies. The work is divided into three components. The first component relates to the construction of a price index. The absence of such an index has been a thorn in the side of Canadian historians as it has limited the ability of historians to obtain real values of wages, output and living standards. This index shows that prices did not follow any trend and remained at a stable level. However, there were episodes of wide swings—mostly due to wars and the monetary experiment of playing card money. The creation of this index lays the foundation of the next component. The second component constructs a standardized real wage series in the form of welfare ratios (a consumption basket divided by nominal wage rate multiplied by length of work year) to compare Canada with France, England and Colonial America. Two measures are derived. The first relies on a “bare bones” definition of consumption with a large share of land-intensive goods. This measure indicates that Canada was poorer than England and Colonial America and not appreciably richer than France. However, this measure overestimates the relative position of Canada to the Old World because of the strong presence of land-intensive goods. A second measure is created using a “respectable” definition of consumption in which the basket includes a larger share of manufactured goods and capital-intensive goods. This second basket better reflects differences in living standards since the abundance of land in Canada (and Colonial America) made it easy to achieve bare subsistence, but the scarcity of capital and skilled labor made the consumption of luxuries and manufactured goods (clothing, lighting, imported goods) highly expensive. With this measure, the advantage of New France over France evaporates and turns slightly negative. In comparison with Britain and Colonial America, the gap widens appreciably. This element is the most important for future research. By showing a reversal because of a shift to a different type of basket, it shows that Old World and New World comparisons are very sensitive to how we measure the cost of living. Furthermore, there are no sustained improvements in living standards over the period regardless of the measure used. Gaps in living standards observed later in the nineteenth century existed as far back as the seventeenth century. In a wider American perspective that includes the Spanish colonies, Canada fares better. The third component computes a new series for Gross Domestic Product (GDP). This is to avoid problems associated with using real wages in the form of welfare ratios which assume a constant labor supply. This assumption is hard to defend in the case of Colonial Canada as there were many signs of increasing industriousness during the eighteenth and nineteenth centuries. The GDP series suggest no long-run trend in living standards (from 1688 to circa 1765). The long peace era of 1713 to 1740 was marked by modest economic growth which offset a steady decline that had started in 1688, but by 1760 (as a result of constant warfare) living standards had sunk below their 1688 levels. These developments are accompanied by observations that suggest that other indicators of living standard declined. The flat-lining of incomes is accompanied by substantial increases in the amount of time worked, rising mortality and rising infant mortality. In addition, comparisons of incomes with the American colonies confirm the results obtained with wages— Canada was considerably poorer. At the end, a long conclusion is provides an exploratory discussion of why Canada would have diverged early on. In structural terms, it is argued that the French colony was plagued by the problem of a small population which prohibited the existence of scale effects. In combination with the fact that it was dispersed throughout the territory, the small population of New France limited the scope for specialization and economies of scale. However, this problem was in part created, and in part aggravated, by institutional factors like seigneurial tenure. The colonial origins of French America’s divergence from the rest of North America are thus partly institutional

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely