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Limited understanding of bladder cancer aetiopathology hampers progress in reducing incidence. Mutational signatures show the anti-viral apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC) enzymes are responsible for the preponderance of mutations in bladder tumour genomes, but no causative viral agent has been identified. BK polyomavirus (BKPyV) is a common childhood infection that remains latent in the adult kidney, where reactivation leads to viruria. This study provides missing mechanistic evidence linking reactivated BKPyV-infection to bladder cancer risk. We used a mitotically-quiescent, functionally-differentiated model of normal human urothelium to examine BKPyV-infection. BKPyV-infection led to significantly elevated APOBEC3A and APOBEC3B protein, increased deaminase activity and greater numbers of apurinic/apyrimidinic sites in the host urothelial genome. BKPyV Large T antigen (LT-Ag) stimulated re-entry from G0 into the cell cycle through inhibition of retinoblastoma protein and activation of EZH2, E2F1 and FOXM1, with cells arresting in G2. The single-stranded DNA displacement loops formed in urothelial cells during BKPyV-infection interacted with LT-Ag to provide a substrate for APOBEC3-activity. Addition of interferon gamma (IFNγ) to infected urothelium suppressed expression of the viral genome. These results support reactivated BKPyV infections in adults as a risk factor for bladder cancer in immune-insufficient populations.

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The glomerulus mediates kidney ultrafiltration through specialised epithelial cells called podocytes which line a basement membrane shared with blood capillary endothelium. Cell-cell crosstalk is critical for glomerular function, but its investigation in childhood glomerular diseases has received little attention.WT1encodes a transcription factor expressed in podocytes, whose heterozygous variants cause devastating kidney disease in childhood. We used single-cell RNA sequencing and ligand-receptor interaction analysis to resolve the glomerular transcriptional landscape of mice that carry an orthologous human mutation in WT1 (Wt1R394W/+). Podocytes were the most dysregulated cell type in early disease, with disrupted angiogenic signalling preceding glomerular capillary loss. Comparative analyses with additional murine and human glomerular disease datasets identified unique transcriptional changes in WT1 glomerular disease, reflecting a non-immunological pathology, whilst revealing a common injury signature across multiple glomerular diseases. Collectively, this work advocates vascular-based therapies over immunosuppressive drugs in the treatment of WT1 glomerular disease.

Urothelium is a transitional, stratified epithelium that lines the lower urinary tract, providing a tight barrier to urine whilst retaining the capacity to stretch and rapidly resolve damage. The role of glycerophospholipids in urothelial barrier function is largely unknown, despite their importance in membrane structural integrity, protein complex assembly, and the master regulatory role of PPARγ in urothelial differentiation. We performed lipidomic and transcriptomic characterisation of urothelial differentiation, revealing a metabolic switch signature from fatty acid synthesis to lipid remodelling, including 5-fold upregulation of LPCAT4. LPCAT4 knockdown urothelial cultures exhibited an impaired proliferation rate but developed elevated trans-epithelial electrical resistances upon differentiation, associated with a reduced and delayed capacity to restitute barrier function after wounding. Specific reduction in 18:1 PC fatty acyl chains upon knockdown was consistent with LPCAT4 specificity, but was unlikely to elicit broad barrier function changes. However, transcriptomic analysis of LPCAT4 knockdown supported an LPC-induced reduction in DAG availability, predicted to limit PKC activity, and TSPO abundance, predicted to limit endogenous ATP. These phenotypes were confirmed by PKC and TSPO inhibition. Together, these data suggest an integral role for lipid mediators in urothelial barrier function and highlight the strength of combined lipidomic and transcriptomic analyses for characterising tissue homeostasis.

Interferon gamma (IFNγ) is central to the inflammatory immune response, such as that entrained by BCG immunotherapy for bladder cancer. However, immune-mediated tumour cell killing is subject to modulation by immunoinhibitory “checkpoint” receptors such as PD-L1. We investigated the effects of IFNγ on barrier-forming in vitro-differentiated normal human urothelium using mRNA-sequencing, and showed canonical upregulation of MHC class I/II and de novo expression of the T cell tropic CXCL9-11 chemokines. Normal urothelium constitutively expressed immunoinhibitory B7 family member VSIR (VISTA), while CD274 (PD-L1) expression was induced/upregulated by IFNγ. We generated a urothelial IFNγ response gene signature. When applied to the unsupervised clustering of non-muscle-invasive bladder cancers, the IFNγ-signature predicted longer recurrence-free survival. In muscle-invasive cancers, the IFNγ-signature split the basal/squamous consensus subtype, with significantly worse overall survival when weak or absent. This study offers novel insights into strategies to enhance immunotherapy via the IFNγ and VISTA/PD-L1 nexus.

The risk of developing urothelial carcinoma of the bladder (UCB) in patients treated by radical nephroureterectomy (RNU) for an upper urinary tract urothelial carcinoma (UTUC) is 22% to 47% in the 2 years after surgery. Subject of debate remains whether UTUC and the subsequent UCB are clonally related or represent separate origins. To investigate the clonal relationship between both entities, we performed targeted DNA sequencing of a panel of 41 genes on matched normal and tumor tissue of 15 primary UTUC patients treated by RNU who later developed 19 UCBs. Based on the detected tumor‐specific DNA aberrations, the paired UTUC and UCB(s) of 11 patients (73.3%) showed a clonal relation, whereas in four patients the molecular results did not indicate a clear clonal relationship. Our results support the hypothesis that UCBs following a primary surgically resected UTUC are predominantly clonally derived recurrences and not separate entities., What's new? Patients treated by radical nephroureterectomy for upper urinary tract cancer have an increased risk of developing bladder carcinoma following surgery. It remains unclear, however, whether the upper urinary tract cancer and subsequent bladder carcinoma are clonally related or have separate origins. This targeted DNA sequencing study shows that almost 75% of patients have tumors that are clonally related, suggesting that seeding of tumor cells is the main mechanism of bladder carcinoma development following radical nephroureterectomy. This result underscores the need to minimalize the risk of seeding during surgery and/or diagnostic ureterorenoscopy plus biopsy, and to apply peri‐operative intravesical instillations with chemotherapy.

Disparity between genome-wide mutations in bladder and other cancers where smoking is a risk factor raises questions about carcinogenesis in different epithelia. To develop an experimental model of bladder carcinogenesis, we clonally expanded in vitro differentiated normal human urothelial (NHU) cells following exposure to an exemplar procarcinogen and used whole-genome DNA sequencing to derive mutational signatures. Benzo[a]pyrene (BaP) was activated by endogenous cytochrome P450 (cytochrome P450 family 1 subfamily A member 1 [CYP1A1]) to create genomically modified NHU cells. Comparison with the Catalogue of Somatic Mutations in Cancer (COSMIC) showed that mutations induced by BaP in NHU cells were similar to smoking-associated signatures in bladder and other cancers, including single- and doublet-base substitution signatures characterised by C > A transversions (COSMIC_SBS4 and COSMIC_DBS2, respectively), and an insertion/deletion signature of C deletions in homopolymer regions (COSMIC ID3). Our study provides the first direct evidence that BaP is activated locally in the urothelium, initiating the well-described smoking-associated mutational signatures. An absence of other common bladder cancer (BLCA)-associated genomic signatures points strongly to other primary causes of BLCA, which the new experimental approach described here is well placed to investigate. Mutational signatures ignore whether genes are affected, but tissue-specific drivers (KMT2D, KMT2C, and CDKN1A) were significantly overmutated in this model, providing insight on the emergent selection pressures. Patient summary In a carefully controlled laboratory setting, we exposed normal human urothelial tissues to a procarcinogen (benzo[a]pyrene) found in cigarette smoke. We show that the urothelial tissues activated the carcinogen and led to mutations forming across the genome in a characteristic pattern. This particular “mutational signature” is found in bladder tumours and other smoking-induced cancers (eg, lung); however, our study highlights that there are other unknown mutational processes in bladder cancer that is not the direct result of smoke carcinogens, and this will require further investigation., Take Home Message Clonal expansion and whole-genome sequencing of finite normal human urothelial cells, which retained their native differentiated and quiescent state during exposure to putative bladder carcinogens, provide new avenues for tissue-relevant research into the causes of bladder cancer.

The chicken reference genome contains two endogenous Avian Leukosis Virus subgroup E (ALVE) insertions, but gaps and unresolved repetitive sequences in previous assemblies has hindered their precise characterisation. Detailed analysis of the most recent reference genome (GRCg6a) now shows both ALVEs within contiguous chromosome assemblies for the first time.ALVE6 (ALVE-JFevA) and ALVE-JFevB are both located on chromosome 1, with ALVE6 close to the p arm telomere. ALVE-JFevB is a structurally intact element containing the ALVE gag, pol and env genes, and is capable of forming replication competent viruses. In contrast, ALVE6 (ALVE-JFevA) contains a 3352 bp 5’ truncation and lacks the entire 5’ LTR and gag gene. Despite this, ALVE6 remains able to produce intact envelope protein, likely due to a mutation in the recognition site for a known inhibitory miRNA (miR-155). Whole genome resequencing datasets from layers, broilers and three independent sources of wild-caught red junglefowl were surveyed for the presence of each of these reference genome ALVEs. ALVE-JFevB was found in no other chicken or red junglefowl genomes, whereas ALVE6 was identified in some layers, broilers and native breeds, but not within any other red junglefowl genome. Improved assembly contiguity has facilitated better characterisation of the two ALVEs of the chicken reference genome. However, both the limited ALVE content and unique presence of ALVE-JFevB suggests that the reference individual is unrepresentative of ancestral Gallus gallus ALVE diversity.

Intravesical Bacillus Calmette-Guérin vaccine (BCG) is an established immunotherapeutic in bladder cancer (BlCa), provoking inflammation leading to tumour-specific immunity. Immune checkpoint blockers such as anti-PD-L1 have potential for enhancing tumour-specific lymphocyte-mediated cytotoxicity in BCG-refractive or advanced disease. In both cases, Interferon-gamma (IFNγ) plays a central role. We investigated the transcriptomic response of normal human urothelium to IFNγ to disentangle mechanisms of BCG and anti-PD-L1 therapy failure.Exposure of differentiated human urothelium to IFNγ resulted in upregulated MHC class I and class II and de novo expression of CXCL9-11 chemokine genes. Normal urothelium expressed only immuno-inhibitory B7 family members: PD-L1 expression was induced by IFNγ, whereas VISTA was expressed constitutively.A urothelial IFNγ response gene set was derived and used for unsupervised clustering of tumours, which predicted longer recurrence-free survival in non-muscle invasive bladder cancer (NMIBC). In muscle invasive bladder cancer (MIBC), the IFNγ-signature split the basal/squamous consensus subtype, with significantly worse overall survival when weak/absent.Normal urothelium has few resident lymphocytes. Tumour cell killing requires recruitment and activation of IFNγ-secreting pro-inflammatory/cytotoxic lymphocytes while surmounting both innate (VISTA) and upregulated (PD-L1) inhibitory mechanisms. This study offers supportive evidence for strategies to enhance immunotherapy via the IFNγ and VISTA/PD-L1 nexus.Patient SummaryImmunotherapy brings promise of harnessing a patient’s own immune system to seek and destroy malignant cells, but it has yet to deliver widespread clinical benefit. We exposed human urothelium to interferon gamma, a key messenger of the immune system and identified a novel signature of 33 genes that predicted cancers with better outcomes. Our study revealed alternative strategies for targeting checkpoint proteins to improve immunotherapy in the future.

Limited understanding of bladder cancer aetiopathology hampers progress in reducing incidence. Mutational signatures show the anti-viral apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC) enzymes are responsible for the preponderance of mutations in bladder tumour genomes, but no causative viral agent has been identified. BK polyomavirus (BKPyV) is a common childhood infection that remains latent in the adult kidney, where reactivation leads to viruria. This study provides missing mechanistic evidence linking reactivated BKPyV-infection to bladder cancer risk. We used a mitotically-quiescent, functionally-differentiated model of normal human urothelium to examine BKPyV-infection. BKPyV-infection led to significantly elevated APOBEC3A and APOBEC3B protein, increased deaminase activity and greater numbers of apurinic/apyrimidinic sites in the host urothelial genome. BKPyV Large T antigen (LT-Ag) stimulated re-entry from G0 into the cell cycle through inhibition of retinoblastoma protein and activation of EZH2, E2F1 and FOXM1, with cells arresting in G2. The single-stranded DNA displacement loops formed in urothelial cells during BKPyV-infection interacted with LT-Ag to provide a substrate for APOBEC3-activity. Addition of interferon gamma (IFNγ) to infected urothelium suppressed expression of the viral genome. These results support reactivated BKPyV infections in adults as a risk factor for bladder cancer in immune-insufficient populations.

In macrolecithal species, cryopreservation of the oocyte and zygote is not possible due to the large size and quantity of lipid deposited within the egg. For birds, this signifies that cryopreserving and regenerating a species from frozen cellular material are currently technically unfeasible. Diploid primordial germ cells (PGCs) are a potential means to freeze down the entire genome and reconstitute an avian species from frozen material. Here, we examine the use of genetically engineered (GE) sterile female layer chicken as surrogate hosts for the transplantation of cryopreserved avian PGCs from rare heritage breeds of chicken. We first amplified PGC numbers in culture before cryopreservation and subsequent transplantation into host GE embryos. We found that all hatched offspring from the chimera GE hens were derived from the donor rare heritage breed broiler PGCs, and using cryopreserved semen, we were able to produce pure offspring. Measurement of the mutation rate of PGCs in culture revealed that 2.7 × 10(−10) de novo single-nucleotide variants (SNVs) were generated per cell division, which is comparable with other stem cell lineages. We also found that endogenous avian leukosis virus (ALV) retroviral insertions were not mobilized during in vitro propagation. Taken together, these results show that mutation rates are no higher than normal stem cells, essential if we are to conserve avian breeds. Thus, GE sterile avian surrogate hosts provide a viable platform to conserve and regenerate avian species using cryopreserved PGCs.

Limited understanding of bladder cancer aetiopathology hampers progress in reducing incidence. BK polyomavirus (BKPyV) is a common childhood infection that can be reactivated in the adult kidney leading to viruria. Here we used a mitotically-quiescent, differentiated, normal human urothelial in vitro model to study BKPyV infection. BKPyV infection led to significantly elevated APOBEC3A and APOBEC3B protein, increased deaminase activity and greater numbers of apurinic/apyrimidinic sites in the host urothelial genome. BKPyV Large T antigen (LT-Ag) stimulated re-entry into the cell cycle via inhibition of Retinoblastoma protein and activation of EZH2, E2F1 and FOXM1, which combined to push urothelial cells from G0 into an arrested G2 cell cycle state. The single-stranded DNA displacement loops formed during BKPyV-infection, provide a substrate for APOBEC3 enzymes where they interacted with LT-Ag. These results support reactivated BKPyV infections in adults as a risk factor for bladder cancer in immune-insufficient populations, including transplant patients and the elderly.

Background Avian leukosis virus subgroup E (ALVE) insertions are endogenous retroviruses (ERV) that are restricted to the domestic chicken and its wild progenitor. In commercial chickens, ALVE are known to have a detrimental effect on productivity and provide a source for recombination with exogenous retroviruses. The wider diversity of ALVE in non-commercial chickens and the role of these elements in ERV-derived immunity (EDI) are yet to be investigated. Results In total, 974 different ALVE were identified from 407 chickens sampled from village populations in Ethiopia, Iraq, and Nigeria, using the recently developed obsERVer bioinformatics identification pipeline. Eighty-eight percent of all identified ALVE were novel, bringing the known number of ALVE integrations to more than 1300 across all analysed chickens. ALVE content was highly lineage-specific and populations generally exhibited a large diversity of ALVE at low frequencies, which is typical for ERV involved in EDI. A significantly larger number of ALVE was found within or near coding regions than expected by chance, although a relative depletion of ALVE was observed within coding regions, which likely reflects selection against deleterious integrations. These effects were less pronounced than in previous analyses of chickens from commercial lines. Conclusions Identification of more than 850 novel ALVE has trebled the known diversity of these retroviral elements. This work provides the basis for future studies to fully quantify the role of ALVE in immunity against exogenous ALV, and development of programmes to improve the productivity and welfare of chickens in developing economies.

BackgroundThe Japanese quail (Coturnix japonica) is a popular domestic poultry species and an increasingly significant model species in avian developmental, behavioural and disease research.ResultsWe have produced a high-quality quail genome sequence, spanning 0.93 Gb assigned to 33 chromosomes. In terms of contiguity, assembly statistics, gene content and chromosomal organisation, the quail genome shows high similarity to the chicken genome. We demonstrate the utility of this genome through three diverse applications. First, we identify selection signatures and candidate genes associated with social behaviour in the quail genome, an important agricultural and domestication trait. Second, we investigate the effects and interaction of photoperiod and temperature on the transcriptome of the quail medial basal hypothalamus, revealing key mechanisms of photoperiodism. Finally, we investigate the response of quail to H5N1 influenza infection. In quail lung, many critical immune genes and pathways were downregulated after H5N1 infection, and this may be key to the susceptibility of quail to H5N1.ConclusionsWe have produced a high-quality genome of the quail which will facilitate further studies into diverse research questions using the quail as a model avian species.

The Japanese quail (Coturnix japonica) is a popular domestic poultry species and an increasingly significant model species in avian developmental, behavioural and disease research. We have produced a high-quality quail genome sequence, spanning 0.93 Gb assigned to 33 chromosomes. In terms of contiguity, assembly statistics, gene content and chromosomal organization, the quail genome shows high similarity to the chicken genome. We demonstrate the utility of this genome through three diverse applications. First, we identify selection signatures and candidate genes associated with social behaviour in the quail genome, an important agricultural and domestication trait. Second, we investigate the effects and interaction of photoperiod and temperature on the transcriptome of the quail medial basal hypothalamus, revealing key mechanisms of photoperiodism. Finally, we investigate the response of quail to H5N1 influenza infection. In quail lung, many critical immune genes and pathways were downregulated, and this may be key to the susceptibility of quail to H5N1. This genome will facilitate further research into diverse research questions using the quail as a model avian species.

Occupational and environmental exposure to cadmium is associated with the development of urothelial cancer. The metallothionein (MT) family of genes encodes proteins that sequester metal ions and modulate physiological processes, including zinc homeostasis. Little is known about the selectivity of expression of the different MT isoforms. Here, we examined the effect of cadmium exposure on MT gene and isoform expression by normal human urothelial (NHU) cell cultures. Baseline and cadmium-induced MT gene expression was characterized by next-generation sequencing and RT-PCR, protein expression was assessed by Western blotting using isoform-specific antibodies. Expression of the zinc transporter-1 (SLC30A1) gene was also assessed. NHU cells displayed transcription of MT-2A, but neither MT-3 nor MT-4 genes. Most striking was a highly inducer-specific expression of MT-1 genes, with cadmium inducing transcription of MT-1A, MT-1G, MT-1H, and MT-1M. Whereas MT-1G was also induced by zinc and nickel ions and MT-1H by iron, both MT-1A and MT-1M were highly cadmium-specific, which was confirmed for protein using isoform-specific antibodies. Protein but not transcript endured post-exposure, probably reflecting sequestration. SLC30A1 transcription was also affected by cadmium ion exposure, potentially reflecting perturbation of intracellular zinc homeostasis. We conclude that human urothelium displays a highly inductive profile of MT-1 gene expression, with two isoforms identified as highly specific to cadmium, providing candidate transcript and long-lived protein biomarkers of cadmium exposure.

Introduction Smoking is the best established risk factor for bladder cancer and direct mutagenesis by smoke carcinogens on the cellular genome can be described in clonal populations as mutational signatures. A mutational signature summarises a lifetime of DNA-damage (caused by interaction between mutagenic processes, tissue-specific gene transcription, and the DNA-repair machinery) as mutational classes in the context of their local genomic chemistry. Our aim was to establish a novel experimental model for understanding carcinogenic initiation in normal human urothelium. Methods Finite normal human urothelial cell cultures were established in vitro and differentiated to form functional barrier epithelia capable of activating the smoke-derived procarcinogen benzo[a]pyrene (BaP), via CYP1A1, into mutagenic metabolites. New in vitro approaches were developed allowing chronic BaP-exposure, subsequent clonal expansion of NHU cells for whole genome DNAseq and mutational signature derivation. This approach retains tissue heterogeneity during the carcinogenic exposure, modelling the early selection pressures in urothelium that lead to clonal expansion and cancer. Results The single-base (SBS) and double-base signatures (DBS) derived from BaP-exposed urothelial tissues were dominated by C>A and CC>AA transversions, respectively. The InDel (ID) signature described cytosine deletions in homopolymer regions. Comparison to the Catalogue of Somatic Mutations in Cancer (COSMIC) using the Signal pipeline showed homology with SBS4, DBS2 and ID3, respectively; which have been detected by others in bladder cancer patients. Mutation enrichment in specific genes (eg KMT2D and CDKN1A) mirrored in situ observations by others; effectively modelling the competitive advantage mutations convey in the carcinogenic tissue environment. Conclusions BaP is detected in urine, metabolically activated by urothelial CYP1A1, and therefore may be a bladder mutagen. However, C>A transversions contribute a minor fraction of all mutations recorded in bladder tumours. Widespread DNA damage caused by chronic BaP exposure did not trigger any of the APOBEC-like mutational processes (SBS2/13) that dominate bladder tumour genomes, indicating a missing factor that the new model system is well positioned to identify.

The importance of the Gallus gallus (chicken) as a model organism and agricultural animal merits a continuation of sequence assembly improvement efforts. We present a new version of the chicken genome assembly (Gallus_gallus-5.0; GCA_000002315.3), built from combined long single molecule sequencing technology, finished BACs, and improved physical maps. In overall assembled bases, we see a gain of 183 Mb, including 16.4 Mb in placed chromosomes with a corresponding gain in the percentage of intact repeat elements characterized. Of the 1.21 Gb genome, we include three previously missing autosomes, GGA30, 31, and 33, and improve sequence contig length 10-fold over the previous Gallus_gallus-4.0. Despite the significant base representation improvements made, 138 Mb of sequence is not yet located to chromosomes. When annotated for gene content, Gallus_gallus-5.0 shows an increase of 4679 annotated genes (2768 noncoding and 1911 protein-coding) over those in Gallus_gallus-4.0. We also revisited the question of what genes are missing in the avian lineage, as assessed by the highest quality avian genome assembly to date, and found that a large fraction of the original set of missing genes are still absent in sequenced bird species. Finally, our new data support a detailed map of MHC-B, encompassing two segments: one with a highly stable gene copy number and another in which the gene copy number is highly variable. The chicken model has been a critical resource for many other fields of study, and this new reference assembly will substantially further these efforts.

Background LTR retrotransposons contribute approximately 10 % of the mammalian genome, but it has been previously reported that there is a deficit of these elements in the chicken relative to both mammals and other birds. A novel LTR retrotransposon classification pipeline, LocaTR, was developed and subsequently utilised to re-examine the chicken LTR retrotransposon annotation, and determine if the proposed chicken deficit is biologically accurate or simply a technical artefact. Results Using LocaTR 3.01 % of the chicken galGal4 genome assembly was annotated as LTR retrotransposon-derived elements (nearly double the previous annotation), including 1,073 that were structurally intact. Element distribution is significantly correlated with chromosome size and is non-random within each chromosome. Elements are significantly depleted within coding regions and enriched in gene sparse areas of the genome. Over 40 % of intact elements are found in clusters, unrelated by age or genera, generally in poorly recombining regions. The transcription of most LTR retrotransposons were suppressed or incomplete, but individual domain and full length retroviral transcripts were produced in some cases, although mostly with regularly interspersed stop codons in all reading frames. Furthermore, RNAseq data from 23 diverse tissues enabled greater characterisation of the co-opted endogenous retrovirus Ovex1. This gene was shown to be expressed ubiquitously but at variable levels across different tissues. LTR retrotransposon content was found to be very variable across the avian lineage and did not correlate with either genome size or phylogenetic position. However, the extent of previous, species-specific LTR retrotransposon annotation appears to be a confounding factor. Conclusions Use of the novel LocaTR pipeline has nearly doubled the annotated LTR retrotransposon content of the chicken genome compared to previous estimates. Further analysis has described element distribution, clustering patterns and degree of expression in a variety of adult tissues, as well as in three embryonic stages. This study also enabled better characterisation of the co-opted gamma retroviral envelope gene Ovex1. Additionally, this work suggests that there is no deficit of LTR retrotransposons within the Galliformes relative to other birds, or to mammalian genomes when scaled for the three-fold difference in genome size. Electronic supplementary material The online version of this article (doi:10.1186/s12864-016-3043-1) contains supplementary material, which is available to authorized users.

L'interpretation traditionnelle du «Timee» de Platon sur la destinee des âmes parle d'une immortalite de la partie superieure, rationnelle, par opposition aux deux autres, plus «basses». L'A. defend cette conception contre l'interpretation de Robinson, qui voit l'âme comme eternelle egalement dans sa composition tripartite, ce qui remettrait en question le role du Demiurge et de la reincarnation

Plato (c.428-347 BCE) stands at the beginning of many debates that have continued throughout the history of philosophy. His literary career spanned fifty years and the influence of his ideas and those of his followers pervaded philosophy throughout antiquity. Andrew Mason’s lucid and engaging introduction, draws on recent scholarship to offer a fresh general survey of Plato’s philosophy. Aware of the methodological challenges that confront any writer on Plato, Mason handles the issue of Plato’s intellectual development and relationship with Socrates with an assured grasp. Thematically structured, the book begins with Plato’s principal contribution to metaphysics, the “Theory of Forms”, which forms a necessary background to his thought in many areas. His theory of knowledge, which is intimately linked with the Forms is explored in detail along with Plato’s views of the soul, an important theme in itself and an entry point to discussion of his ethics, one of Plato’s major concerns. Finally, the book deals with two areas of Plato’s thought which have had an especially important historical impact, not confined to academic philosophy: his theory of God and nature, and his aesthetics. Throughout, Mason highlights the continuing themes in Plato’s work and how they develop from one dialogue to another.